Mosaic BRCA1 promoter methylation contribution in hereditary breast/ovarian cancer pedigrees

Purpose Mosaic BRCA1 promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed. Patients Blood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1/2, PALB2 or RAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATM and BARD1), and 8 of 18 others (44%) carried BRCA1meth (vs none of the 20 age-matched controls). Involvement of BRCA1 in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectable BRCA1meth in blood, including one with high methylation levels in two non-tumour tissues. Conclusions The high prevalence of mosaic BRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.

[1]  P. Kristel,et al.  Homologous recombination deficiency derived from whole-genome sequencing predicts platinum response in triple-negative breast cancers , 2023, Nature Communications.

[2]  P. Nederlof,et al.  Identifying the BRCA1 c.-107A > T variant in Dutch patients with a tumor BRCA1 promoter hypermethylation , 2022, Familial Cancer.

[3]  P. Lønning,et al.  Constitutional BRCA1 Methylation and Risk of Incident Triple-Negative Breast Cancer and High-grade Serous Ovarian Cancer , 2022, JAMA oncology.

[4]  D. Easton,et al.  CanRisk Tool—A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants , 2020, Cancer Epidemiology, Biomarkers & Prevention.

[5]  L. Saal,et al.  Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers , 2020, Nature Communications.

[6]  François-Clément Bidard,et al.  ShallowHRD: detection of homologous recombination deficiency from shallow whole genome sequencing , 2020, Bioinform..

[7]  A. Laner,et al.  Analysis of 3297 individuals suggests that the pathogenic germline 5′-UTR variant BRCA1 c.-107A > T is not common in south-east Germany , 2020, Familial Cancer.

[8]  A. Jakubowska,et al.  BRCA1 promoter methylation in peripheral blood is associated with the risk of triple‐negative breast cancer , 2020, International journal of cancer.

[9]  M. Southey,et al.  Integrating DNA methylation measures to improve clinical risk assessment: are we there yet? The case of BRCA1 methylation marks to improve clinical risk assessment of breast cancer , 2020, British Journal of Cancer.

[10]  M. García-Closas,et al.  Correction: BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors , 2019, Genetics in Medicine.

[11]  Leslie Burke,et al.  Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition , 2018, Cancers.

[12]  P. Lønning,et al.  BRCA1 methylation in newborns: genetic disposition, maternal transfer, environmental influence, or by chance only? , 2018, Clinical Epigenetics.

[13]  Javier Santoyo-Lopez,et al.  A Dominantly Inherited 5′ UTR Variant Causing Methylation-Associated Silencing of BRCA1 as a Cause of Breast and Ovarian Cancer , 2018, American journal of human genetics.

[14]  A. Howell,et al.  White Blood Cell BRCA1 Promoter Methylation Status and Ovarian Cancer Risk , 2018, Annals of Internal Medicine.

[15]  F. Couch,et al.  Author Correction: The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk , 2017, npj Breast Cancer.

[16]  Robert Huether,et al.  Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer , 2017, JAMA oncology.

[17]  Steven N. Hart,et al.  The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk , 2017, npj Breast Cancer.

[18]  Li Zhang,et al.  Association of BRCA1 promoter methylation with sporadic breast cancers: Evidence from 40 studies , 2015, Scientific Reports.

[19]  Kenneth Offit,et al.  Two Decades After BRCA: Setting Paradigms in Personalized Cancer Care and Prevention , 2014, Science.

[20]  T. Haaf,et al.  Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer , 2012, Human molecular genetics.

[21]  S. Fox,et al.  Constitutional Methylation of the BRCA1 Promoter Is Specifically Associated with BRCA1 Mutation-Associated Pathology in Early-Onset Breast Cancer , 2010, Cancer Prevention Research.

[22]  A. Dobrovic,et al.  Methylation-sensitive high resolution melting (MS-HRM): a new approach for sensitive and high-throughput assessment of methylation , 2007, Nucleic acids research.

[23]  J. Hopper,et al.  Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. , 2003, American journal of human genetics.