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Characterization of HPV-induced vaginal and vulvar carcinoma
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Örebro: Örebro university , 2014. , 83 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 112
Keyword [en]
vaginal carcinoma, vulvar carcinoma, HPV, integration, methylation, genotyping
National Category
Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-38173ISBN: 978-91-7529-052-2 (print)OAI: oai:DiVA.org:oru-38173DiVA: diva2:758349
Public defence
2014-12-19, Universitetssjukhuset, Wilandersalen, Södra Grev Rosengatan, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-10-27 Created: 2014-10-27 Last updated: 2017-10-17Bibliographically approved
List of papers
1. Human Papillomavirus (HPV) and HPV 16-Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden
Open this publication in new window or tab >>Human Papillomavirus (HPV) and HPV 16-Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden
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2012 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 22, no 8, 1413-1419 p.Article in journal (Refereed) Published
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.

Keyword
Vulvar carcinoma, Human papillomavirus, HPV 16 variants
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-43018 (URN)10.1097/IGC.0b013e31826a0471 (DOI)000309543700023 ()23013732 (PubMedID)2-s2.0-84867268780 (Scopus ID)
Available from: 2015-02-27 Created: 2015-02-27 Last updated: 2017-10-18Bibliographically approved
2. Prognostic impact of human papilloma virus (HPV) genotyping and HPV-16 subtyping in vaginal carcinoma
Open this publication in new window or tab >>Prognostic impact of human papilloma virus (HPV) genotyping and HPV-16 subtyping in vaginal carcinoma
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2013 (English)In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 129, no 2, 406-411 p.Article in journal (Refereed) Published
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.

Keyword
Vaginal carcinoma, Human papilloma virus, HPV-16-variants, Prognosis
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-29270 (URN)10.1016/j.ygyno.2013.02.004 (DOI)000318058600024 ()23402906 (PubMedID)2-s2.0-84876292443 (Scopus ID)
Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2017-10-18Bibliographically approved
3. Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas
Open this publication in new window or tab >>Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, e112839Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Public Library Science, 2014
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-42542 (URN)10.1371/journal.pone.0112839 (DOI)000347709300111 ()2-s2.0-84911948854 (Scopus ID)
Note

Funding Agency:

Örebro County Council Research Committee OLL-324811 OLL-259341

Available from: 2015-02-09 Created: 2015-02-09 Last updated: 2017-10-18Bibliographically approved
4. HPV genotyping assays for archival clinical samples: an evaluation study
Open this publication in new window or tab >>HPV genotyping assays for archival clinical samples: an evaluation study
(English)Manuscript (preprint) (Other academic)
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:oru:diva-43020 (URN)
Available from: 2015-02-27 Created: 2015-02-27 Last updated: 2017-10-17Bibliographically approved

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