Prenatal BRCA1 methylation and breast and ovarian cancer risk.

In 2022, we have completed one of the two major goals of this project. Thus, in the first part of this project, evaluating risk of triple negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC), in collaboration with the US Women health Initiative (WHI) we have successfully analyzed WBC methylation status among healthy women subsequently developing TNBC or HGSOC and controls in a nested case – control design. Doing so, we found methylation of the BRCA1 (breast cancer type-1 gene) methylation to be associated with an elevated risk of both cancer forms, with a HR of 2.4 for TNBC and 1.8 for HGSOC. The results have been reported in a high-impact peer-reviewed medical journal (the JAMA Oncology). Importantly; while in previous studies investigators have explored WBC BRCA1 methylation status among individuals already diagnosed with a TNBC or HGSOC, meaning they could not preclude tumour-initiated secondary effects, we found BRCA1 methylation to predict a significantly elevated risk of both cancer forms > 5 years after WBC DNA sampling. These findings contributes important novel information to our understanding of the risk of these cancer forms. As for the second part of the project, determining BRCA1 methylation among newborns and their parents, this part of the project has suffered from major delays due to logistic problems related to the Covid epidemic. However, we now have completed analysis of a large cohort of newborn girls and their parents, and have obtained important preliminary information. As for the last part of the project, currently we are analyzing BRCA1 methylation status among twins. The final analysis in the project we aim at completing during the spring of 2023, by which time we should have data significantly adding to our understanding (genetic risk, versus environmental influence and / or random variation only) before publishing.The results from the first part of the study were reported in JAMA Oncology in the autumn of 2022 (Lønning et al), and a follow-up paper is under review. Further, we reveal allele-spesific methylation with concordance between methylated tumour cells and white blood cells. According to this work, constitutional BRCA1 methylation seems to be the initial triggering event in about 20% of all triple-negative breast cancer. Regarding early life events as the biological cause of the methylation, we have been able to generate important preliminary data, to be taken into a final study assessing these mechanisms (has been suffering delays in collecting adequate twin samples, as we need spesific information related to perinatal events, including chorionic status in monozygotes).

Resultatene fra studien er konseptuelle, i det de, for første gang, viser at konstitusjonell methylering av BRCA1 genet (methylering som inntreffer i normalvev i kroppen før fødselen) er en årsak til trippel-negativ brystkreft samt høygradig malign eggstokkreft. Vi må anta at tilsvarende effekter gjelder or andre gener i relasjon til andre kreftsykdommer, og at funnene på sikt vil ha stor innvirkning på vår forståelse av årsakene til flere kreftsykdommer.

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.