Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations
Higinio Dopeso, Andrea Gazzo, Fatemeh Derakhshan, David N. Brown, Pier Selenica, Sahar Jalali, Arnaud Da Cruz Paula, Antonio Marra, Edaise M. da Silva, Thais Basili, Laxmi Gusain, Lorraine Colon-Cartagena, Shirin Issa Bhaloo, Hunter Green, Chad Vanderbilt, Steffi Oesterreich, Anne Grabenstetter, M. Gabriela Kuba, Dara S. Ross, Dilip D. Giri, Hannah Y. Wen, Hong Zhang, Edi Brogi, Britta Weigelt, Fresia Pareja, Jorge S. Reis‐Filho
Abstract
CDH1 (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.