Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

It is largely unknown how the risk of development of breast cancer is transduced by somatic genetic alterations. To address this lacuna of knowledge and acknowledging that benign breast disease (BBD) is an established risk factor for breast cancer, we established a case-control study: The Benign Breast & Cancer Risk (BBCAR) Study. Cases are women with BBD who developed subsequent invasive breast cancer (IBC) at least 3 years after the biopsy and controls are women with BBD who did not develop IBC (median follow-up 16.6 years). We selected 135 cases and individually matched controls (1:2) to cases based on age and type of benign disease: non-proliferative or proliferation without atypia. Whole exome sequencing was performed on DNA from the benign lesions and from subsets with available germline DNA or tumor DNA. Although the number of cases and controls with copy number variation data is limited, several amplifications and deletions are exclusive to the cases. In addition to two known mutational signatures, a novel signature was identified that is significantly (p=0.007) associated with triple negative breast cancer. The somatic mutation rate in benign lesions is similar to that of invasive breast cancer and does not differ between cases and controls. Two mutated genes are significantly associated with time to the diagnosis of breast cancer, and mutations shared between the benign biopsy tissue and the breast malignancy for the ten cases for which we had matched pairs were identified. BBD tissue is a rich source of clues to breast oncogenesis.\n\nOne Sentence SummaryGenetic aberrations in benign breast lesions distinguish breast cancer cases from controls and predict cancer risk.