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- Title
Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations.
- Authors
Dopeso, Higinio; Gazzo, Andrea M.; Derakhshan, Fatemeh; Brown, David N.; Selenica, Pier; Jalali, Sahar; Da Cruz Paula, Arnaud; Marra, Antonio; da Silva, Edaise M.; Basili, Thais; Gusain, Laxmi; Colon-Cartagena, Lorraine; Bhaloo, Shirin Issa; Green, Hunter; Vanderbilt, Chad; Oesterreich, Steffi; Grabenstetter, Anne; Kuba, M. Gabriela; Ross, Dara; Giri, Dilip
- 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.
- Subjects
LOBULAR carcinoma; WHOLE genome sequencing; EPIGENOMICS; CELL adhesion; ANOIKIS; EPIGENETICS
- Publication
NPJ Precision Oncology, 2024, Vol 8, Issue 1, p1
- ISSN
2397-768X
- Publication type
Article
- DOI
10.1038/s41698-024-00508-x