About 3.300 women are diagnosed with breast cancer and nearly 500 with ovarian cancer annually in Norway. High-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) both constitute particularly aggressive subtypes. Women carrying BRCA1 germline mutations are at particular risk of developing HGSOC as well as TNBC. However, for the majority of patients with these cancer subtypes the cause of their disease remains unknown.
Recently, we found mosaic BRCA1 promoter methylation in white blood cell (WBC) to be associated with HGSOC (1); however, blood samples were collected from patients already diagnosed with HGSOC, leaving the possibility of confounding factors. Here, we aim to explore constitutional BRCA1 methylation as a risk factor for both incidental TNBC and HGSOC in a larger patient cohort by analysing samples from a large American population-based cohort, the Women’s Health Initiative Study (WHI).Our group has extensive experience with genomic and epigenetic analyses in relation to translational research on cancer and has over the recent years performed several studies assessing SNP variants in respect to cancer risk. Moreover, we will assess the heritability of BRCA1 methylation and characterize the dynamics of methylation early in life, including its potential impact on factors such as gestational length. The main hypothesis of the present proposal is that normal cell BRCA1 promoter methylation is partly an inheritable event, occurring early in life, and leading to significantly elevated risk of high grade serous ovarian cancer as well as triple-negative breast cancer. If this turns out to be correct, the project potentially may generate novel data of profound significance to our understanding of early life events in respect to cancer risk. Importantly, it may lead to improved identification of adult women at increased risk of TNBC and HGSOC, with potential implications to selective screening procedures.