Peripheral blood DNA methylation analysis reveals epigenetic marks associated with hereditary breast and ovarian cancer risk. 231 HBOC patients

Hereditary breast and ovarian cancer syndrome (HBOC) is the most prevalent form of hereditary breast cancer (BC) associated with pathogenic variants in several genes, revealing a significant locus heterogeneity. However, only a fraction of 15-20% of patients with HBOC carry pathogenic coding variants at the genetic level. Therefore, other pathogenic molecular mechanisms could explain the etiopathology of the syndrome. Aberrant germline DNA methylation has been well described as one of the possible causes of the first transcriptional silencing hit of a tumor suppressor gene and a key initiator in BC development. Thus, we aimed to discover novel methylation marks associated with HBOC risk in a Mexican cohort case-control study (231 incident cases negative for pathogenic variants and 156 matched population-based healthy controls) using peripheral blood DNA. We performed a methylation analysis by Bisulfite Sequencing PCR (NGS-Illumina) on an internal panel of 18 tumor suppressor gene promoter regions associated with hereditary breast cancer. We identified 36 aberrant DNA methylation patterns of which 4 marks are potentially associated with hereditary breast cancer risk (FANCI site cg89786999, PALB2 site cg23652916, MSH2 site cg47630224, and EPCAM site cg47596828). We report four novel DNA methylation markers associated with hereditary breast cancer risk with potential application in early hereditary breast cancer detection.