Microglandular adenosis, triple negative breast carcinoma and DNA repair defects

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.