Assessing the risk of cervical neoplasia in the post‐HPV vaccination era

This review is based on the recent EUROGIN scientific session: “Assessing risk of cervical cancer in the post‐vaccination era,” which addressed the demands of cervical intraepithelial neoplasia (CIN)/squamous intraepithelial lesion (SIL) triage now that the prevalence of vaccine‐targeted oncogenic high‐risk (hr) human papillomaviruses (HPVs) is decreasing. Change in the prevalence distribution of oncogenic HPV types that follows national HPV vaccination programs is setting the stage for loss of positive predictive value of conventional but possibly also new triage modalities. Understanding the contribution of the latter, most notably hypermethylation of cellular and viral genes in a new setting where most oncogenic HPV types are no longer present, requires studies on their performance in vaccinated women with CIN/SIL that are associated with nonvaccine HPV types. Lessons learned from this research may highlight the potential of cervical cells for risk prediction of all women's cancers.

[1]  M. Poljak,et al.  FAM19A4/miR124-2 Methylation Testing and Human Papillomavirus (HPV) 16/18 Genotyping in HPV-Positive Women Under the Age of 30 Years , 2022, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[2]  J. Berkhof,et al.  Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study) , 2022, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  J. Cuzick,et al.  DNA methylation testing with S5 for triage of high‐risk HPV positive women , 2022, International journal of cancer.

[4]  M. Lehtinen,et al.  In 30 years, gender-neutral vaccination eradicates oncogenic human papillomavirus (HPV) types while screening eliminates HPV-associated cancers , 2022, Expert review of vaccines.

[5]  Thomas E. Bartlett,et al.  Susceptibility to hormone-mediated cancer is reflected by different tick rates of the epithelial and general epigenetic clock , 2022, Genome biology.

[6]  M. Widschwendter,et al.  The DNA methylome of cervical cells can predict the presence of ovarian cancer , 2022, Nature Communications.

[7]  A. Ryan,et al.  The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples , 2022, Nature Communications.

[8]  D. Hanahan Hallmarks of Cancer: New Dimensions. , 2022, Cancer discovery.

[9]  J. Berkhof,et al.  Risk-stratification of HPV-positive women with low-grade cytology by FAM19A4/miR124-2 methylation and HPV genotyping , 2021, British journal of cancer.

[10]  J. Cuzick,et al.  Clinical performance of methylation as a biomarker for cervical carcinoma in situ and cancer diagnosis: A worldwide study , 2021, International journal of cancer.

[11]  J. Gargano,et al.  Declines in Prevalence of Human Papillomavirus Vaccine-Type Infection Among Females after Introduction of Vaccine — United States, 2003–2018 , 2021, MMWR. Morbidity and mortality weekly report.

[12]  M. Poljak,et al.  Classification of high‐grade cervical intraepithelial neoplasia by p16ink4a, Ki‐67, HPV E4 and FAM19A4/miR124‐2 methylation status demonstrates considerable heterogeneity with potential consequences for management , 2021, International journal of cancer.

[13]  J. Cuzick,et al.  Effective methylation triage of HPV positive women with abnormal cytology in a middle‐income country , 2020, International journal of cancer.

[14]  P. Sparén,et al.  HPV Vaccination and the Risk of Invasive Cervical Cancer. , 2020, The New England journal of medicine.

[15]  M. Poljak,et al.  Methylation markers FAM19A4 and miR124‐2 as triage strategy for primary human papillomavirus screen positive women: A large European multicenter study , 2020, International journal of cancer.

[16]  P. Sparén,et al.  Impact of HPV vaccination on cervical screening performance: a population-based cohort study , 2020, British Journal of Cancer.

[17]  J. Berkhof,et al.  FAM19A4/miR124-2 methylation analysis as a triage test for HPV-positive women: cross-sectional and longitudinal data from a Dutch screening cohort. , 2020, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[18]  A. Giuliano,et al.  Methylation of HPV 16 and EPB41L3 in oral gargles: Associations with oropharyngeal cancer detection and tumor characteristics , 2020, International journal of cancer.

[19]  L. Mirabello,et al.  The use of human papillomavirus DNA methylation in cervical intraepithelial neoplasia: A systematic review and meta-analysis , 2019, EBioMedicine.

[20]  J. Cuzick,et al.  Methylation estimates the risk of precancer in HPV-infected women with discrepant results between cytology and HPV16/18 genotyping , 2019, Clinical Epigenetics.

[21]  S. de Sanjosé,et al.  Performance of DNA methylation assays for detection of high-grade cervical intraepithelial neoplasia (CIN2+): a systematic review and meta-analysis , 2019, British Journal of Cancer.

[22]  M. Poljak,et al.  FAM19A4/miR124‐2 methylation in invasive cervical cancer: A retrospective cross‐sectional worldwide study , 2019, International journal of cancer.

[23]  J. Berkhof,et al.  Long-term CIN3+ risk of HPV positive women after triage with FAM19A4/miR124-2 methylation analysis. , 2019, Gynecologic oncology.

[24]  J. Dillner,et al.  Methylation in Predicting Progression of Untreated High-grade Cervical Intraepithelial Neoplasia , 2019, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[25]  F. Sultana,et al.  Is the positive predictive value of high‐grade cytology in predicting high‐grade cervical disease falling due to HPV vaccination? , 2019, International journal of cancer.

[26]  M. Cruickshank,et al.  Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study , 2019, BMJ.

[27]  J. Cuzick,et al.  Evaluation of a validated methylation triage signature for human papillomavirus positive women in the HPV FOCAL cervical cancer screening trial , 2018, International journal of cancer.

[28]  S. de Sanjosé,et al.  Distinct geographic clustering of oncogenic human papillomaviruses multiple infections in cervical cancers: Results from a worldwide cross‐sectional study , 2018, International journal of cancer.

[29]  W. Quint,et al.  Defining hrHPV genotypes in cervical intraepithelial neoplasia by laser capture microdissection supports reflex triage of self-samples using HPV16/18 and FAM19A4/miR124-2 methylation. , 2018, Gynecologic oncology.

[30]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[31]  M. Lehtinen,et al.  Gender‐neutral vaccination provides improved control of human papillomavirus types 18/31/33/35 through herd immunity: Results of a community randomized trial (III) , 2018, International journal of cancer.

[32]  E. Schuuring,et al.  Host-cell DNA methylation patterns during high-risk HPV-induced carcinogenesis reveal a heterogeneous nature of cervical pre-cancer , 2018, Epigenetics.

[33]  J. Cuzick,et al.  Molecular progression to cervical precancer, epigenetic switch or sequential model? , 2018, International journal of cancer.

[34]  C. Houldcroft,et al.  The Role of aDNA in Understanding the Coevolutionary Patterns of Human Sexually Transmitted Infections , 2018, Genes.

[35]  J. Berkhof,et al.  Cervical cancer risk in HPV‐positive women after a negative FAM19A4/mir124‐2 methylation test: A post hoc analysis in the POBASCAM trial with 14 year follow‐up , 2018, International journal of cancer.

[36]  W. Xiong,et al.  EPB41L3 is a potential tumor suppressor gene and prognostic indicator in esophageal squamous cell carcinoma , 2018, International journal of oncology.

[37]  Andrew E. Teschendorff,et al.  Epigenome-based cancer risk prediction: rationale, opportunities and challenges , 2018, Nature Reviews Clinical Oncology.

[38]  A. Willis Rarefaction, Alpha Diversity, and Statistics , 2017, bioRxiv.

[39]  H. Cubie,et al.  Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study. , 2017, The Lancet. Infectious diseases.

[40]  M. Schiffman,et al.  Discovery and validation of candidate host DNA methylation markers for detection of cervical precancer and cancer , 2017, International journal of cancer.

[41]  Amanda J Lee,et al.  Lifetime cancer risk and combined oral contraceptives: the Royal College of General Practitioners' Oral Contraception Study , 2017, American journal of obstetrics and gynecology.

[42]  Thomas E. Bartlett,et al.  Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution , 2016, Nature Communications.

[43]  A. Teschendorff,et al.  Stochastic epigenetic outliers can define field defects in cancer , 2016, BMC Bioinformatics.

[44]  E. Franco,et al.  Cervical cancer screening of HPV vaccinated populations: Cytology, molecular testing, both or none. , 2016, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[45]  Dong Wang,et al.  Aberrant expression of the candidate tumor suppressor gene DAL-1 due to hypermethylation in gastric cancer , 2016, Scientific Reports.

[46]  S. Cotton,et al.  HPV immunisation and cervical screening—confirmation of changed performance of cytology as a screening test in immunised women: a retrospective population-based cohort study , 2016, British Journal of Cancer.

[47]  Matthias W. Beckmann,et al.  DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer , 2016, Nature Communications.

[48]  D. Gertig,et al.  Effectiveness of less than three doses of quadrivalent human papillomavirus vaccine against cervical intraepithelial neoplasia when administered using a standard dose spacing schedule: Observational cohort of young women in Australia , 2015, Papillomavirus Research.

[49]  J. Cuzick,et al.  HPV33 DNA methylation measurement improves cervical pre-cancer risk estimation of an HPV16, HPV18, HPV31 and \textit{EPB41L3} methylation classifier. , 2015, Cancer biomarkers : section A of Disease markers.

[50]  H. Chesson,et al.  The Estimated Lifetime Probability of Acquiring Human Papillomavirus in the United States , 2014, Sexually transmitted diseases.

[51]  J. Berkhof,et al.  Methylation Analysis of the FAM19A4 Gene in Cervical Scrapes Is Highly Efficient in Detecting Cervical Carcinomas and Advanced CIN2/3 Lesions , 2014, Cancer Prevention Research.

[52]  M. Tibayrenc,et al.  Vaccination: an evolutionary engine for pathogens? Conference report. , 2014, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[53]  C. Meijer,et al.  Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions , 2014, Nature Reviews Cancer.

[54]  Mariska Bierkens,et al.  CADM1 and MAL promoter methylation levels in hrHPV‐positive cervical scrapes increase proportional to degree and duration of underlying cervical disease , 2013, International journal of cancer.

[55]  S. Wacholder,et al.  Methylation of human papillomavirus type 16 genome and risk of cervical precancer in a Costa Rican population. , 2012, Journal of the National Cancer Institute.

[56]  H. Kitchener,et al.  Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation , 2012, Genome Medicine.

[57]  Joel s. Brown,et al.  Evolutionary ecology of human papillomavirus: trade-offs, coexistence, and origins of high-risk and low-risk types. , 2012, The Journal of infectious diseases.

[58]  P. Hartge,et al.  Adverse health outcomes in women exposed in utero to diethylstilbestrol. , 2011, The New England journal of medicine.

[59]  L. Dubeau,et al.  The cell of origin of ovarian epithelial tumours. , 2008, The Lancet. Oncology.

[60]  M. Widschwendter,et al.  Analysis of Aberrant DNA Methylation and Human Papillomavirus DNA in Cervicovaginal Specimens to Detect Invasive Cervical Cancer and Its Precursors , 2004, Clinical Cancer Research.

[61]  M. Widschwendter,et al.  Methylated DNA collected by tampons--a new tool to detect endometrial cancer. , 2004, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[62]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[63]  J. Peto,et al.  Human papillomavirus is a necessary cause of invasive cervical cancer worldwide , 1999, The Journal of pathology.

[64]  O. Bogler,et al.  A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer. , 1999, Cancer research.