Risk-stratification of HPV-positive women with low-grade cytology by FAM19A4/miR124-2 methylation and HPV genotyping

Dick, Stefanie; Vink, Frederique J; Heideman, Daniëlle A.M.; Lissenberg‐Witte, Birgit I.; Meijer, Chris J.L.M.; Berkhof, Johannes

doi:10.1038/s41416-021-01614-4

Cited by 22 publications

(19 citation statements)

References 34 publications

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“… 35 - 37 A recent post hoc analysis of two Dutch screening trials showed that HPV-positive women with ASC-US/LSIL and a negative methylation test have a CIN3+ risk of only 9.8% compared with a CIN3+ risk of 33.1% in women with ASC-US/LSIL and a positive methylation test. 38 Our current study showed that even when CIN2/3 is detected in methylation-negative women with ASC-US/LSIL, the probability of regression is nearly 90%. Together, these results support the implementation of methylation in cervical screening, possibly in combination with HPV16 genotyping, to triage HPV-positive women with ASC-US/LSIL for colposcopy.…”

Section: Discussionmentioning

confidence: 46%

Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study)

Kremer

Dick

Heideman

et al. 2022

JCO

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PURPOSE Cervical screening can prevent cancer by detection and treatment of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3). Screening also results in considerable overtreatment because many CIN2/3 lesions show spontaneous regression when left untreated. In this multicenter longitudinal cohort study of women with untreated CIN2/3, the prognostic value of FAM19A4/miR124-2 methylation was evaluated for clinical regression. PATIENTS AND METHODS Women with CIN2/3 were prospectively followed for 24 months. Surgical excision was replaced by a wait-and-see policy. FAM19A4/miR124-2 methylation was evaluated on all clinician-collected samples and self-collected samples collected at baseline. Every 6 months, human papillomavirus (HPV) testing and cytology were conducted on a clinician-collected sample, and a colposcopic examination was performed by a gynecologist to exclude progression. At the final study visit, two biopsies were taken. Clinical regression was defined as histologically confirmed absence of CIN2+ or an HPV-negative clinician-collected sample with normal cytology. Regression incidences were estimated using the Kaplan-Meier method. RESULTS One hundred fourteen women (median age, 30 years; range, 20-53 years) were included, 80 of whom were diagnosed with CIN2 and 34 with CIN3. During the study, 65.8% of women (75/114) did not receive surgical treatment. Women with a negative FAM19A4/miR124-2 result on the baseline clinician-collected sample showed more clinical regression (74.7%) than women with a positive methylation result (51.4%, P = .013). Regression in women with a negative FAM19A4/miR124-2 methylation test was highest when cytology was atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (88.4%) or HPV16 was negative (85.1%). CONCLUSION Most women with untreated CIN2/3 and a negative baseline FAM19A4/miR124-2 methylation test showed clinical regression. Methylation, in combination with cytology or HPV genotyping, can be used to support a wait-and-see policy in women with CIN2/3.

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Section: Discussionmentioning

confidence: 46%

Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study)

Kremer

Dick

Heideman

et al. 2022

JCO

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“…Retrospective longitudinal screening studies showed that HPV‐positive but FAM19A4/miR124‐2 methylation‐negative women had a 14‐year CIN3+ risk equal to that of negative cytology triage outcome, and notably they had a lower risk for cervical cancer 16,55–57 . Recent data show that additional risk‐stratification of HPV‐positive women with low‐grade cytological abnormalities by FAM19A4/miR124‐2 methylation could substantially reduce direct colposcopy referral rate, while retaining high CIN3+ sensitivity 58 . Altogether, these findings support the use of cellular methylation markers as an interesting new molecular means for future cervical cancer screening, and the need to evaluate their performance in cohorts of vaccinated women.…”

Section: Methylation Of Cellular Genes and Risk Of Cervical Neoplasia...mentioning

confidence: 99%

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

Lehtinen

Pimenoff

Nedjai

et al. 2022

Intl Journal of Cancer

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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.

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“…Various candidate genes, targeting either host or HPV viral genomes, were studied in recent years as the targets of methylation sites [13][14][15][16] , resulting in signi cant heterogeneity between studies. Among these, a combination of methylation panels targeting the human gene EPB41L3 and the most carcinogenic HPV types-HPV16/18/31/33 (named S5 classi er) was one of the most studied methylation tests among different populations, such as among cancer patients [17] , HPV positive women with mild cytology abnormalities [18,19] , colposcopy referral population due to HPV16/18 + and/or cytology abnormalities [20] , or selected hrHPV + women derived from a population-based screening program [21,22] , even in HIV women [23] . All mentioned studies exhibited the desirable accuracy and feasibility of S5 classi er test, while population-based prospective studies are still lacking.…”

Section: Discussionmentioning

confidence: 99%

Triage performance of human gene EPB41L3 and HPV 16/18 viral DNA methylation among hrHPV positive women: a cohort study

Rezhake

Wang

Shen

et al. 2022

Preprint

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Background: Methylation-based biomarkers show promise in triaging hrHPV positive women, however, more evidence from population-based prospective studies is required to confirm its utility in real-world settings. Methods: 2000 women from Xinjiang, China were screened for cervical cancer in 2018 and annually followed-up until 2020. Swab samples of baseline hrHPV positive women were used to perform a methylation test targeting the host gene EPB41L3 and HPV16/18 DNA L1/L2 regions. Triage accuracy and predictive values of the methylation test were evaluated in comparison with HPV16/18 and cytology triage using cross-sectional and 24-months outcomes. Results: Overall methylation positivity was 12.4% among hrHPV positive women, and test positivity increased by the histology lesions (7.7% in normal, 9.1% in CIN1, 62.5% in CIN2, 75.0% in CIN3 and 100% in cancer cases, ptrend<0.05). Women being methylation positive at baseline had a significantly higher risk of hrHPV persistence at 12-month and 24-month follow-up (RR12M=1.9, 95%CI: 1.4-2.5 and RR24M=1.7, 95%CI: 1.1-2.5). The specificity of methylation (92.1%) was substantially higher than either HPV16/18 (78.7%, p<0.001) and cytology (79.2%, p <0.001). For CIN2+, the cross-sectional triage sensitivity of methylation appeared slightly higher than HPV16/18 but less than cytology triage with values of 70.6%, 64.7%, and 94.1% respectively (pexact=1.000, and pexact=0.213 respectively) .The longitudinal sensitivity of methylation over 24-month follow-up was 56.0%, as compared to 64.0% (pexact=0.688) for HPV16/18 and 76.0%, (pexact=0.125) for cytology. Methylation test showed high positive predictive values for CIN2+ (41.4% at baseline and 50.0% at 24-month follow-up), while the CIN2+ risk of methylation negative women (cNPV) remained considerable (2.5% at baseline and 6.9% at 24-month follow-up). Conclusions: Methylation could improve triage specificity and colposcopy efficiency, and predict elevated risk of hrHPV persistence and CIN2+ during 24-month follow-up, suggesting that DNA methylation could be a useful triage tool for hrHPV positive women. Women negative by either methylation, HPV16/18 or cytology would still require careful follow-up.

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Risk-stratification of HPV-positive women with low-grade cytology by FAM19A4/miR124-2 methylation and HPV genotyping

Cited by 22 publications

References 34 publications

Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study)

Clinical Regression of High-Grade Cervical Intraepithelial Neoplasia Is Associated With Absence of FAM19A4/miR124-2 DNA Methylation (CONCERVE Study)

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

Triage performance of human gene EPB41L3 and HPV 16/18 viral DNA methylation among hrHPV positive women: a cohort study

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