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  • 1.
    Alhamdow, Ayman
    et al.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lindh, Christian
    Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Hagberg, Jessika
    Örebro University, School of Science and Technology. Department of Occupational and Environmental Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Graff, Pål
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Occupational and Environmental Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; National Institute of Occupational Health, Oslo, Norway.
    Westberg, Håkan
    Örebro University, School of Science and Technology. Department of Occupational and Environmental Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Krais, Annette M.
    Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Albin, Maria
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden; Centre for Occupational and Environmental Medicine (CAMM), Stockholm County Council, Stockholm, Sweden.
    Gustavsson, Per
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Occupational and Environmental Medicine (CAMM), Stockholm County Council, Stockholm, Sweden.
    Tinnerberg, Håkan
    Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Broberg, Karin
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    DNA-methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons2018In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 39, no 7, p. 869-878Article in journal (Refereed)
    Abstract [en]

    Some polycyclic aromatic hydrocarbons (PAH) are known carcinogens and workplace PAH exposure may increase the risk of cancer. Monitoring early cancer-related changes can indicate whether the exposure is carcinogenic. Here, we enrolled 151 chimney sweeps, 152 controls, and 19 creosote-exposed male workers from Sweden. We measured urinary PAH metabolites using LC/MS/MS, the cancer-related markers telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) using qPCR, and DNA methylation of lung cancer-related genes F2RL3 and AHRR using pyrosequencing. The median 1-hydroxypyrene (PAH metabolite) concentrations were highest in creosote-exposed workers (8.0 μg/g creatinine) followed by chimney sweeps (0.34 μg/g creatinine) and controls (0.05 μg/g creatinine). TL and mtDNAcn did not differ between study groups. Chimney sweeps and creosote-exposed workers had significantly lower methylation of AHRR CpG site cg05575921 (88.1% and 84.9%, respectively) than controls (90%). Creosote-exposed workers (73.3%), but not chimney sweeps (76.6%) had lower methylation of F2RL3 cg03636183 than controls (76.7%). Linear regression analyses showed that chimney sweeps had lower AHRR cg05575921 methylation (B=-2.04; P<0.057, adjusted for smoking and age) and lower average AHRR methylation (B=-2.05; P<0.035), and non-smoking chimney sweeps had lower average F2RL3 methylation (B=-0.81; P<0.042, adjusted for age) compared with controls. These cancer-related markers were not associated with urinary concentrations of PAH metabolites. In conclusion, although we found no associations with PAH metabolites in urine (short-term exposure), our results suggest dose-response relationship between PAH exposure and DNA hypomethylation of lung cancer-related loci. These findings indicate that further protective measures should be taken to reduce PAH exposure.

  • 2.
    Ali, Imran
    et al.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Julin, Bettina
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Glynn, Anders
    The National Food Agency, Uppsala, Sweden.
    Högberg, Johan
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Berglund, Marika
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan-Erik
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giovannucci, Edward
    Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston MA, United States; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston MA, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, United States.
    Wolk, Alicja
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Stenius, Ulla
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Åkesson, Agneta
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Exposure to polychlorinated biphenyls and prostate cancer: population-based prospective cohort and experimental studies2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 12, p. 1144-1151Article in journal (Refereed)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer.

  • 3.
    Hemminki, K.
    et al.
    Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.
    Jiang, Y.
    Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.
    Ma, X.
    Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.
    Yang, K.
    Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden.
    Egevad, L.
    Department of Pathology and Cytology, Karolinska Hospital, Stockholm, Sweden.
    Lindblad, Per
    Department of Urology, Sundsvall Hospital, Sundsvall, Sweden.
    Molecular epidemiology of VHL gene mutations in renal cell carcinoma patients: relation to dietary and other factors2002In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 23, no 5, p. 809-815Article in journal (Refereed)
    Abstract [en]

    Carcinogenic chemicals act through DNA damage and mitogenic effects. No established mechanism explains the cancer preventive effects, if any, of food items, such as vegetables and fruit. If such data were available, preferably on tumor-initiating genes, the evidence for the protective effects would become stronger. The von Hipple-Lindau (VHL) gene is the tumor suppressor gene predisposing to both sporadic renal cell carcinoma (RCC) and von Hippel-Lindau disease. We have earlier analyzed VHL mutations in RCCs from 102 Swedish patients identified in a case-control study and here examine associations between patient characteristics, including dietary habits and mutations, considering the type of mutation. The results are given as odds ratios (OR), separately for smokers and all patients. In univariate analysis, consumption of vegetables and citrus fruit decreased the frequency of VHL mutations among smokers and citrus fruit among all patients. In multivariate analysis of smokers' characteristics, welding fumes showed a risk of 5.63 for multiple VHL mutations. In smokers, citrus fruit decreased the OR of GC to AT mutations to 0.13 and that of multiple mutations to 0.17; vegetables decreased the OR for single mutations to 0.22. Among all subjects, welding fumes were a risk factor and citrus fruit a protective factor. Additionally, an intake of selenium protected against multiple mutations. The present results provide evidence that the intake of vegetables, selenium and particularly of citrus fruit protects the renal VHL gene from mutational insults that may be endogenous or common in a population. Even though most of the associations are biologically plausible, and vegetables and fruit were an a priori hypothesis, fortuitous results cannot be ruled out in this relatively small study.

  • 4.
    Meyer, Mara S.
    et al.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Penney, Kathryn L.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Stark, Jennifer R.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Schumacher, Fredrick R.
    Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA.
    Sesso, Howard D.
    Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, USA.
    Loda, Massimo
    Harvard Radiation Oncology Program Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, USA.
    Fiorentino, Michelangelo
    Harvard Radiation Oncology Program Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, USA.
    Finn, Stephen
    Harvard Radiation Oncology Program Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, USA.
    Flavin, Richard J.
    Harvard Radiation Oncology Program Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, USA.
    Kurth, Tobias
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, USA.
    Price, Alkes L.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Department of Biostatistics, Harvard School of Public Health, Boston, USA.
    Giovannucci, Edward L.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Department of Nutrition, Harvard School of Public Health, Boston,USA.
    Fall, Katja
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Stampfer, Meir J.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Ma, Jing
    Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Genetic variation in RNASEL associated with prostate cancer risk and progression2010In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 31, no 9, p. 1597-603Article in journal (Refereed)
    Abstract [en]

    Variation in genes contributing to the host immune response may mediate the relationship between inflammation and prostate carcinogenesis. RNASEL at chromosome 1q25 encodes ribonuclease L, part of the interferon-mediated immune response to viral infection. We therefore investigated the association between variation in RNASEL and prostate cancer risk and progression in a study of 1286 cases and 1264 controls nested within the prospective Physicians' Health Study. Eleven single-nucleotide polymorphisms (SNPs) were selected using the web-based 'Tagger' in the HapMap CEPH panel (Utah residents of Northern and Western European Ancestry). Unconditional logistic regression models assessed the relationship between each SNP and incident advanced stage (T(3)/T(4), T(0)-T(4)/M(1) and lethal disease) and high Gleason grade (>/=7) prostate cancer. Further analyses were stratified by calendar year of diagnosis. Cox proportional hazards models examined the relationship between genotype and prostate cancer-specific survival. We also explored associations between genotype and serum inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor-alpha receptor 2 using linear regression. Individuals homozygous for the variant allele of rs12757998 had an increased risk of prostate cancer [AA versus GG; odds ratio (OR): 1.63, 95% confidence interval (CI): 1.18-2.25), and more specifically, high-grade tumors (OR: 1.90, 95% CI: 1.25-2.89). The same genotype was associated with increased CRP (P = 0.02) and IL-6 (P = 0.05) levels. Missense mutations R462Q and D541E were associated with an increased risk of advanced stage disease only in the pre-prostate-specific antigen era. There were no significant associations with survival. The results of this study support a link between RNASEL and prostate cancer and suggest that the association may be mediated through inflammation. These novel findings warrant replication in future studies.

  • 5.
    Sinnott, Jennifer A.
    et al.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Department of Biostatistics, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gerke, Travis
    Department of Epidemiology, College of Medicine and College of Public Health and Health Professions, University of Florida, Gainesville, USA.
    Tyekucheva, Svitlana
    Department of Biostatistics, Harvard School of Public Health, Boston, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA.
    Penney, Kathryn L.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Sesso, Howard D.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Loda, Massimo
    Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Stampfer, Meir J.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Pawitan, Yudi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Andersson, Sven-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Molecular differences in transition zone and peripheral zone prostate tumors2015In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 36, no 6, p. 632-638Article in journal (Refereed)
    Abstract [en]

    Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20-30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on ~6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P < 0.0001). Our findings that zonal differences in normal tissue persist in tumor tissue and that these differences are associated with Gleason score and sample type suggest that subtypes potentially resulting from different etiologic pathways might arise in these zones. Zone of origin may be important to consider in prostate tumor biomarker research.

  • 6.
    Stopsack, Konrad H.
    et al.
    Department of Internal Medicine, Mayo Clinic, Rochester MN, United States.
    Gerke, Travis A
    Department of Internal Medicine, Mayo Clinic, Rochester MN, United States.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden; School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.
    Giovannucci, Edward L.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston MA, USA.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA.
    Rider, Jennifer R
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    Cholesterol uptake and regulation in high-grade and lethal prostate cancers2017In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 38, no 8, p. 806-811Article in journal (Refereed)
    Abstract [en]

    Lethal prostate cancers have higher expression of squalene monooxygenase (SQLE), the second rate-limiting enzyme of cholesterol synthesis. Preclinical studies suggested that aberrant cholesterol regulators, receptors and transporters contribute to cholesterol accumulation uniformly. We assessed their association with features of aggressive cancers. In the prospective prostate cancer cohorts within the Health Professional Follow-up Study, the Physicians' Health Study and the Swedish Watchful Waiting Study, tumor mRNA expression profiling was performed. Lethal disease was defined as mortality or metastases from prostate cancer (n = 266) in contrast to non-lethal disease without metastases after >8 years of follow-up (n = 476). Associations with Gleason grade were additionally assessed using The Cancer Genome Atlas primary prostate cancer dataset (n = 333). Higher Gleason grade was associated with lower LDLR expression, lower SOAT1 and higher SQLE expression. Besides high SQLE expression, cancers that became lethal despite primary treatment were characterized by low LDLR expression (odds ratio for highest versus lowest quintile, 0.37; 95% CI 0.18-0.76) and by low SOAT1 expression (odds ratio, 0.41; 95% CI 0.21-0.83). The association of LDLR expression and lethality was not present in tumors with high IDOL expression. ABCA1, PCSK9 or SCARB1 expressions were not associated with Gleason grade or lethal cancer. In summary, prostate cancers that progress to lethal disease rely on de novo cholesterol synthesis (via SQLE), rather than transcellular uptake (via LDLR) or cholesterol esterification (via SOAT1). These results may help design pharmacotherapy for high-risk patients.

  • 7.
    Thorgeirsson, Tryggvi
    et al.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Public Health Sciences, University of Iceland, Reykjavik, Iceland.
    Jordahl, Kristina M.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Flavin, Richard
    Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, USA; Department of Histopathology, St. James’s Hospital Dublin, Dublin, Ireland; Trinity College Dublin, Dublin, Ireland.
    Epstein, Mara Meyer
    Department of Medicine and the Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester, USA.
    Fiorentino, Michelangelo
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; F. Addarii” Institute of Oncology and Transplantation Pathology, S.Orsola-Malpighi Hospital, Bologna University, Bologna, USA.
    Andersson, Swen-Olof
    Örebro University, School of Health Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Mosquera, Juan Miguel
    Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, USA; Institute for Precision Medicine of Weill Cornell Medical College and New York Presbyterian, New York, USA.
    Ingoldsby, Helen
    National University of Ireland, Galway, Ireland.
    Fall, Katja
    Örebro University, School of Medical Sciences. Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health.
    Tryggvadottir, Laufey
    Icelandic Cancer Registry, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Public Health Sciences, University of Iceland, Reykjavik, Iceland.
    Intracellular location of BRCA2 protein expression and prostate cancer progression in the Swedish Watchful Waiting Cohort2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 3, p. 262-268Article in journal (Refereed)
    Abstract [en]

    Prostate cancer patients with inherited BRCA2 mutations have a survival disadvantage. However, it is unknown whether progression is associated with BRCA2 protein expression in diagnostic prostate cancer tissue, among men without inherited mutations. We conducted a nested case-control study within the Swedish Watchful Waiting cohort. The case group included all 71 patients who died from prostate cancer within 5 years from diagnosis and controls were all patients (n = 165) who lived at least 7 years after diagnosis. Tissue microarrays were stained using antibodies for C- and N-terminal domains of the BRCA2 protein. Location (nuclear, cytoplasmic and membranous) and magnitude (intensity and percentage) of expression were assessed. Logistic regression models produced odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, year of diagnosis and Gleason score. Positive BRCA2 staining at the cell membrane was associated with reduced risk of death within 5 years (N-terminal: OR = 0.47, 95% CI = 0.21-1.04, P = 0.06; C-terminal: OR = 0.41, 95% CI = 0.18-0.91, P = 0.03) and low Gleason scores (P = 0.006). Positive cytoplasmic C-terminal staining was associated with higher Gleason scores and increased lethality (OR = 3.61, 95% CI = 1.61-8.07, P = 0.002). BRCA2 protein expression at the cell membrane and lack of C-terminal expression in the cytoplasm were associated with a reduced risk of rapidly fatal prostate cancer. BRCA2 protein expression in prostate cancer tissue may have independent prognostic value. The potential biological significance of BRCA2 expression at the cell membrane warrants further investigation.

  • 8.
    Ungerbäck, Jonas
    et al.
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Belenki, Dimitri
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Jawas ul-Hassan, Aksa
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Fredrikson, Mats
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Elander, Nils
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Verma, Deepti
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Söderkvist, Peter
    Division of Cell biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer2012In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 33, no 11, p. 2126-2134Article in journal (Refereed)
    Abstract [en]

    Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor-kappa B (NFκB) is a major regulator of inflammation and variation in NFκB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFκB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.

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