The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

Barrett, James E.; Herzog, Chiara; Jones, Allison; Leavy, Olivia C.; Evans, Iona; Knapp, S.; Reisel, Daniel; Nazarenko, Tatiana; Kim, Yoo-Na; Franchi, D.; Ryan, Andy; Franks, Joanna; Bjørge, Line; Zikán, Michal; Cibula, David; Harbeck, Nadia; Colombo, Nicoletta; Dudbridge, Frank; Jones, Louise; Sundström, Karin; Dillner, Joakim; Rådestad, Angelique Flöter; Danielsson, Kristina Gemzell; Pashayan, Nora; Widschwendter, Martin

doi:10.1038/s41467-021-27918-w

Cited by 28 publications

(41 citation statements)

References 49 publications

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“…We have demonstrated the unprecedented performance of a comprehensive DNA methylation classifier — the WID-CIN test — in identifying hrHPV-pos women with or at future risk of CIN3+. The fact that the test principle (i.e., analysis of DNAme of a combination of CpGs on an array) not only identifies women with CIN3+ but also women with ovarian [ 37 ] and breast cancer [ 29 ] (WID-OC and WID-BC) suggests that the WID-CIN test could be rapidly prioritized for cost-effectiveness analyses and potential quick implementation in the clinical arena. In addition to array-based detection of CIN3+, in ongoing work, we have developed a multiplexed MethyLight PCR-based test, the WID-qCIN test, that amplifies regions in the genes DPP6 , RALYL , and GSX1 and exhibits excellent sensitivity and specificity in both diagnostic and predictive settings (Herzog, Sundström et al, submitted).…”

Section: Discussionmentioning

confidence: 99%

“…Contamination by immune cells presented a challenge with respect to the identification of differentially methylated positions (DMPs) as differential methylation that occurred solely in epithelial cells was diminished in samples with a high proportion of immune cells (IC) and vice versa. In order to overcome this (as previously described [ 29 ]), we linearly regressed the beta values on IC for each CpG site, the linear models being fitted to cases and controls separately. The intercept points at IC = 0 were used as estimates of mean beta values in cases and controls in a pure epithelial cell population.…”

Section: Methodsmentioning

confidence: 99%

“…The R package glmnet [ 30 ] was used to train classifiers with a mixing parameter value of alpha = 0 (ridge penalty) and alpha = 1 (lasso penalty) with binomial response type as previously described [ 29 ]. Data from the discovery set were used to fit the classifiers.…”

Section: Methodsmentioning

confidence: 99%

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The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer

et al. 2022

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Background Cervical screening is transitioning from primary cytology to primary human papillomavirus (HPV) testing. HPV testing is highly sensitive but there is currently no high-specificity triage method for colposcopy referral to detect cervical intraepithelial neoplasia grade 3 or above (CIN3+) in women positive for high-risk (hr) HPV subtypes. An objective, automatable test that could accurately perform triage, independently of sample heterogeneity and age, is urgently required. Methods We analyzed DNA methylation at ~850,000 CpG sites across the genome in a total of 1254 cervical liquid-based cytology (LBC) samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). Samples were provided by a state-of-the-art population-based cohort biobank and consisted of (i) a discovery set of 170 CIN3+ cases and 202 hrHPV-positive/cytology-negative controls; (ii) a diagnostic validation set of 87 CIN3+, 90 CIN2, 166 CIN1, and 111 hrHPV-positive/cytology-negative controls; and (iii) a predictive validation set of 428 cytology-negative samples (418 hrHPV-positive) of which 210 were diagnosed with CIN3+ in the upcoming 1–4 years and 218 remained disease-free. Results We developed the WID-CIN (Women’s cancer risk IDentification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites. The receiver operating characteristic area under the curve (AUC) in the independent diagnostic validation set was 0.92 (95% CI 0.88–0.96). At 75% specificity (≤CIN1), the overall sensitivity to detect CIN3+ is 89.7% (83.3–96.1) in all and 92.7% (85.9–99.6) and 65.6% (49.2–82.1) in women aged ≥30 and <30. In hrHPV-positive/cytology-negative samples in the predictive validation set, the WID-CIN detected 54.8% (48.0–61.5) cases developing 1–4 years after sample donation in all ages or 56.9% (47.6–66.2) and 53.5% (43.7–63.2) in ≥30 and <30-year-old women, at a specificity of 75%. Conclusions The WID-CIN test identifies the vast majority of hrHPV-positive women with current CIN3+ lesions. In the absence of cytologic abnormalities, a positive WID-CIN test result is likely to indicate a significantly increased risk of developing CIN3+ in the near future.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer

et al. 2022

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“…DNA methylation occurs before protein translation, which might have greater value in the early diagnosis of breast cancer than the detection of cancer-related protein expression. Although individual gene methylation showed good specificity for breast cancer, it was often less sensitive for breast cancer diagnosis alone, so it was necessary to jointly detect changes in multiple gene methylation sites and construct a detailed methylation map (43).…”

Section: Discussionmentioning

confidence: 99%

Clinical significance and prognostic value of small nucleolar RNA SNORA38 in breast cancer

Song

Zheng

et al. 2022

Front. Oncol.

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BackgroundBreast cancer is the most common malignant tumor among women worldwide, and breast cancer stem cells (BCSCs) are believed to be the source of tumorigenesis. New findings suggest that small nucleolar RNAs (snoRNAs) play a significant role in tumor development.MethodsThe Cancer Genome Atlas (TCGA) and Kaplan–Meier survival analysis were used to demonstrate expression and survival of SNORA38 signature. In situ hybridization (ISH) and immunohistochemical (IHC) were conducted to analyze the correlation between SNORA38 and stemness biomarker in 77 BC samples. Gene Set Enrichment Analysis (GSEA) was performed to investigate the mechanisms related to SNORA38 expression in BC. Real-time qPCR was employed to evaluate the expression of SNORA38 in breast cancer cell lines.ResultsIn the public database and patients’ biopsies, SNORA38 was significantly up-regulated in breast cancer. Furthermore, the expression of SNORA38 was significantly correlated with tumor size, lymph node metastasis, and TNM stage, among which tumor size was an independent factor for SNORA38 expression. Higher SNORA38 expression was associated with shorter overall survival (OS). Meanwhile, SNORA38 was positively associated with the stem cell marker OCT-4, which suggested that SNORA38 might be related to breast cancer stemness.ConclusionsSNORA38 is an important carcinogenic snoRNA in breast cancer and might be a prognostic biomarker for breast cancer.

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“…Our recent work has addressed these issues: a DNA methylation array-based signature, the WID-CIN, is able to identify women with, or at risk of, cervical malignancies, offers high sensitivity and specificity even below the age of 30, and outperforms cytology as an indicator for future disease risk [ 20 ]. The advantage of the array-based WID-CIN signature is the ability to detect or predict the risk also for the other women’s cancers using a single cervical sample and one single assay as demonstrated recently for breast, ovarian, and endometrial cancer [ 24 , 25 ] (latter currently under review).…”

Section: Introductionmentioning

confidence: 99%

DNA methylation-based detection and prediction of cervical intraepithelial neoplasia grade 3 and invasive cervical cancer with the WID™-qCIN test

et al. 2022

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Background Cervical screening using primary human papilloma virus (HPV) testing and cytology is being implemented in several countries. Cytology as triage for colposcopy referral suffers from several shortcomings. HPV testing overcomes some of these but lacks specificity in women under 30. Here, we aimed to develop and validate an automatable triage test that is highly sensitive and specific independently of age and sample heterogeneity, and predicts progression to CIN3+ in HPV+ patients. Results The WID™-qCIN, assessing three regions in human genes DPP6, RALYL, and GSX1, was validated in both a diagnostic (case–control) and predictive setting (nested case–control), in a total of 761 samples. Using a predefined threshold, the sensitivity of the WID™-qCIN test was 100% and 78% to detect invasive cancer and CIN3, respectively. Sensitivity to detect CIN3+ was 65% and 83% for women < and ≥ 30 years of age. The specificity was 90%. Importantly, the WID™-qCIN test identified 52% of ≥ 30-year-old women with a cytology negative (cyt−) index sample who were diagnosed with CIN3 1–4 years after sample donation. Conclusion We identified suitable DNAme regions in an epigenome-wide discovery using HPV+ controls and CIN3+ cases and established the WID™-qCIN, a PCR-based DNAme test. The WID™-qCIN test has a high sensitivity and specificity that may outperform conventional cervical triage tests and can in an objective, cheap, and scalable fashion identify most women with and at risk of (pre-)invasive cervical cancer. However, evaluation was limited to case–control settings and future studies will assess performance and generalisability in a randomised controlled trial.

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The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples

Cited by 28 publications

References 49 publications

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer

The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer

Clinical significance and prognostic value of small nucleolar RNA SNORA38 in breast cancer

DNA methylation-based detection and prediction of cervical intraepithelial neoplasia grade 3 and invasive cervical cancer with the WID™-qCIN test

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