Genomic alterations in normal breast tissues preceding breast cancer diagnosis.

Abstract

Background: Normal breast tissues adjacent to cancer often harbor many of the same genomic alterations as the cancer itself. However, it remains unclear whether histologically normal breast tissues carry genomic changes related to cancer development years before a cancer diagnosis.

Methods: Whole exome sequencing was performed to examine germline and somatic alterations in histologically normal breast tissues from women who subsequently developed breast cancer (n = 79, pre-diagnosis tissues) and compared these with results from breast tissues of women who did not (n = 81). No patient had germline mutations in cancer predisposition genes.

Results: The pre-diagnosis tissues had significantly more high functional impact germline variants per sample than the healthy controls (P = 0.034), 36.5% of affected genes were cancer hallmark genes, among these 62.4% were involved with evading growth suppressors and 5.7% with genome instability. The average number of somatic mutations were similar between the two cohorts. Mutation signature analysis revealed COSMIC signatures 3 (associated with impaired homologous recombination) as a dominant signature more frequent in pre-diagnosis tissues. At gene and variant level, nine common germline polymorphisms in two immune regulatory genes, FCGBP and TPSBP2, and along with three somatic mutations in F13A1, FRY and TMLHE, were significantly more frequently mutated in the pre-diagnosis samples.

Conclusions: Individuals who develop breast cancer have a higher germline variant burden in normal breast tissues leading to subtle deficiencies in DNA repair that in the context of other germline and somatic mutations could facilitate malignant transformation.