Posttreatment monitoring by ASCL1/LHX8 methylation analysis in women with HIV treated for cervical intraepithelial neoplasia grade 2/3

Vink, Frederique J; Kremer, Wieke W.; Lissenberg‐Witte, Birgit I.; Heideman, Daniëlle A.M.; Bleeker, Maaike; Zummeren, Marjolein van; Breytenbach, Erika; Visser, Cathy; Lukhwareni, Azwidowi; Meijer, Chris J.L.M.; Dreyer, Greta

doi:10.1097/qad.0000000000003197

Cited by 3 publications

(3 citation statements)

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“…Third, we excluded patients who were positive for HIV or pregnant women from the training and validation sets. This limitation could have hampered the extrapolation of the DNA methylation assay to a large cohort, as reported previously ( 68 , 69 ).…”

Section: Discussionmentioning

confidence: 98%

Cytological DNA methylation for cervical cancer screening: a validation set

Kong,

Wang,

Wang

et al. 2023

Front. Oncol.

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BackgroundIn a previous training set with a case-controlled design, cutoff values for host EPB41L3 and JAM3 gene methylation were obtained for the detection of cervical intraepithelial neoplasia (CIN) 2 or more severe lesions (CIN2+). This validation trial was conducted to evaluate the role of DNA methylation in screening for CIN2+ by cervical cytology among unselected participants.MethodsFrom June 1, 2019, to September 1, 2019, in our study center, we collected liquid-based samples from cervical swabs for methylation assays and hrHPV testing in eligible patients. The primary endpoint was the diagnostic accuracy of DNA methylation and hrHPV genotyping for CIN2+ according to confirmed histology results.ResultsAmong 307 participants, compared with hrHPV testing, the methylation assay for CIN2+ had lower sensitivity (68.7% versus 86.1%, p=0.002) but higher specificity (96.7% versus 0.696, p<0.001). The methylation assay also had favorable sensitivity and specificity in patients with negative hrHPV testing (56.3% and 96.9%) and in patients with cervical adenocarcinoma (73.7% and 92.7%). DNA methylation had higher specificity than the hrHPV assay (100.0% versus 44.4%, p<0.001) for identifying residual CIN2+ in patients without residual lesions. Positive cervical DNA methylation was associated with a diagnostic probability of endometrial carcinoma (odds ratio 15.5 [95% confidence interval 4.1-58.6]) but not of ovarian epithelial carcinoma (1.4 [0.3-6.5]).ConclusionsThe host EPB41L3 and JAM3 gene methylation assay in cervical cytology had favorable diagnostic accuracy for CIN2+ and was highly specific for residual CIN2+ lesions The methylation assay is a promising triage tool in hrHPV+ women, or even an independent tool for cervical cancer screening. The methylation status in cervical cytology could also serve as a prognostic biomarker. Its role in detecting endometrial carcinomas is worthy of further exploration.

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Section: Discussionmentioning

confidence: 98%

Cytological DNA methylation for cervical cancer screening: a validation set

Kong,

Wang,

Wang

et al. 2023

Front. Oncol.

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“…An important finding was that recurrent CIN2/3 caused by a persistent HPV infection had significantly higher methylation positivity rates compared with recurrent CIN2/3 and an incident or absent HPV infection. In WLHIV from South-Africa, ASCL1/LHX8 showed a 4-year recurrent CIN2/3 risk after a negative methylation test similarly low as compared with a negative cytology result or a negative HPV result 114 . In conclusion, methylation analysis provides a good alternative to HPV and/or cytology post-treatment monitoring enabling the differentiation between re-treatment and conservative management in case of recurrent CIN.…”

Section: Post-treatment Monitoring Of Cin2/3mentioning

confidence: 90%

“…Validation of these markers on clinician-collected samples showed an area under the curve (AUC) varying between 0.86 to 0.89 for the detection of CIN3 and cervical cancer. In another discovery screen using HPV-positive self-collected cervical samples ASCL1, LHX8 and ST6GALNAC5 were identified as methylation markers for the detection of CIN3 and cervical cancer 114 . The combined performance of these markers showed an AUC of 0.90 in brush self-collected samples.…”

Section: Host-cell Dna Methylation Markersmentioning

confidence: 99%

Methylation markers for risk-stratification in cervical cancer screening and management of CIN

Dick

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Cervical cancer is one of the most preventable and treatable forms of cancer. The development of cervical cancer is preceded by cervical intraepithelial neoplasia (CIN). This offers possibilities for screening and treatment before CIN lesions progress to cervical cancer. Novel biomarkers offer the opportunity to improve screening and tailor management. The ultimate goal is to mainly refer women for colposcopy and to consequently only treat women with high-grade CIN (CIN2/3) with a high chance of progression to cervical cancer. Chapter 1 provided a general introduction on cervical carcinogenesis, cervical screening and management of CIN2/3. Part 1.Screening Host-cell DNA methylation markers have shown a good performance in the detection of CIN3 and cervical cancer (CIN3+) in HPV-based cervical screening as a triage test. In Chapter 2, six novel methylation markers were evaluated and compared for the detection of CIN3 and cervical cancer. We showed that all six methylation markers had a high performance. ASCL1 and LHX8 showed complementarity in the detection of CIN3 with an AUC of 0.890, resulting in a sensitivity of 84.0% and specificity of 83.2%. The bi-marker panel detected all 50 cervical cancers. The implementation of HPV-based screening with cytology triage led to an increased colposcopy referral rate. This increase in mainly caused by the direct referral of women with borderline or mild cytological abnormalities. In Chapter 3, we evaluated whether the FAM19A4/miR124-2 methylation test can be applied as an additional triage test in HPV-positive women with borderline or mild dyskaryosis cytology to reduce overreferral. The CIN3+ risk after a positive or negative methylation result was 33.1% and 9.8%, respectively. The direct colposcopy referral rate could be reduced with 66% after additional risk-stratification with FAM19A4/miR124-2 methylation while retaining high CIN3+ sensitivity. In Chapter 4, we determined the long-term performance of the FAM19A4/miR124-2 methylation test in HPV-positive women. The 14-year cumulative CIN3+ incidence after a positive or negative methylation test was 39.8% and 16.3%, respectively. The 14-year cumulative CIN3+ incidence after a positive or negative cytology test was 46.5% and 15.6%, respectively. These results indicate that a negative methylation test provides a similar long-term safety against CIN3+ compared with a negative cytology. Part 2. Management Women with an abnormal screening result are referred for colposcopy. The histological result of colposcopy-guided biopsies largely determines the management of women with CIN. Accurate and consistent histological grading of CIN lesions is important to decide between conservative management and excisional treatment. In Chapter 5, we described the immunohistochemical expression patterns of p16INK4a, Ki-67 and HPV E4 in relation to the FAM19A4/miR124-2 DNA methylation. A great heterogeneity was found in immunohistochemical expression and DNA methylation status. In Chapter 6, we evaluated the prognostic value of the FAM19A4/miR124-2 DNA methylation test in a longitudinal cohort study of women with untreated CIN2/3 in the prediction of clinical regression. Clinical regression was significantly associated with a negative methylation test. Women with a negative methylation result showed regression in 75% and women with a positive methylation result in 51%. Host-cell DNA methylation can be used to support a wait-and-see policy in women with CIN2/3 to prevent overtreatment. Women treated for CIN2/3 with LLETZ remain at increased risk for the development of recurrent CIN and cervical cancer. Therefore, post-treatment monitoring is necessary. In Chapter 7, methylation of FAM19A4/miR124-2 and ASCL1/LHX8 was in the detection of recurrent CIN2/3. Both methylation marker panels showed a >92% detection rate of recurrent CIN3, while <9% of ≤CIN1 tested methylation positive. Chapter 8 provided a general discussion of the results of this thesis and presented an overview of the clinical indications of host-cell DNA methylation in cervical screening and management of women with CIN.

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