Whole-genome sequencing links microglandular adenosis to genomic instability in triple-negative breast cancer

Original abstract

AIMS: A subset of microglandular adenosis (MGA) displays protein expression and molecular genetic alterations similar to those of synchronous triple-negative breast carcinoma (TNBC), supporting the hypothesis that MGA is a non-obligate precursor lesion to a subset of breast carcinomas. Here, we further explore this association in the context of genomic instability. METHODS: We use whole-genome sequencing to investigate the genetic landscape of two unusual cases of MGA associated with carcinoma in the setting of two distinct varieties of genomic instability. RESULTS: The first case describes a patient with Lynch Syndrome developing a low-grade TNBC of the left breast with adenoid cystic-like and MGA-like growth patterns and a contralateral, right breast MGA. Both carcinoma and contralateral MGA showed loss of MSH2 and MSH6 proteins. Molecular studies identified somatic TP53 hotspot mutation only in carcinoma. A germline MSH2 mutation was detected in all samples, and somatic MSH2 pathogenic mutation was detected only in carcinoma components, while the contralateral MGA displayed loss-of-heterozygosity of the wild-type allele, indicating distinct mechanisms of biallelic inactivation of MSH2 between the samples. The second case consists of atypical MGA and associated high-grade TNBC arising in a setting of homologous recombination deficiency (HRD) with molecular signatures suggestive of BRCA2-like/HRD-associated mutational features in addition to shared TP53 alterations. CONCLUSIONS: Genomic instability, either due to mismatch repair protein deficiency or due to HRD, may play a role in MGA, MGA-associated carcinogenesis and distinct morphological patterns.