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1.
Cancer Med ; 7(9): 4542-4553, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30030907

RESUMO

Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VINVSCC ) and women who did not develop VSCC during follow-up (VINnoVSCC ). HPV-testing resulted in 41 HPV-positive (16 VINVSCC , 14 VINnoVSCC , and 11 VSCC) and 24 HPV-negative (11 VINVSCC and 13 VSCC) lesions. HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than HPV-negative VSCC (P = .009), but shared chromosome 8 alterations. HPV-positive VINnoVSCC had less CNA than VINVSCC (P = .022). Interestingly, 1pq gain was detected in 81% of HPV-positive VINVSCC and only in 21% of VINnoVSCC (P = .001). In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV-positive cases.


Assuntos
Transformação Celular Neoplásica , Transformação Celular Viral , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Neoplasias Vulvares/etiologia , Biomarcadores , Carcinoma de Células Escamosas/etiologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Variações do Número de Cópias de DNA , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estadiamento de Neoplasias , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Lesões Pré-Cancerosas/etiologia , Neoplasias Vulvares/metabolismo , Neoplasias Vulvares/patologia
2.
Hum Reprod ; 31(2): 280-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26724799

RESUMO

STUDY QUESTION: Is the presence of human papillomavirus (HPV) in semen associated with impairment of semen quality? SUMMARY ANSWER: In a large cohort of males seeking fertility evaluation, no associations were observed between seminal HPV presence and semen parameters. WHAT IS KNOWN ALREADY: HPV is commonly detected in semen samples. Whether the presence of HPV is related to impairment of semen quality, remains unclear. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included a cohort of 430 males. PARTICIPANTS/MATERIALS, SETTING, METHODS: Male partners in couples seeking fertility evaluation provided one semen sample per person. Semen samples were tested for HPV-DNA using GP5+/6+-PCR. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. The presence of antisperm antibodies was assessed by a mixed agglutination reaction (MAR)-test. MAIN RESULTS AND THE ROLE OF CHANCE: Overall HPV was detected in 14.9% (64/430) of semen samples, including 2.1% (9/430) that contained both high-risk (hr) HPV and low-risk (lr) HPV types, 8.8% (38/430) with exclusively hrHPV types and 4.0% (17/430) with exclusively lrHPV types. The presence of HPV in semen was not associated with the age of the participants, seminal pH, semen volume, total sperm count, sperm concentration, progressive motility or the presence of antisperm antibodies. LIMITATIONS, REASONS FOR CAUTION: This study did not observe an association between HPV presence in semen and impairment of semen quality. However, we cannot exclude an effect of seminal HPV on early embryo development and clinical reproductive outcomes. WIDER IMPLICATIONS OF THE FINDINGS: As HPV is frequently present in semen, screening of donor semen for HPV should be considered to prevent iatrogenic cervical HPV infections in the recipient. However our findings do not support standardized HPV testing of semen in the diagnostic work-up of subfertile couples. STUDY FUNDING/COMPETING INTERESTS: This study was sponsored by an unrestricted grant of Stichting Researchfonds Pathology Amsterdam, the Netherlands. P.J.F.S. has been on the speakers bureau of Roche, Gen-Probe, Abbott, Qiagen and Seegene and has been a consultant for Crucell B.V. J.B. has been on the speakers bureau of Qiagen and has been a consultant for Roche, DDL Diagnostic Laboratory, GlaxoSmithKline and Merck. D.A.M.H. has been member of the scientific advisory boards of Amgen and Pfizer, and has been on the speakers bureau of Hologic/Gen-Probe. C.J.L.M.M. has been on the speakers bureau of GlaxoSmithKline, Qiagen, Merck, Roche, Menarini and Seegene, has served occasionally on the scientific advisory board of GlaxoSmithKline, Qiagen, Merck, Roche and Genticel, and has occasionally been a consultant for Qiagen. Formerly, C.J.L.M.M. was a minority shareholder of Delphi Biosciences, which bankrupted in 2014. C.J.L.M.M. is a minority shareholder of Diassay B.V. P.J.F.S., D.A.M.H. and C.J.L.M.M. have minority stake in Self-Screen B.V., a spin-off company of VU University Medical Center. R.L., M.G.D., P.G.A.H., D.T.M.P., and I.H. do not have any conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: Not applicable.


Assuntos
Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Sêmen/virologia , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Adulto , Estudos de Coortes , Humanos , Masculino , Países Baixos , Infecções por Papillomavirus/epidemiologia , Análise do Sêmen
3.
Fertil Steril ; 104(4): 838-844.e8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26211884

RESUMO

OBJECTIVE: To study the source of human papillomavirus (HPV) in semen. DESIGN: Observational study (CCMO-NL3248800010). SETTING: Academic hospital-based laboratory. PATIENT(S): Healthy male volunteers (n = 213). INTERVENTION(S): One penile scrape and three semen samples were obtained per participant for HPV-DNA testing by both GP5+/6+ polymerase chain reaction (PCR) and SPF10-PCR to detect moderate/high and low viral loads, respectively; flat penile lesions (FPL) were detected by penoscopy. MAIN OUTCOME MEASURE(S): HPV-DNA presence in semen and penile scrapes, and the presence of FPL. RESULT(S): HPV-DNA at moderate/high viral loads (i.e., GP5+/6+ PCR-positive) was detected in ≥1 semen sample(s) in 27% of participants. Most men with moderate/high viral loads in the penile scrape also had moderate/high viral loads in semen (85%). Men with a HPV-negative penile scrape were very unlikely to have moderate/high viral loads in semen (3%). The presence of HPV in semen was associated with the presence of HPV in the penile scrape also on a genotype-specific level. Having FPL was a risk factor for HPV presence in semen. CONCLUSION(S): HPV-DNA presence in semen of healthy men is common and associated with HPV infections of the penile epithelium. HPV-DNA presence in semen may result from desquamation of HPV-infected penile cells.


Assuntos
Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/patologia , Doenças do Pênis/virologia , Sêmen/virologia , Adolescente , Adulto , DNA Viral/análise , Epitélio/patologia , Epitélio/virologia , Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Doenças do Pênis/epidemiologia , Doenças do Pênis/patologia , Pênis/patologia , Pênis/virologia , Reação em Cadeia da Polimerase , Sêmen/metabolismo , Doenças Virais Sexualmente Transmissíveis/epidemiologia , Doenças Virais Sexualmente Transmissíveis/virologia , Carga Viral , Adulto Jovem
4.
J Urol ; 193(2): 526-31, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25150641

RESUMO

PURPOSE: The incidence of penile cancer is increasing, and is suggested to be explained by changes in sexual practice and increased exposure of men to sexually transmitted high risk human papillomavirus infection. In penile cancers from a Dutch population treated in 1963 to 2001 we found a high risk human papillomavirus prevalence of about 30%. In this study we assessed the prevalence of high risk human papillomavirus-DNA in a more recent, contemporary penile cancer cohort and its association with patient survival. MATERIALS AND METHODS: High risk human papillomavirus-DNA presence was assessed by GP5+6+ polymerase chain reaction in 212 formalin fixed, paraffin embedded invasive penile tumor specimens of patients treated between 2001 and 2009. The 5-year disease specific survival was calculated using the Kaplan-Meier method with the log rank test and Cox regression. RESULTS: High risk human papillomavirus-DNA was detected in a subset of penile cancer cases (25%, 95% CI 19-31). HPV16 was the predominant type, representing 79% (42 of 53) of all high risk human papillomavirus infections. The 5-year disease specific survival in the high risk human papillomavirus negative group and the high risk human papillomavirus positive group was 82% and 96%, respectively (log rank test p=0.016). Adjusted for stage, grade, lymphovascular invasion and age, human papillomavirus status was still prognostic for disease specific survival (p=0.030) with a hazard ratio of 0.2 (95% CI 0.1-0.9). CONCLUSIONS: High risk human papillomavirus-DNA was observed in a quarter of penile cancer cases. No relevant increase in high risk human papillomavirus prevalence in recent decades was observed. The presence of high risk human papillomavirus-DNA in penile cancer confers a survival advantage.


Assuntos
Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Neoplasias Penianas/patologia , Neoplasias Penianas/virologia , Idoso , Sondas de DNA de HPV , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Infecções por Papillomavirus/diagnóstico , Neoplasias Penianas/mortalidade , Prevalência , Taxa de Sobrevida , Resultado do Tratamento
5.
Virchows Arch ; 461(6): 629-38, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23064619

RESUMO

For treatment purposes, distinction between squamous cell carcinoma and adenocarcinoma is important. The aim of this study is to examine the diagnostic accuracy on lung cancer small biopsies for the distinction between adenocarcinoma and squamous cell carcinoma and relate these to immunohistochemical and KRAS and EGFR mutation analysis. An interobserver study was performed on 110 prospectively collected biopsies obtained by bronchoscopy or transthoracic needle biopsy of patients with non-small cell lung cancer. The diagnosis was correlated with immunohistochemical (IHC) analysis for markers of adeno- (TTF1 and/or mucin positivity) and squamous cell differentiation (P63 and CK5/6) as well as KRAS and EGFR mutation analysis. Eleven observers independently read H&E-stained slides of 110 cases, resulting in a kappa value of 0.55 ± 0.10. The diagnosis non-small cell lung cancer not otherwise specified was given on average on 29.5 % of the biopsies. A high concordance was observed between hematoxylin-eosin-based consensus diagnosis (≥8/11 readings concordant) and IHC markers. In all cases with EGFR (n = 1) and KRAS (n = 20) mutations, adenodifferentiation as determined by IHC was present and p63 staining was absent. In 2 of 25 cases with a consensus diagnosis of squamous cell carcinoma, additional stainings favored adenodifferentation, and a KRAS mutation was present. P63 is most useful for distinction between EGFR/KRAS mutation positive and negative patients. In the diagnostic work-up of non-small cell lung carcinoma the limited reproducibility on small biopsies is optimized with immunohistochemical analysis, resulting in reliable delineation for predictive analysis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/patologia , Proteínas de Membrana/análise , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/análise , Proteínas ras/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Análise Mutacional de DNA , Amarelo de Eosina-(YS) , Hematoxilina , Humanos , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras) , Reprodutibilidade dos Testes , Coloração e Rotulagem
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