Abstract
It is largely unknown how the development of breast cancer (BC) is transduced by somatic genetic alterations in the benign breast. Since benign breast disease is an established risk factor for BC, we established a case-control study of women with a history of benign breast biopsy (BBB). Cases developed BC at least one year after BBB and controls did not develop BC over an average of 17 years following BBB. 135 cases were matched to 69 controls by age and type of benign change: non-proliferative or proliferation without atypia (PDWA). Whole-exome sequencing (WES) was performed for the BBB. Germline DNA (available from n = 26 participants) was utilized to develop a mutation-calling pipeline, to allow differentiation of somatic from germline variants. Among the 204 subjects, two known mutational signatures were identified, along with a currently uncatalogued signature that was significantly associated with triple negative BC (TNBC) (p = 0.007). The uncatalogued mutational signature was validated in 109 TNBCs from TCGA (p = 0.001). Compared to non-proliferative samples, PDWA harbors more abundant mutations at PIK3CA pH1047R (p < 0.001). Among the 26 BBB whose somatic copy number variation could be assessed, deletion of MLH3 is significantly associated with the mismatch repair mutational signature (p < 0.001). Matched BBB-cancer pairs were available for ten cases; several mutations were shared between BBB and cancers. This initial study of WES of BBB shows its potential for the identification of genetic alterations that portend breast oncogenesis. In future larger studies, robust personalized breast cancer risk indicators leading to novel interception paradigms can be assessed.
Highlights
From 1989 to 2016 the mortality rate for breast cancer (BC) in the United States decreased by 40%1, a testament to the efficacy of targeted therapies, as well as to combinations and schedules of chemotherapeutics
Of the 1.7 million breast biopsies each year in the U.S.10, about 75%. Of these return a diagnosis of benign breast disease, including atypical hyperplasia[9]. This provides a window into the somatic genetic environment of the breast, prompting us to evaluate the genetic landscape of benign breast biopsy (BBB), and identify patterns associated with subsequent malignancy
In addition to profiling the overall BBB mutational landscape, we have determined that mutations differ as a function of the type of benign breast disease, that the PIK3CA pH1047R hotspot mutation is more frequent in proliferative disease without atypia (PDWA) compared to non-proliferative disease (p < 0.001); our data reveals a presently uncatalogued mutational signature associated with triple negative BC (TNBC) (p = 0.007), which was validated in 109 TCGA TNBC samples (p = 0.001); and we observed multiple recurrent copy number variations (CNVs), including a MLH3 deletion, which is significantly associated with a mismatch repair signature (p < 0.001)
Summary
From 1989 to 2016 the mortality rate for breast cancer (BC) in the United States decreased by 40%1, a testament to the efficacy of targeted therapies, as well as to combinations and schedules of chemotherapeutics. Of these return a diagnosis of benign breast disease, including atypical hyperplasia[9] This provides a window into the somatic genetic environment of the breast, prompting us to evaluate the genetic landscape of benign breast biopsy (BBB), and identify patterns associated with subsequent malignancy. The focus on non-atypical lesions was a deliberate choice as nonatypical lesions predict a generalized risk of subsequent breast cancer, occurring frequently in both breasts[9]. They are far more common than atypical changes, comprising over 90% of all breast biopsies[21], so that elucidation of their molecular profiles will impact the majority of women who undergo BBB. AClass 1/non-proliferative: “Non-proliferation” and “Benign, NOS”. bClass 2/proliferative: “Proliferative lesion without atypia” (includes nonatypical hyperplasia, radial scar, sclerosing adenosis)
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