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  • 1.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Health Sciences. Department of Women’s Health, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women2018In: International Journal of Gynecology & Obstetrics, ISSN 0020-7292, E-ISSN 1879-3479, Vol. 142, no 3, p. 359-364Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate whether self-sampling is as reliable as professional sampling for HPV testing and genotype detection among postmenopausal women.

    METHODS: In the present prospective cross-sectional study, women in Örebro County, Sweden, who had high-risk HPV (hrHPV) and normal cytology results in exit screening tests conducted in between January 1, 2012, and December 31, 2014, were invited to follow-up screenings between February 24, 2015 and May 15, 2015, that included professional sampling and self-sampling. HPV genotypes were identified by a DNA-based assay that could detect 35 HPV genotypes. Findings between the different sampling methods were compared.

    RESULTS: Of 143 women who participated, 119 returned a self-sample. Completely concordant results were observed in 67 of these samples when both hrHPV and low-risk HPV genotypes were analyzed. Overall, 99 (83.2%) women had the same clinically relevant finding from both sampling methods. Twenty women had discordant hrHPV results (hrHPV detected in 10 self-samples vs 10 professionally collected samples; Cohen κ 0.66, 95% confidence interval 0.53-0.80). There was no significant difference between the two sampling methods for clinically significant infections (P>0.99) or extended genotyping (P=0.827).

    CONCLUSION: Postmenopausal women could be offered self-sampling devices to increase screening-program coverage while maintaining test quality.

  • 2.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Health Sciences. Dept. of Women's Health.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Dept. of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Dept. of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Dept. of Laboratory Medicine.
    HPV-based screening for cervical cancer among women 55-59 years of age2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0217108Article in journal (Refereed)
    Abstract [en]

    AIM: Many cervical cancers occurs among women over 65 and prevalence of HPV genotypes in this age cohort is sparingly studied. One aim of this study was to study the prevalence and distribution of HPV genotypes in women 55-59 years, with normal cytology when exiting the screening program. Secondly, HPV clearance as well as the value of HPV genotyping and/or liquid based cytology as triage tests for identifying histological dysplasia among women with persistent HPV was studied.

    METHODS: Women that exited the screening program with normal cytology, between the years 2012-2014, in Örebro County, Sweden, were invited to this study. A total of 2946 samples were analyzed with a broad-spectrum assay to detect both hrHPV and lrHPV in order to investigate the distribution of genotypes. In the consent group, women with a positive hrHPV test were offered a follow-up test and a cone biopsy for histological confirmation, and a follow up sample 6 months post cone.

    RESULTS: The overall prevalence of hrHPV was 7.4% and 59% of them remained hrHPV positive in a follow-up test after 12 months. A total of 99 women had a cone biopsy done, where 19% showed histological dysplasia. HPV 53 was the most common genotype, and among women with histology confirmed LSIL or HSIL, HPV 31 was most common. A positive hrHPV result showed a PPV of 25% for LSIL+ and 12.5%for HSIL+. Using detection of HPV 16/18 genotypes as a triage test for hrHPV positive tests, indicated FNR for histological LSIL+ and HSIL+ of 94% and 87.5% respectively, whilst triage based on cervical cytology had a FNR of 69% for LSIL+ and 37.5% for HSIL+.

    CONCLUSION: The most common hrHPV genotypes among women 55-59 years of age were non HPV16/18 genotypes, and in this population, these genotypes represented most of the histological verified HSIL lesions. This result does not support the proposition of a HPV 16/18 triaging test after a positive hrHPV test as a marker of histological HSIL+ cervical lesions in women over 55 years of age. Similarly, cytological triage after a positive hrHPV showed no additional benefit in this population. Specific triaging tests should be validated to follow post-menopausal women with a positive hrHPV test.

  • 3.
    Botling, Johan
    et al.
    Departments of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Edlund, Karolina
    Departments of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Lohr, Miriam
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Hellwig, Birte
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Holmberg, Lars
    Dept. Surgical Sciences, Uppsala University, Uppsala, Sweden; Regional Cancer Center Uppsala Örebro, Akademiska sjukhuset, Uppsala, Sweden; Division of Cancer Studies, King's College Medical School, London, United Kingdom.
    Lambe, Mats G.
    Regional Cancer Center Uppsala Örebro, Akademiska sjukhuset, Uppsala, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Berglund, Anders
    Regional Cancer Center Uppsala Örebro, Akademiska sjukhuset, Uppsala, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ekman, Simon
    Radiology, Oncology and Radiation Sciences, Section of Oncology, Uppsala University, Uppsala, Sweden.
    Bergqvist, Michael
    Radiology, Oncology and Radiation Sciences, Section of Oncology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Departments of 1Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    König, André
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Fernandes, Oswaldo
    Cardiothoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats
    Örebro University Hospital. Laboratory Medicine.
    Helenius, Gisela
    Örebro University Hospital. Laboratory Medicine.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rahnenfuehrer, Jörg
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Hengstler, Jan G.
    Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany.
    Micke, Patrick
    Departments of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Biomarker Discovery in Non-Small Cell Lung Cancer: Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 1, p. 194-204Article in journal (Refereed)
    Abstract [en]

    Purpose: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.

    Experimental Design: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).

    Results: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate < 1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.

    Conclusions: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics. Clin Cancer Res; 19(1); 194-204. (c) 2012 AACR.

  • 4.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences.
    Davidsson, Sabina
    Örebro University, School of Health and Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Lubovac, Zelmina
    University of Skövde, Skövde, Sweden.
    Andrén, Ove
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Olsson, Björn
    University of Skövde, Skövde, Sweden.
    Klinga-Levan, Karin
    University of Skövde, Skövde, Sweden.
    A miRNA expression signature that separates between normal and malignant prostate tissues2011In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, no 11, p. 14-Article in journal (Refereed)
    Abstract [en]

    Background

    MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that post-transcriptionally regulate genes involved in several key biological processes and thus are involved in various diseases, including cancer. In this study we aimed to identify a miRNA expression signature that could be used to separate between normal and malignant prostate tissues.

    Results

    Nine miRNAs were found to be differentially expressed (p <0.00001). With the exception of two samples, this expression signature could be used to separate between the normal and malignant tissues. A cross-validation procedure confirmed the generality of this expression signature. We also identified 16 miRNAs that possibly could be used as a complement to current methods for grading of prostate tumor tissues.

    Conclusions

    We found an expression signature based on nine differentially expressed miRNAs that with high accuracy (85%) could classify the normal and malignant prostate tissues in patients from the Swedish Watchful Waiting cohort. The results show that there are significant differences in miRNA expression between normal and malignant prostate tissue, indicating that these small RNA molecules might be important in the biogenesis of prostate cancer and potentially useful for clinical diagnosis of the disease.

  • 5.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Klinga-Levan, Karin
    Systems Biology Research Centre, Tumor Biology, School of Life Sciences, University of Skövde, Skövde, Sweden.
    Olsson, Björn
    Systems Biology Research Centre, Bioinformatics, School of Life Sciences, University of Skövde, Skövde, Sweden.
    Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, article id 362Article in journal (Refereed)
    Abstract [en]

    Background: The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.

    Methods: Patients with prostate cancer were included in the study if they had a tumor with Gleason grade 3 in the PZ, the TZ, or both (n=16). Normal prostate tissue was collected from men undergoing cystoprostatectomy (n=20). The expression of 667 unique miRNAs was investigated using TaqMan low density arrays for miRNAs. Student's t-test was used in order to identify differentially expressed miRNAs, followed by hierarchical clustering and principal component analysis (PCA) to study the separation of the tissues. The ADtree algorithm was used to identify markers for classification of tissues and a cross-validation procedure was used to test the generality of the identified miRNA-based classifiers.

    Results: The t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentially expressed miRNAs between normal and malignant tissues showed perfect separation between samples, while the corresponding analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmed these results and several potential miRNA markers were identified.

    Conclusions: The results of this study indicate that the major differences in the transcription program are those arising during tumor development, rather than during normal tissue development. In addition, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the different zones. MicroRNA signatures that are specific for PZ and TZ tumors could also lead to more accurate prognoses, since tumors arising in the PZ tend to be more aggressive than tumors arising in the TZ.

  • 6.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences. Univ Skövde, Skövde, Sweden.
    Helenius, Gisela
    Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats
    Örebro University Hospital, Örebro, Sweden.
    Lubovac, Zelmina
    Syst Biol Res Ctr Bioinfomat, Univ Skövde, Skövde, Sweden.
    Andrén, Ove
    Örebro University Hospital, Örebro, Sweden.
    Olsson, Björn
    Syst Biol Res Ctr Bioinfomat, Univ Skövde, Skövde, Sweden.
    Klinga-Levan, Karin
    Syst Biol Res Ctr Tumor Biol, Dept Life Sci, Univ Skövde, Skövde, Sweden.
    Validation of suitable endogenous control genes for expression studies of miRNA in prostate cancer tissues2010In: Cancer Genetics and Cytogenetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 202, no 2, p. 71-75Article in journal (Refereed)
    Abstract [en]

    When performing quantitative polymerase chain reaction analysis, there is a need for correction of technical variation between experiments. This correction is most commonly performed by using endogenous control genes, which are stably expressed across samples, as reference genes for normal expression in a specific tissue. In microRNA (miRNA) studies, two types of control genes are commonly used: small nuclear RNAs and small nucleolar RNAs. In this study, six different endogenous control genes for miRNA studies were investigated in prostate tissue material from the Swedish Watchful Waiting cohort. The stability of the controls was investigated using two different software applications, NormFinder and BestKeeper. RNU24 was the most suitable endogenous control gene for miRNA studies in prostate tissue materials. (C) 2010 Elsevier Inc. All rights reserved.

  • 7.
    Falck, Eva
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Karlsson, Sandra
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Helenius, Gisela
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Klinga-Levan, Karin
    Loss of glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma2010In: Cancer cell international, ISSN 1475-2867, Vol. 10, article id 46Article in journal (Refereed)
    Abstract [en]

    Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions.

  • 8.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medicine, Div. of Gastroenterol., Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Department of Medicine, Div of Gastroenterol, Örebro Univ Hosp, Örebro, Sweden; Fac of Med and Hlth, Örebro Univ, Örebro, Sweden.
    Hultgren, Olof
    Örebro University, School of Medical Sciences. Department of Microbiology and Immunology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Oligoclonal T-cell Receptor Repertoire in Colonic Biopsies of Patients with Microscopic Colitis and Ulcerative Colitis2017In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 23, no 6, p. 932-945Article in journal (Refereed)
    Abstract [en]

    Background: Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a type of variation of inflammatory bowel diseases. Local T-cell infiltration in the mucosa plays a major role in MC immunopathology.

    Methods: To understand diversity and clonality of infiltrating T cells, we analyzed the T-cell receptor beta (TCR beta) chains in colonic biopsies of MC, ulcerative colitis (UC), and their remission counterparts (CC/LC-HR [histological remission] or UC-R [remission]) compared with patients with non-inflamed colons using next-generation sequencing.

    Results: Compared with controls and patients with CC, patients with LC had significantly lower diversity with significantly lower evenness and richness in TCRVb-Jb gene segments. Similarly, patients with LC-HR had lower diversity because of significantly lower TCRVb-Jb clone richness. Patients with UC and UC-R showed significantly higher diversity and richness. Univariate and multivariate analyses were performed to identify TCRVb-Jb gene segments differentiating disease types from controls or their remission counterparts. Patients with LC were discriminated from controls by 12 clones and from patients with CC by 8 clones. Neither univariate nor multivariate analyses showed significance for patients with CC or CC-HR compared with controls. Patients with UC and UC-R had 16 and 14 discriminating clones, respectively, compared with controls.

    Conclusions: Altogether, patients with MC and UC showed an oligoclonal TCRb distribution. TCRVb-Jb clone types and their diversity were distinctive between patients with CC and LC, as well as for patients with UC, suggesting different pathophysiological mechanisms according to disease type and stage. This study suggests that CC and LC are different entities because of differences in immunoregulatory responses, as mirrored by their T-cell repertoire.

  • 9.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patientsManuscript (preprint) (Other academic)
  • 10.
    Helenius, Gisela
    et al.
    Örebro University, School of Medical Sciences.
    Lillsunde-Larsson, Gabriella
    Bergengren, Lovisa
    Örebro University, School of Health Sciences.
    Kaliff, Malin
    Örebro University, School of Medical Sciences.
    Karlsson, Mats
    Örebro University, School of Medical Sciences.
    Preliminary data from a Swedish self- sampling study in postmenopausal women2019Conference paper (Other academic)
    Abstract [en]

    Background: An updated screening algorithm was introduced in Sweden 2015. Primary HPV test for women >30 years old and a prolonged screening with the last test after 64 years of age were some of the changes. In the region of Örebro County, the previous cut-off age was 60 years and with a screening interval of 5 years, women left their last sample when they were 55-59 years old. In the shift between two screening programs, a group of women, 60-64 years old, that left the program 5-10 years ago were now included in the new screening. For re-inclusion, a two year long program was formed to catch-up this group of women and screen them according to the new screening algorithm. At the same time a research project investigating self-sampling was launched. At the same time as the women were invited for a last screening sample they were also asked to participate in a study where they should take a vaginal self-test up to one week after their ordinary screening sample was taken by a midwife. Method Postmenopausal women between 64-70 years was included in the study. HPV status in samples from midwife sampling (MS) was compared to self-sampling (SS) samples. HPV was analyzed using HPV Aptima and all HPV positive samples, independent of sampling method, was triaged with cytology and followed-up according to national guidelines. Results So far, 585 women with paired samples have been included in the study. In the MS, 4% of the women are positive for hrHPV compared to 11% in the SS group. In 486/585 women, the results of the two samples are concordant. Among the non-concordant samples (13%), 62% were positive in SS and negative in MS. The opposite, negative in SS and positive in MS were seen in 4% of the samples. Among the MS negative samples, 32% were invalid in SS. Cytology was used as a triage test for HPV positive women, both for MS and SS. Of 23 hrHPV positive, 18 had normal cytology, 2 ASCUS, 1 LSIL and 1 HSIL. In the samples with abnormal cytology, 4/5 were hrHPV positive in both SS and MS. One sample was positive in SS but negative in MS. Discussion In this age group, more women are hrHPV positive in SS compared to MS. This is in line with what other have seen. Among the very few hrHPV positive samples with abnormal cytology, the majority was hrHPV positive in both MS and SS. But since cytology is a poor triage marker in this age group clinical follow-up is needed before the effectiveness of the both sampling methods can be concluded.

  • 11.
    Helenius, Gisela
    et al.
    Örebro University, School of Medical Sciences.
    Ottestig, Elin
    Kaliff, Malin
    Örebro University, School of Medical Sciences.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences.
    Karlsson, Mats
    Örebro University, School of Medical Sciences.
    Bergengren, Lovisa
    Örebro University, School of Medical Sciences.
    Distribution of HPV-genotypes in a Swedish screening population2018Conference paper (Refereed)
  • 12.
    Kaliff, Malin
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Sorbe, Bengt
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mordhorst, Louise Bohr
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 27, p. 18786-18796Article in journal (Refereed)
    Abstract [en]

    Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate.

  • 13.
    Karlsson, Christina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Helenius, Gisela
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Fernandes, Oswaldo
    Department of Thoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Thoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Oestrogen receptor ss in NSCLC: prevalence, proliferative influence, prognostic impact and smoking2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 6, p. 451-458Article in journal (Refereed)
    Abstract [en]

    In non-small-cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for oestrogen receptor (ER) signalling has been proposed. The role for ER beta in NSCLC is still not clear, especially concerning the impact of smoking. In a material of NSCLC (n = 262), ER beta and cyclins A1 and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ER beta) and cyclin A1 were performed. Data were correlated to histology, gender, smoking habits, stage and clinical outcome. ER beta was expressed in 86% of the cases. ER beta was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ER beta expression and cyclins was observed in ADCA, also with a male predominance. ER beta transcripts had a positive prognostic impact in ADCA. ER beta transcripts were increased in NSCLC among smokers compared to non-smokers. In conclusion, our data support a role for ER beta in lung ADCAs, proposing a role for ER beta in lungcarcinogenesis, especially among smokers.

  • 14.
    Kirrander, Peter
    et al.
    Örebro University Hospital, Örebro, Sweden.
    Kolaric, Aleksandra
    Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University Hospital, Örebro, Sweden.
    Stark, Jennifer Rider
    Örebro University Hospital, Örebro, Sweden; Brigham & Women’s Hospital, Boston MA, USA; Harvard Medical School, Boston MA, USA.
    Lillsunde-Larsson, Gabriella
    Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Örebro University, School of Health and Medical Sciences. Umeå University, Umeå, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Human papillomavirus prevalence, distribution and correlation to histopathological parameters in a large Swedish cohort of men with penile carcinoma2011In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 108, no 3, p. 355-359Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To analyse the overall and type-specific human papillomavirus (HPV) prevalence and distribution in penile carcinoma and determine the correlation to histopathological parameters.

    PATIENTS AND METHODS In this retrospective study, we analysed HPV status in 241 patients with penile carcinoma, treated at Orebro University Hospital, Orebro, Sweden, between 1984 and 2008. Age and date at diagnosis was recorded. The tumour specimens were categorized according to the UICC 2002 TNM classification. A subset of patients was operatively staged with regard to lymph node status. A commercially available Real Time PCR was used to detect 13 different types of HPV (6,11,16,18,31,33,35,45,51,52,56,58 and 59).

    RESULTS We excluded 25 patients due to low DNA quality. Of the remaining 216, 179 (82.9%) tumour specimens were HPV infected. The majority of cases positive for HPV (70.4%) were infected by a single-type. The most frequent type was HPV 16 followed by HPV 18. No significant association between HPV status and pathological tumour stage, grade or lymph node status was found.

    CONCLUSION The HPV prevalence found is higher than in most other studies, further strengthening HPV as an etiological agent in penile carcinoma. Furthermore, the high prevalence of HPV 16 and 18 raises the question of what potential impact current HPV vaccines that target these specific HPV types might have on penile carcinoma. No significant association between HPV status and histopathological parameters was found in the present study. Additional investigations are needed to draw final conclusions on the prognostic value of HPV status in penile carcinoma.

  • 15.
    Kumakech, Edward
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Makerere University College of Health Sciences, Kampala, Uganda.
    Berggren, Vanja
    Medical Faculty, Lund University, Lund; Global Health, Karolinska Institute, Stockholm.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Kaliff, Malin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University.
    Karlsson, Mats
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Musubika, Carol
    Makerere University College of Health Sciences, Kampala, Uganda.
    Kirimunda, Samuel
    Makerere University College of Health Sciences, Kampala, Uganda.
    Wabinga, Henry
    Makerere University College of Health Sciences, Kampala, Uganda.
    Andersson, Sören
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University.
    Prevalence, genotypes and risk factors for vaccine and non-vaccine types of Human Papillomavirus (HPV) infections among Bivalent HPV-16/18 vaccinated and non-vaccinated young women in Ibanda district Uganda: 5 year follow up studyManuscript (preprint) (Other academic)
  • 16.
    Kumakech, Edward
    et al.
    Örebro University, School of Health Sciences. Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Berggren, Vanja
    Faculty of Medicine, Lund University, Lund, Sweden; Department of Public Health (Global Health/IHCAR), Karolinska Institute, Stockholm, Sweden.
    Wabinga, Henry
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Kaliff, Malin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital and Örebro University, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Kirimunda, Samuel
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Musubika, Caroline
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Andersson, Sören
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Significantly Reduced Genoprevalence of Vaccine-Type HPV-16/18 Infections among Vaccinated Compared to Non-Vaccinated Young Women 5.5 Years after a Bivalent HPV-16/18 Vaccine (Cervarix®) Pilot Project in Uganda2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160099Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to determine the prevalence and some predictors for vaccine and non-vaccine types of HPV infections among bivalent HPV vaccinated and non-vaccinated young women in Uganda. This was a comparative cross sectional study 5.5 years after a bivalent HPV 16/18 vaccination (Cervarix®, GlaxoSmithKline, Belgium) pilot project in western Uganda. Cervical swabs were collected between July 2014-August 2014 and analyzed with a HPV genotyping test, CLART® HPV2 assay (Genomica, Madrid Spain) which is based on PCR followed by microarray for determination of genotype. Blood samples were also tested for HIV and syphilis infections as well as CD4 and CD8 lymphocyte levels. The age range of the participants was 15-24 years and mean age was 18.6(SD 1.4). Vaccine-type HPV-16/18 strains were significantly less prevalent among vaccinated women compared to non-vaccinated women (0.5% vs 5.6%, p 0.006, OR 95% CI 0.08(0.01-0.64). At type-specific level, significant difference was observed for HPV16 only. Other STIs (HIV/syphilis) were important risk factors for HPV infections including both vaccine types and non-vaccine types. In addition, for non-vaccine HPV types, living in an urban area, having a low BMI, low CD4 count and having had a high number of life time sexual partners were also significant risk factors. Our data concurs with the existing literature from other parts of the world regarding the effectiveness of bivalent HPV-16/18 vaccine in reducing the prevalence of HPV infections particularly vaccine HPV- 16/18 strains among vaccinated women. This study reinforces the recommendation to vaccinate young girls before sexual debut and integrate other STI particularly HIV and syphilis interventions into HPV vaccination packages.

  • 17.
    Larsson, Gabriella Lillsunde
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    HPV testing of biobanked liquid-based cytology: a validation study2016In: International Journal of Biological Markers, ISSN 0393-6155, E-ISSN 1724-6008, Vol. 31, no 2, p. E218-E223Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of the study was to investigate whether biobanked liquid-based cytology (LBC) vaginal samples could be reanalyzed for the biomarkers HPV DNA and mRNA without loss of sensitivity.

    Methods: One hundred LBC samples with ASCUS or CIN1 were tested for HPV DNA and mRNA before and after biobanking. DNA analysis targeted the viral genes E6 and E7, 12 high-risk and 2 low-risk HPV types together with the human control gene HBB, using real-time PCR. The Aptima HPV assay was used for mRNA analysis of 14 high-risk HPV types.

    Results: With Aptima there was 84% agreement between results before and after biobanking. The sensitivity and specificity were 0.79 (95% CI, 0.68-0.88) and 0.94 (95% CI, 0.80-0.99), respectively. With the DNA-based method, the agreement between results was 87%, the sensitivity 0.85 (95% CI, 0.75-0.92) and the specificity 0.95 (95% CI, 0.77-1.00). Both methods presented a significant difference between positive results before and after biobanking; McNemar test: p = 0.004, p = 0.003, Cohen's kappa: 0.67 (95% CI, 0.53-0.81), 0.68 (95% CI, 0.52-0.84). Cycle threshold values for the DNA method were higher for all genotypes after biobanking, except for HPV-59. Some loss of sensitivity was seen after biobanking but the concordance between HPV detection before and after biobanking was good for both evaluated methods.

    Conclusions: Biobanking of LBC vaginal samples offers a good platform for HPV testing and could be extended to further molecular analyses. However, in order to ensure a valid test result a larger portion needs to be analyzed from the biobanked sample.

  • 18.
    Lillsunde Larsson, Gabriella
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Kaliff, M.
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bergengren, Lovisa
    Department of Women's health, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    HPV Genotyping from the high risk mRNA Aptima assay: a direct approach using DNA from Aptima sample tubes2016In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 235, p. 80-84Article in journal (Refereed)
    Abstract [en]

    The underlying cause of cervical cancer is infection with the human papilloma virus (HPV) and HPV testing can be used for cervical cancer screening. The Aptima HPV assay from Hologic is an mRNA HPV test used to identify clinically relevant infections but the method does not discriminate between the different high risk genotypes. The aim of the current study was to evaluate if analyzed Aptima sample transfer tubes could be used as a source for HPV genotyping, using sample DNA. Study samples (n=108); were HPV-tested with mRNA Aptima assay and in parallel DNA was extracted and genotyped with Anyplex II HPV28. Analyzed mRNA Aptima tubes were thereafter used as source for a second DNA extraction and genotyping. Using mRNA Aptima result as reference, 90% of the samples (35/39) were high risk positive with the Anyplex II HPV28. Cohen's kappa 0.78 (95% CI: 0.66-0.90), sensitivity 0.90 (95% CI: 0.76-0.97) and specificity 0.90 (95% CI: 0.80-0.96). Two discordant samples carried low-risk genotypes (HPV 82 and HPV 44) and two were negative. DNA-genotyping results, in parallel to and after mRNA testing, were compared and differed significantly (McNemar test: P=0.021) possibly due to sample extraction volume difference. Cohen's kappa 0.81 (95% CI: 0.70-0.92), sensitivity 0.85 (95% CI: 0.74-0.93) and specificity 0.98 (95% CI: 0.88-1.00). In conclusion, analyzed mRNA Aptima sample tubes could be used as a source for DNA HPV genotyping. The sample volume used for extraction needs to be further explored.

  • 19.
    Lillsunde Larsson, Gabriella
    et al.
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Sorbe, Bengt
    Örebro University, School of Health Sciences. Department of Oncology.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    HPV16 viral characteristics in primary, recurrent and metastatic vulvar carcinoma2018In: Papillomavirus research, ISSN 2405-8521, Vol. 6, p. 63-69Article in journal (Refereed)
    Abstract [en]

    Vulvar carcinoma is the fourth most common gynecological malignancy. Two separate carcinogenic pathways are suggested, where one is associated with the human papillomavirus (HPV) and HPV16 the most common genotype.

    The aim of this study was to evaluate HPV-markers in a set of primary tumors, metastases and recurrent lesions of vulvar squamous cell carcinomas (VSCC). Ten HPV16-positive VSCC with metastatic regional lymph nodes, distant lymphoid/hematogenous metastases or local recurrent lesions were investigated for HPV genotype, HPV16 variant, HPV16 viral load, HPV16 integration and HPV16 E2BS3 and 4 methylation.

    In all 10 analyzed case series, the same HPV genotype (HPV16), HPV16 variant and level of viral load were detected in all lesions within a patient case. Primary tumors with a high E2/E6 ratio were found to have fewer vulvar recurrences and/or metastases after diagnosis and treatment. Also, a significantly lower viral load was evident in regional lymph nodes compared to primary tumors.

    The data presented strengthens the evidence for a clonal HPV-induced pathway for vulvar carcinoma.

  • 20.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Evaluation of HPV Genotyping Assays for Archival Clinical Samples2015In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 3, p. 293-301Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) testing and genotyping of FFPE tissue samples is important in epidemiological investigations. Here, we compare four different HPV genotyping methods for use in FFPE clinical samples. Comparative testing was performed on 99 samples with a clinical suspicion of HPV. Specimens were analyzed with Anyplex II HPV28 detecting 28 genotypes using real-time PCR and melting curve analysis, CLART HPV2 detecting 35 genotypes using PCR and microarray detection, and MGP5+/6+ consensus primer system together with pyrosequencing. Results were compared to a real-time PCR reference protocol detecting 14 genotypes. In total, 68% of the samples were positive for an HPV genotype using the reference protocol and MGP5+/6+ primer system. Anyplex II HPV28 analysis and CLART HPV2 had 82% and 72% positive samples, respectively. All four methods showed good agreement when comparing the 14 genotypes included in the reference protocol. When evaluating all genotypes, the Anyplex II HPV28 assay and the CLART assay changed the status of the sample (individually or together) from negative with respect to the reference protocol to positive for either a Group 1 (n = 4) or Group 2 (n = 6) genotype. We conclude from this study that for an extended genotyping approach with a high sensitivity for FFPE specimens, both the Anyplex II HPV28 and CLART HPV2 assays are suitable alternatives despite minor intra-assay differences.

  • 21.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Carlsson, Jessica
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    HPV genotyping assays for archival clinical samples: an evaluation studyManuscript (preprint) (Other academic)
  • 22.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Digital droplet PCR (ddPCR) for the detection and quantification of HPV 16, 18, 33 and 45: a short report2017In: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436, Vol. 40, no 5, p. 521-527Article in journal (Refereed)
    Abstract [en]

    Human papilloma virus (HPV) infection is associated with several anogenital malignancies. Here, we set out to evaluate digital droplet PCR (ddPCR) as a tool for HPV 16, 18, 33 and 45 viral load quantification and, in addition, to compare the efficacy of the ddPCR assay for HPV 16 detection with that of quantitative real-time PCR (qPCR).

    Clinical samples, positive for HPV genotypes 16, 18, 33 and 45 were analyzed for viral load using ddPCR. Sample DNA was cleaved before droplet generation and PCR. Droplets positive for VIC and FAM fluorescence were read in a QX200 Droplet reader (TM) (BIO-RAD) after which the viral load was calculated using Quantasoft software.

    We found that DNAs extracted from formalin fixed paraffin embedded (FFPE) tissue samples yielded lower amplification signals compared to those obtained from liquid based cytology (LBC) samples, but they were clearly distinguishable from negative background signals. The viral limit of detection was 1.6 copies of HPV 16, 2.8 copies of HPV 18, 4.6 copies of HPV 33 and 1.6 copies of HPV 45. The mean inter-assay coefficients of variability (CV) for the assays ranged from 3.4 to 7.0%, and the mean intra-assay CV from 2.6 to 8.2%. The viral load in the different cohorts of tumor samples ranged from 154 to 340,200 copies for HPV 16, 244 to 31,300 copies for HPV 18 and 738 to 69,100 copies for HPV 33. One sample positive for HPV 45 contained 1331 viral copies. When comparing qPCR data with ddPCR copy number data, the qPCR values were found to be 1 to 31 times higher.

    Separation of fragments in nanodroplets may facilitate the amplification of fragmented human and viral DNA. The method of digital droplet PCR may, thus, provide a new and promising tool for evaluating the HPV viral load in clinical samples.

  • 23.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Andersson, Sören
    Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Umeå University Hospital, Umeå, Sweden.
    Sorbe, Bengt
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital, Örebro, Sweden.
    Human Papillomavirus (HPV) and HPV 16-Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden2012In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 22, no 8, p. 1413-1419Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the human papillomavirus (HPV) and HPV type 16-variant distribution in a series of vulvar squamous cell carcinomas (VSCC) and to evaluate the impact of HPV and HPV 16-variant on prognosis.

    Methods: A series of 133 patients who had a diagnosis of VSCC (1983-2008) was selected for the study. Detection of 11 high-risk HPV types (16, 18, 31, 33, 39, 45, 51, 52, 56, 58, and 59) and 2 low-risk HPV types (6 and 11) was performed with real-time polymerase chain reaction. Samples positive for HPV 16 were further analyzed for variant determination of 7 positions in the E6 gene with polymerase chain reaction and pyrosequencing.

    Results: Forty (30.8%) of 130 tumors were found to be HPV positive. Human papillomavirus type 16 was found in 31 cases, HPV 18 was found in 2 cases, HPV 33 was found in 5 cases, and HPV 56 and HPV 59 were found in one case each. All but one tumor harboring HPV 16 were of European linage, and the 3 most common variants were E-p (n = 13), E-G350 (n = 7), and E-G131 (n = 5). HPV positivity was associated with the basaloid tumor type and occurred in significantly younger patients. Overall and recurrence-free survival rates were better in HPV-positive cases, but after correction for age and tumor size, HPV status was no longer an independent and significant prognostic factor. The survival rates of the various HPV 16 variants were not significantly different, but there was a trend of worse outcome for the E-G131-variant group.

    Conclusions: Human papillomavirus positivity of 30.8% is similar to other reports on VSCC. To our knowledge, this first variant determination of HPV 16 in vulvar carcinoma in a Swedish cohort indicated that the variant E-G131 may have an increased oncogenic potential in patients with VSCC.

  • 24.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Andersson, Sören
    Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Sorbe, Bengt
    Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital. Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Prognostic impact of human papilloma virus (HPV) genotyping and HPV-16 subtyping in vaginal carcinoma2013In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 129, no 2, p. 406-411Article in journal (Refereed)
    Abstract [en]

    Objective

    The objectives of this study are to investigate the human papilloma virus (HPV) distribution in vaginal cancer and to evaluate HPV-genotype as well as HPV16-variant impact on prognosis.

    Methods

    Sixty-nine patients diagnosed with primary vaginal carcinoma (1975-2002) were included in the study. Detection of twelve high-risk HPV (hr HPV) and two low-risk HPV (lr HPV) was performed with realtime-PCR. Samples positive for HPV-16 were analyzed for variants in the E6-gene with PCR and pyrosequencing.

    Results

    53.6% (37/69) of the tumors were found to be HPV-positive, mostly for HPV-16 (N=26). Other HPV-types were HPV-18 (N=2), HPV-31 (N=2), HPV-33 (N=2), HPV-45 (N=1), HPV-52 (N=2), HPV-56 (N=1) and HPV-58 (N=1). Only European subtypes of HPV-16 were represented and the two most common HPV-16-variants were E-p (N=13) and E-G350 (N=11). Patients with HPV-positive tumors (N=37) had a significantly (log-rank test=3341; p = 0.0008) superior 5-year overall survival rate as well as cancer-specific survival rate and progression-free survival rate (p = 0.0002; p = 0.0004), compared with patients with HPV-negative tumors (N=32). Interestingly, patients with HPV-16-positive tumors had a superior overall survival compared with patients with tumors containing other HPV-genotypes. In a Cox proportional multivariate analysis age, tumor size, and HPV-status were independent and significant prognostic factors with regard to overall survival rate.

    Conclusions

    HPV-status is of prognostic importance in vaginal carcinoma and varies with viral genotype. In this era of HPV-vaccination, genotypes other than those included in the vaccination program could still lead to vaginal carcinoma with unfavorable prognosis.

  • 25.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, article id e112839Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate if viral load, integration and methylation of E2BS3 and 4 represent different ways of tumor transformation in vaginal and vulvar carcinoma and to elucidate its clinical impact.

    Methods: Fifty-seven samples, positive for HPV16, were selected for the study. Detection of viral load was made with realtime-PCR using copy numbers of E6 and integration was calculated from comparing E2 to E6-copies. Methylation of E2BS3 and 4 was analysed using bisulphite treatment of tumor DNA, followed by PCR and pyrosequencing.

    Results: Vaginal tumors were found to have a higher viral load (p=0.024) compared to vulvar tumors but a high copy number (> median value, 15 000) as well as high methylation (> 50%) was significantly (p=0.010 and p=0.045) associated with a worse cancer-specific survival rate in vulvar carcinoma, but not in vaginal carcinoma. Four groups could be defined for the complete series using a Cluster Two step analysis; (1) tumors holding episomal viral DNA, viral load below 150 000 copies not highly methylated (n=25, 46.3%); (2) tumors harboring episomal viral DNA and being highly methylated (>50%; n=6, 11.1%); (3) tumors with viral DNA fully integrated (n=11, 20.4%), and (4) tumors harboring episomal viral DNA and being medium-or unmethylated (< 50%) and having a high viral load (> total mean value 150 000; n=12, 22.2%). The completely integrated tumors were found to be distinct group, whilst some overlap between the groups with high methylation and high viral load was observed.

    Conclusion: HPV16-related integration, methylation in E2BS3 and 4 and viral load may represent different viral characteristics driving vaginal and vulvar carcinogenesis. HPV16-related parameters were found to be of clinical importance in the vulvar series only.

  • 26.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hansen, Marit
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Comparison of mRNA and DNA HPV levels in HRHPV-positive primary screening samples using digital droplet PCR2017Conference paper (Refereed)
  • 27.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health Sciences.
    Kaliff, Malin
    Örebro University, School of Medical Sciences.
    Ottestig, Elin
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    HPV genotyping of HPV primary screening positive samples in Örebro, Sweden2018Conference paper (Other academic)
  • 28.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health Sciences. Dep. of Laboratory Medicine.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Dep. of Laboratory Medicine.
    Sorbe, Bengt
    2Faculty of Medicine and Health- Örebro University, Dep. Of Oncology, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Dep. of Laboratory Medicine.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Dep. of Laboratory Medicine.
    HPV16 VIRAL CHARACTERISTICS IN PRIMARY AND RECURRENT VULVAR CARCINOMA2018Conference paper (Other academic)
  • 29.
    Mattsson, Johanna S. M.
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Bergman, Bengt
    Department of Respiratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Grinberg, Marianna
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Edlund, Karolina
    Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
    Marincevic, Millaray
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Jirström, Karin
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hengstler, Jan G.
    Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
    Rahnenführer, Joerg
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Gulyas, Miklos
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression2015In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 356, no 2, p. 837-845Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n = 1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n = 616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

  • 30.
    Mattsson, Johanna S. M.
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Brunnström, Hans
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Jabs, Verena
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Edlund, Karolina
    Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, Dortmund, Germany.
    Jirström, Karin
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
    Mindus, Stephanie
    Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
    la Fleur, Linnéa
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Research and Education.
    Karlsson, Christina
    Örebro University, School of Health Sciences.
    Koyi, Hirsh
    Department of Respiratory Medicine, Gävle hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University, Uppsala, Sweden; County Council of Gävleborg, Gävle, Sweden.
    Brandén, Eva
    Department of Respiratory Medicine, Gävle hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/County Council of Gävleborg, Gävle, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Svensson, Maria A
    Clinical Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer2016In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, no 1, article id 603Article in journal (Refereed)
    Abstract [en]

    Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.

    Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.

    Results: ALK rearrangements were detected in 1.7 % in the complete cohort and 2.0 % in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.8 and 1.4 % when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (> 98 %), while the sensitivity was between 69 % (Ventana) and 62 % (in house Dako protocol). Furthermore, only 67 % of the ALK IHC positive cases were positive with both IHC assays. Gene expression analysis revealed that 6/194 (3 %) tumors showed high ALK gene expression (≥ 6 AU) and of them only three were positive by either FISH or IHC.

    Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.

  • 31.
    Mattsson, Johanna S. M.
    et al.
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Svensson, Maria A.
    Institutionen för hälsovetenskap och medicin, Department of Pathology, Örebro universitet, Örebro, Sweden.
    Hallström, Bjorn
    Sci Life Lab, KTH Royal Inst Technol, Stockholm, Sweden.
    Koyi, Hirsh
    Dept Resp Med, Gävle Cent Hosp, Gävle, Sweden.
    Branden, Eva
    Dept Resp Med, Gävle Cent Hosp, Gävle, Sweden.
    Brunnström, Hans
    Dept Clin Sci Lund, Div Oncol & Pathol, Lund Univ, Lund, Sweden.
    Edlund, Karolina
    Leibniz Res Ctr Working Environm & Human Factors, Dortmund TU, Dortmund, Germany.
    Ekman, Simon
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    La Fleur, Linnea
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Grinberg, Marianna
    Dept Stat, Dortmund TU, Dortmund, Germany.
    Rahnenfuehrer, Joerg
    Dept Stat, Dortmund TU, Dortmund, Germany.
    Jirström, Karin
    Dept Clin Sci Lund, Div Oncol & Pathol, Lund Univ, Lund, Sweden.
    Ponten, Fredrik
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Uhlen, Mathias
    Sci Life Lab, KTH Royal Inst Technol, Stockholm, Sweden.
    Botling, Johan
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Micke, Patrick
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    ALK Rearrangements in Non-Small Cell Lung Cancer: Comprehensive Integration of Genomic, Gene Expression and Protein Analysis2015In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, p. S298-S298Article in journal (Other academic)
  • 32.
    Nyberg, Jan
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Dahlin, Christer
    Sahlgrenska Academy University of Gothenburg; NU-hospital organization, Trollhättan, Sweden.
    Johansson, Carina B.
    Sahlgrenska Academy University of Gothenburg.
    Omar, Omar
    Sahlgrenska Academy University of Gothenburg.
    Effect of radiotherapy on osseointegration: in vivo gene expression and implant stability after single high-dose irradiationManuscript (preprint) (Other academic)
  • 33.
    Nyberg, Jan
    et al.
    Department of Oral and Maxillofacial Surgery, Örebro University Hospital, Örebro, Sweden; School of Health and Medical Sciences, Department of Clinical Medicine, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Dahlin, Christer
    Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Oral and Maxillofacial Surgery, NU-hospital organization, Trollhättan, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
    Johansson, Carina B.
    Department of Prosthodontics/Dental Materials Science, Sahlgrenska Academy, Gothenburg, Sweden; Institute of Odontology, University of Gothenburg, Gothenburg, Sweden.
    Omar, Omar
    Department of Biomaterials, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; BIOMATCELL VINN Excellence Center of Biomaterials and Cell Therapy, Gothenburg, Sweden.
    Molecular Activity and Osseointegration After Single-Dose Irradiation: An In Vivo Study2017In: International Journal of Oral & Maxillofacial Implants, ISSN 0882-2786, E-ISSN 1942-4434, Vol. 32, no 5, p. 1033-1038Article in journal (Refereed)
    Abstract [en]

    Purpose: Irradiation results in deleterious effects on bone healing and integration of titanium implants. The impact of irradiation on osseointegration has been demonstrated in histologic studies, but the underlying molecular mechanisms have not been explored. This study aimed to investigate the effects of single-dose irradiation on the expression of biologic mediators crucial for inflammation, bone formation, and bone remodeling and to relate these molecular activities to implant stability after a 5-week healing period.

    Materials and Methods: A rat tibia model was used. An external single-dose irradiation of 20 Gy was administered to one leg while the second leg was used as a control. After 8 weeks, the irradiated and non-irradiated tibiae received titanium implants. Five weeks following implantation, implant stability was evaluated by removal torque measurement. Then, the implant and the bone surrounding the implant were retrieved for gene expression analysis of the implant-adherent cells and peri-implant bone, respectively.

    Results: Irradiation resulted in 55% reduction in removal torque. The implant-adherent cells in irradiated sites revealed downregulation of genes related to bone formation (ALP and OC) and upregulation of pro-inflammatory (TNF-alpha) and pro-fibrogenic (PDGF-b) genes. Conversely, the peri-implant bone in irradiated sites revealed upregulation of bone formation and bone remodeling genes. Removal torque showed a negative correlation with pro-inflammatory activity and a positive correlation with osteoblastic activity in the implant-adherent cells.

    Conclusion: The impact of high (20 Gy) single-dose irradiation on osseointegration involves a reduction in bone formation activity and upregulation of pro-inflammatory and pro-fibrogenic activities in the implant-adherent cells. It is also suggested that this single-dose irradiation elicits a different molecular pattern at a distance from the implant surface, characterized by increased bone formation and remodeling activities in the peri-implant bone.

  • 34.
    Qvick, Alvida
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Sorbe, Bengt
    Örebro University Hospital. Örebro University, School of Health Sciences. Department of Oncology.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Lillsunde Larsson, Gabriella
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Does p53 codon 72 polymorphism have a prognostic value in carcinoma of the vulva and vagina?2017In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 34, no 3, article id 36Article in journal (Refereed)
    Abstract [en]

    Human papilloma virus (HPV) is considered to be responsible for a large part of vaginal and vulvar carcinomas, and the p53 codon 72 polymorphism has been implicated in susceptibility to cancer induced by this virus, but with contradicting results. In this study, we have investigated the prognostic value of the codon 72 polymorphism by real-time PCR (qPCR) in two cohorts of vaginal (n = 66) and vulvar (n = 123) carcinomas. In vaginal carcinoma, arginine homozygous patients were significantly associated with a higher primary cure rate (p = 0.023) but also associated with a higher recurrence rate (p = 0.073), significant at distant locations (p = 0.009). No significant differences were found in overall survival rate (p = 0.499) or cancer-specific survival rate (p = 0.222). A higher frequency of arginine homozygosity was noted in HPV-positive tumors (p = 0.190) in comparison with HPV-negative tumors. In vulvar carcinoma, the genotype homozygous for arginine was significantly associated with a larger tumor size at diagnosis in the entire cohort (p = 0.015) and a lower cancer-specific survival rate (p = 0.024) compared with heterozygous (arginine/proline) in HPV-negative tumors. Our results indicate that the relation between HPV and the p53 codon 72 polymorphism is complex and the significance and mechanisms responsible for this relationship need to be further elucidated.

  • 35.
    Qvick, Alvida
    et al.
    Örebro University, School of Medical Sciences. Region Örebro län, Örebro, Sweden.
    Wirén, Anders
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Rönnqvist, Maria
    Södersjukhuset, Stockholm, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Region Örebro län, Örebro, Sweden.
    Circulating miRNA: a biomarker for classification of lung cancer and benign lung disease2019In: Journal of Thoracic Oncology, ISSN 1556-0864, Vol. 14, no 10, p. 311-311, article id MA15.07Article in journal (Other academic)
    Abstract [en]

    Background Circulating biomarkers for cancer have great potential for diagnosis as well as follow up of treatment. MicroRNAs (miRNA) are involved in the expression of a majority of proteins with different cell types having different miRNA expression. The aim of this study was to create a circulating miRNA-based model to discriminate patients with lung cancer from patients with benign lung disease. Methods Samples were collected from patients under investigation for lung cancer at Örebro University hospital. Patients were then divided into groups based on diagnosis, which resulted in NSCLC adenocarcinoma (n=24), NSCLC squamous cell carcinoma (n=13), SCLC (n=4) and a heterogeneous group consisting of different benign lung diseases (n=19). Healthy controls were collected separately (n=17). Circulating miRNA was processed using the extraction-free library preparation miRNA Whole Transcriptome Assay with probes for 2083 human mature miRNAs and analyzed with massive parallel sequencing. Differential expression between groups was estimated using edgeR. MiRNAs that had the highest impact on patient grouping were used in a sPLS discriminant analysis. The resulting classification model was validated using the leave-one-out method. Results The final model for comparison between patients with benign lung disease and patients with lung cancer contained 19 miRNAs. The model had an error rate of 15 % with errors distributed evenly between groups. A sub-analysis of patients with mutations in EGFR (n=5) and KRAS (n=6) was performed showing two distinct patterns in miRNA expression. Conclusion MiRNA shows promise as a circulating biomarker for lung cancer but may not be sufficient as an independent classifier. The predictive power may be improved by using several biomarkers in combination. The difference in expression between tumors with different mutations may be derived from alternate driving processes in these tumors.Sequencing results were standardized as counts per million (cpm), miRNA with cpm < 100 was filtered out and quantile normalization and log2 transformation was performed. Differential expression was analyzed using regression model (R software v. 3.5.1, package edgeR v. 3.24.1) with Benjamini-Hochberg correction. The miRNAs that, after correction, had a significant impact on sample groups were kept and analyzed with sparse partial least squares-regression. The resulting model was validated using leave-one-out method.

  • 36.
    Svensson, Maria A.
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Perner, S.
    Dept. of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
    Ohlson, A-L.
    Dept. of Urology, University Hospital of Örebro, Sweden; Dept. of Laboratory Medicine, University Hospital of Örebro, Sweden.
    Day, J. R.
    Hologic Gen-Probe, San Diego, USA.
    Kirsten, R.
    Dept. of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
    Groskopf, J.
    Hologic Gen-Probe, San Diego, USA.
    Sollie, T.
    Dept. of Laboratory Medicine, University Hospital of Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Demichelis, F.
    Centre for Integrative Biology, University of Trento, Trento, Italy; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, USA.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rubin, M. A.
    Dept. of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, USA.
    A comparative study of ERG status assessment on DNA-, mRNA-, and proteinlevels using unique samples from a Swedish biopsy cohortManuscript (preprint) (Other academic)
    Abstract [en]

    The ERG rearrangement is identified in approximately 50% of prostate cancer (PCa) screened cohorts and is known to be highly specific. This genetic aberration, most commonly leading to the TMPRSS2-ERG fusion, but also SLC45A3-ERG or NDRG1- ERG fusions, all leading to an over expression of a truncated ERG protein. Most studies have applied in situ hybridization (FISH) methods or mRNA based assays to investigate the ERG status. Recently, studies showed that ERG protein levels assessed by ERG antibodies can be used as a surrogate marker for ERG rearrangement. In the current study we investigate ERG status on a series of diagnostic biopsies using DNA-, mRNA- and protein based assays. We formally compare three assay results (i.e. FISH, fusion mRNA and immunohistochemistry) to identify which method could be most appropriate to use when having limited amount of tissue. ERG rearrangement was found in 56% of the cases. Comparing ERG rearrangement status by FISH with ERG over expression and TMPRSS2-ERG fusion transcript we found 95.1% (154/162, Fisher’s exact test 9.50E-36) and 85.2% (138/162, Fisher’s exact test 7.26E-22) concordance, respectively. We show that the ERG antibody highly correlates with the ERG rearrangement with high sensitivity and specificity. We also identified the most common TMPRSS2-ERG isoform in the majority of ERG rearranged cases. These results provide compelling evidence that the ERG antibody can be used to further investigate the role of ERG in PCa.

  • 37.
    Svensson, Maria A.
    et al.
    Örebro University Hospital. Department of Laboratory Medicine, Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Perner, Sven
    Inst Pathol, Dept Prostate Canc Res, Univ Hosp Bonn, Bonn, Germany.
    Ohlson, Anna-Lena
    Department of Laboratory Medicine, University Hospital of Örebro, Örebro, Sweden; Department of Urology, University Hospital of Örebro, Örebro, Sweden.
    Day, John R.
    Hol Gen Probe, San Diego CA, USA.
    Groskopf, Jack
    Hol Gen Probe, San Diego CA, USA.
    Kirsten, Robert
    Inst Pathol, Dept Prostate Canc Res, Univ Hosp Bonn, Bonn, Germany.
    Sollie, Thomas
    Department of Laboratory Medicine, University Hospital of Örebro, Örebro, Sweden.
    Helenius, Gisela
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Demichelis, Francesca
    Ctr Integrat Biol, Univ Trento, Trento, Italy; Inst Computat Biomed, Weill Cornell Med Coll, New York NY, USA.
    Andrén, Ove
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Rubin, Mark A.
    Dept Pathol & Lab Med, Weill Cornell Med Coll, New York NY, USA.
    A Comparative Study of ERG Status Assessment on DNA, mRNA, and Protein Levels Using Unique Samples from a Swedish Biopsy Cohort2014In: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 22, no 2, p. 136-141Article in journal (Refereed)
    Abstract [en]

    The ERG rearrangement is identified in approximately 50% of prostate cancer screened cohorts and is known to be highly specific. This genetic aberration, most commonly leading to the TMPRSS2-ERG fusion, but also SLC45A3-ERG or NDRG1-ERG fusions, all leading to an overexpression of a truncated ERG protein. Most studies have applied in situ hybridization (FISH) methods or mRNA-based assays to investigate the ERG status. Recently, studies showed that ERG protein levels assessed by ERG antibodies can be used as a surrogate marker for ERG rearrangement. In the current study, we investigate ERG status on a series of diagnostic biopsies using DNA-based, mRNA-based, and protein-based assays. We formally compared 3 assay results (ie, FISH, fusion mRNA, and immunohistochemistry) to identify which method could be most appropriate to use when having limited amount of tissue. ERG rearrangement was found in 56% of the cases. Comparing ERG rearrangement status by FISH with ERG overexpression and TMPRSS2-ERG fusion transcript we found 95.1% (154/162, Fisher exact test 9.50E-36) and 85.2% (138/162, Fisher exact test 7.26E-22) concordance, respectively. We show that the ERG antibody highly correlates with the ERG rearrangement with high sensitivity and specificity. We also identified the most common TMPRSS2-ERG isoform in the majority of ERG rearranged cases. These results provide compelling evidence that the ERG antibody can be used to further investigate the role of ERG in prostate cancer.

  • 38.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences.
    Kruse, Robert
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Infants born small-for-gestational age have different placental expression of microRNAs2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no Suppl. 1, p. 100-101, article id P1-508Article in journal (Other academic)
  • 39.
    Östling, Hanna
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynecology.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pediatrics.
    Placental expression of microRNAs in infants born small for gestational age2019In: Placenta, ISSN 0143-4004, E-ISSN 1532-3102, Vol. 81, p. 46-53Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The molecular mechanisms behind poor foetal growth are not fully known. The aim of this study was to explore global microRNA expression in placentas of infants born small for gestational age (SGA) compared to infants with a normal birth weight (NBW).

    METHODS: Placental biopsies from term infants were identified in a biobank and divided into four groups: infants born SGA with (n = 13) or without (n = 9) exposure to low maternal gestational weight gain (GWG) and infants born with NBWs with (n = 20) or without (n = 26) exposure to low GWG. All women and infants were healthy, and no woman smoked during pregnancy. Only vaginal deliveries were included. Next-generation sequencing was performed with single read sequencing of >9 million reads per sample. Differential microRNA expression was analysed using ANOVA for unequal variances (Welch) with multiple testing corrections through the Benjamini-Hochberg method. A fold change >2 and a corrected p value < 0.05 were considered significant. Adjustments for possible confounding factors were made using a linear regression model.

    RESULTS: A total of 1870 known, mature human microRNAs were detected in the sample. MiR-3679-5p and miR-193b-3p were significantly upregulated, and miR-379-3p, miR-335-3p, miR-4532, miR-519e-3p, miR-3065-5p, and miR-105-5p were significantly downregulated after adjustment for potential confounding factors in SGA infants with normal GWG compared to infants with NBWs and normal GWG.

    DISCUSSION: Infants born unexplained SGA show differential microRNA expression in their placenta. Important pathways for the differentially expressed microRNAs include inflammation and the insulin-IGF system.

1 - 39 of 39
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