Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations

Author:

Dopeso HiginioORCID,Gazzo Andrea M.,Derakhshan FatemehORCID,Brown David N.,Selenica Pier,Jalali Sahar,Da Cruz Paula ArnaudORCID,Marra AntonioORCID,da Silva Edaise M.ORCID,Basili Thais,Gusain Laxmi,Colon-Cartagena Lorraine,Bhaloo Shirin Issa,Green HunterORCID,Vanderbilt Chad,Oesterreich Steffi,Grabenstetter Anne,Kuba M. Gabriela,Ross Dara,Giri Dilip,Wen Hannah Y.,Zhang Hong,Brogi Edi,Weigelt Britta,Pareja FresiaORCID,Reis-Filho Jorge S.

Abstract

AbstractCDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.

Funder

U.S. Department of Health & Human Services | NIH | National Cancer Institute

Breast Cancer Research Foundation

Publisher

Springer Science and Business Media LLC

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