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

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

Authors:	Dopeso, H.; Gazzo, A. M.; Derakhshan, F.; Brown, D. N.; Selenica, P.; Jalali, S.; Da Cruz Paula, A.; Marra, A.; da Silva, E. M.; Basili, T.; Gusain, L.; Colon-Cartagena, L.; Bhaloo, S. I.; Green, H.; Vanderbilt, C.; Oesterreich, S.; Grabenstetter, A.; Kuba, M. G.; Ross, D.; Giri, D.; Wen, H. Y.; Zhang, H.; Brogi, E.; Weigelt, B.; Pareja, F.; Reis-Filho, J. S.
Article Title:	Genomic and epigenomic basis of breast invasive lobular carcinomas lacking CDH1 genetic alterations
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. © The Author(s) 2024.
Keywords:	immunohistochemistry; controlled study; human tissue; unclassified drug; promoter region; somatic mutation; clinical feature; histopathology; phenotype; cell viability; homologous recombination; reverse transcription polymerase chain reaction; protein depletion; uvomorulin; dna methylation; messenger rna; epigenetics; fusion gene; cell migration; cell adhesion; chromosome loss; loss of function mutation; genomic dna; chromosome 16q; lobular carcinoma in situ; axin; axin 2; fusion protein; copy number variation; nucleic acid base substitution; indel mutation; catenin; estrogen receptor positive breast cancer; human epidermal growth factor receptor 2 positive breast cancer; anoikis; human; article; whole genome sequencing; three dimensional cell culture; estrogen receptor negative breast cancer; droplet digital polymerase chain reaction; oncogenomics; crispr-cas9 system; mcf-7 cell line; gene knockout; human epidermal growth factor receptor 2 negative breast cancer; mrna expression level; ductal breast carcinoma in situ; invasive lobular breast carcinoma; estrogen receptor-positive, her2-negative breast cancer; ctnnd1 protein; methylation specific polymerase chain reaction; nonsynonymous substitution
Journal Title:	npj Precision Oncology
Volume:	8
ISSN:	2397-768X
Publisher:	Springer Nature
Date Published:	2024-02-12
Start Page:	33
Language:	English
DOI:	10.1038/s41698-024-00508-x
PROVIDER:	scopus
PMCID:	PMC10861500
PUBMED:	38347189
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85185133847&doi=10.1038%2fs41698-024-00508-x&partnerID=40&md5=0b1adc1b6eddcac31ab99b0e406f375b
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK authors: Jorge S. Reis-Filho -- Source: Scopus