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

Abstract

Lobular carcinoma (LCIS) is a preinvasive lesion of the breast. We sought to define its genomic landscape, whether intralesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers. 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 [9 ductal carcinomas (DCIS), 13 invasive lobular carcinomas (ILC), and 5 invasive ductal carcinomas (IDC)]. Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic trees were defined using validated computational methods. WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with 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. Intralesion genetic heterogeneity was higher among LCIS clonally related to DCIS/ILC than in those nonclonally 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. Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a nonobligate precursor of breast cancer. Intralesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.

Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B

“…Third, A3B overexpression triggers strong DNA damage responses and overt cytotoxicity (Burns, Lackey, et al, 2013;Nikkila et al, 2017;Serebrenik et al, 2019;Taylor et al, 2013;Yamazaki et al, 2020). Fourth, A3B expression correlates positively with APOBEC signature mutation loads in breast cancer (Burns, Lackey, et al, 2013), and its overexpression associates with branched evolution in breast and lung cancer (E. C. de Bruin et al, 2014;Lee et al, 2019;Roper et al, 2019). Fifth, A3B expression is induced by human papillomavirus (HPV) and polyomavirus (PyV) infections, which relates to the fact that many cervical, head/neck, and bladder cancers have high proportions of APOBEC signature mutations (Gillison et al, 2019;Henderson, Chakravarthy, Su, Boshoff, & Fenton, 2014;Starrett et al, 2019;Verhalen, Starrett, Harris, & Jiang, 2016;Vieira et al, 2014).…”

The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas

“…To infer the clonal relatedness between the histologically distinct components of each MBC (n=11) and UCS (n=6), we defined the "clonality index" (CI) as the probability of two lesions sharing mutations not expected to have co-occurred by chance based on a previously validated method [43] (see Supplementary Methods).…”

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

“…Yet the level of intra-tumoural heterogeneity seen within precursor lesions of an individual specimen points to a more complex situation. For instance, within a surgical specimen both DCIS and LCIS can exhibit morphological (e.g., different grades/level of differentiation) and biological (e.g., variable expression of ER, PR, HER2, Ki67) heterogeneity as well as evidence of subclonal genomic diversity [52][53][54]; these lesions can also co-exist, even admixed within the same duct ( Figures 2C and 3). Whilst a linear process of evolution might occur, there is more likely a complex array of parallel/branching clones evolving within the normal ductal structure, and that this probably arises from an underlying bed of genetic instability already present in normal breast epithelium (Figures 2 and 3).…”