Germline variation in homologous recombination repair genes in Hispanic/Latina women to predict breast cancer risk and response to treatment

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

ABSTRACT Breast cancer (BC) is a heritable disease with 10 known high- and intermediate-penetrance genes and several hundred common genetic variants associated with risk to develop disease. Most of the genes known to affect BC risk, such as BRCA1, BRCA2 and PALB2, are part of the homologous recombination repair (HRR) pathway. However, there are still additional genes to be identified that increase risk, and we hypothesize that some of these additional genes are in the HRR pathway. Moreover, drugs that inhibit poly-adenosine diphosphate-ribose polymerase (PARP) and platinum-based chemotherapy are extremely effective in patients with pathogenic genetic variants that cause HRR deficiency. Therefore, identifying other genes in this pathway has important implications for genetic cancer risk assessment for prevention, early detection, and treatment. Hispanic/Latina (H/L) women and other minority populations are limited in participating in genetic studies. We recently completed a large sequencing study of breast cancer among H/L women that included over 4,000 cases and 4,000 controls. In that study, we identified a strong association between loss-of-function (LoF) variants in FANCM and estrogen-receptor (ER)-negative breast cancer, as well as with known breast cancer genes. FANCM is involved in initiating the HRR pathway. We also identified suggestive associations with other genes in HRR and breast cancer risk including ATR. Therefore, we propose to focus on genes in HRR in H/L women using a larger dataset. Our objective is to improve genetic risk assessment for breast cancer in H/L women. In Aim 1, we will discover additional variants in HRR genes associated with BC in H/L women, expanding our numbers to include ~12,000 H/L breast cancer cases and ~30,000 controls. We will use a novel deep-learning approach to classify missense variants in order to improve power for discovery. In Aim 2, we will characterize the effects of LoF variants in FANCM and other novel HRR genes on the somatic mutational landscape in tumors. Using cell line models, we will measure the effects of LoF variants on DNA repair and on treatment response to PARP inhibitors and platinum-based therapies. In addition, we will evaluate the LoF variants in FANCM for their effects in repair of stalled replication forks and protection of common fragile sites. In Aim 3, we will assess the joint association of breast cancer polygenic risk scores (PRS) and pathogenic variants in breast cancer susceptibility genes and risk of developing breast cancer. Impact: H/L women have poorer outcomes from breast cancer compared to Non-H/L White women yet are under-studied for genomics of breast cancer. This exacerbates disparities and increases mortality rates because there are insufficient data for identifying many women at the highest risk of breast cancer. Insufficient data also limit prevention efforts and the identification of women who may benefit from targeted therapy once they develop breast cancer. Our study will provide much-needed data to improve risk prediction and provide tools for clinicians to detect BC earlier. Our findings also may be important to guide therapy for women carrying HRR gene variants.