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

ABSTRACT: Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.

SUBMITTER: Barrett JE

PROVIDER: S-EPMC8807602 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Barrett James E JE Herzog Chiara C Jones Allison A Leavy Olivia C OC Evans Iona I Knapp Susanne S Reisel Daniel D Nazarenko Tatiana T Kim Yoo-Na YN Franchi Dorella D Ryan Andy A Franks Joanna J Bjørge Line L Zikan Michal M Cibula David D Harbeck Nadia N Colombo Nicoletta N Dudbridge Frank F Jones Louise L Sundström Karin K Dillner Joakim J Rådestad Angelique Flöter AF Gemzell-Danielsson Kristina K Pashayan Nora N Widschwendter Martin M

Nature communications 20220201 1

Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast C ...[more]

PMID: 35105882

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Project description:BackgroundTo explore the diagnostic value of FAM19A4 methylation in high-risk human papilloma virus (hrHPV)-positive cervical samples from Chinese women for estimating cervical cancer or its precancerous lesions.MethodsCervical samples from 215 women infected with high-risk HPV were collected by smear testing. We purposely chose 61 patients with cervical cancer, 57 with high-grade squamous intraepithelial lesions (HSIL), 31 with low-grade squamous intraepithelial lesions (LSIL), and 66 without cervical intraepithelial neoplasia (CIN) after histological confirmation. Taqman probe-based quantitative PCR (qPCR) was utilized to detect the methylation status of FAM19A4 in the cervical samples and further evaluate the use of this gene in the diagnosis of cervical cancer.Results(1) An increasing level of FAM19A4 methylation was detected with increasing progression of cervical lesions, with methylation rates of 10.61%(7/66), 35.48%(11/31), 56.14%(32/57) and 93.44%(57/61) in no CIN, LSIL, HSIL and cervical carcinoma samples respectively. (2) In all hrHPV-positive samples, the levels of FAM19A4 methylation in HPV16/18 groups were higher than that in 12 other hrHPV groups (P < 0.05), but there was no significant difference between two groups after grouping cervical lesions into cervical cancer, HSIL, LSIL and no CIN groups (P>0.05). (3)There were no significant differences of FAM19A4 methylation in different clinicopathological parameters of cervical cancer. (4) Though the sensitivity of FAM19A4 methylation test was inferior to that of cytology and FAM19A4 combining with HPV16/18 genotyping, but showed the best specificity with 81.44% both for detection HSIL alone and ≥ HSIL, with favorable youden index (YI) and area under curve (AUC).ConclusionFAM19A4 is a specific biomarker of cancerous lesions of the cervix. FAM19A4 methylation analysis may serve as an auxiliary screening method for diagnosis of cervical (pre)cancer. However, in consideration of the limitations of this retrospective study, prospective population-based studies are necessary for further confirmation of the diagnostic value of FAM19A4 methylation for detection of cervical (pre)cancer in Chinese women.

Project description:BackgroundAcute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia.ResultsHistone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior.ConclusionThis study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.

Project description:BACKGROUND:Treatment resistance is a major clinical challenge of diffuse large B-cell lymphoma (DLBCL) where approximately 40% of the patients have refractory disease or relapse. Since DLBCL is characterized by great clinical and molecular heterogeneity, the purpose of the present study was to investigate whether miRNAs associated to single drug components of R-CHOP can improve robustness of individual markers and serve as a prognostic classifier. METHODS:Fifteen DLBCL cell lines were tested for sensitivity towards single drug compounds of the standard treatment R-CHOP: rituximab (R), cyclophosphamide (C), doxorubicin (H), and vincristine (O). For each drug, cell lines were ranked using the area under the dose-response curve and grouped as either sensitive, intermediate or resistant. Baseline miRNA expression data were obtained for each cell line in untreated condition, and differential miRNA expression analysis between sensitive and resistant cell lines identified 43 miRNAs associated to growth response after exposure towards single drugs of R-CHOP. Using the Affymetrix HG-U133 platform, expression levels of miRNA precursors were assessed in 701 diagnostic DLBCL biopsies, and miRNA-panel classifiers predicting disease progression were build using multiple Cox regression or random survival forest. Classifiers were validated and ranked by repeated cross-validation. RESULTS:Prognostic accuracies were assessed by Brier Scores and time-varying area under the ROC curves, which revealed better performance of multivariate Cox models compared to random survival forest models. The Cox model including miR-146a, miR-155, miR-21, miR-34a, and miR-23a~miR-27a~miR-24-2 cluster performed the best and successfully stratified GCB-DLBCL patients into high- and low-risk of disease progression. In addition, combination of the Cox miRNA-panel and IPI substantially increased prognostic performance in GCB classified patients. CONCLUSION:As a proof of concept, we found that expression data of drug associated miRNAs display prognostic utility and adding these to IPI improves prognostic stratification of GCB-DLBCL patients treated with R-CHOP.

Dataset Information

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

Publications

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

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