Lobular Carcinomas In Situ Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma

Purpose:Lobular carcinoma in situ (LCIS) is a pre-invasive lesion of the breast. We sought to define its genomic landscape, whether intra-lesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers. Experimental Design: We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically-advanced lesions from 24 patients (nine ductal carcinomas in situ (DCIS), 13 invasive lobular carcinomas (ILCs) and five invasive ductal carcinomas (IDCs)). Somatic genetic alterations, mutational signatures, clonal composition and phylogenetic trees were defined using validated computational methods. Results: WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with CDH1 mutations present in 81% of the lesions. Forty-two percent (18/43) of LCIS were found to be clonally-related to synchronous DCIS and/or ILCs, with clonal evolutionary patterns indicative of clonal selection and/or parallel/branched progression. Intra-lesion genetic heterogeneity was higher among LCIS clonally-related to DCIS/ILC than in those non-clonally related to DCIS/ILC. A shift from aging to APOBEC-related mutational processes was observed in the progression from LCIS to DCIS and/or ILC in a subset of cases. Conclusions:Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a non-obligate precursor of breast cancer. Intra-lesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.