Synapse - ATM germline-mutated gastroesophageal junction adenocarcinomas: Clinical descriptors, molecular characteristics, and potential therapeutic implications

ATM germline-mutated gastroesophageal junction adenocarcinomas: Clinical descriptors, molecular characteristics, and potential therapeutic implications Journal Article

Authors:	El Jabbour, T.; Misyura, M.; Cowzer, D.; Zimmermann, M.; Rimkunas, V.; Marra, A.; Derakhshan, F.; Selenica, P.; Parilla, M.; Setton, J. S.; Ceyhan-Birsoy, O.; Kemel, Y.; Catchings, A.; Ranganathan, M.; Ku, G. Y.; Janjigian, Y. Y.; Zinda, M.; Koehler, M.; Stadler, Z.; Shia, J.; Reis-Filho, J. S.; Mandelker, D.
Article Title:	ATM germline-mutated gastroesophageal junction adenocarcinomas: Clinical descriptors, molecular characteristics, and potential therapeutic implications
Abstract:	Background Gastroesophageal junction (GEJ) adenocarcinoma is a rare cancer associated with poor prognosis. The genetic factors conferring predisposition to GEJ adenocarcinoma have yet to be identified. Methods We analyzed germline testing results from 23 381 cancer patients undergoing tumor-normal sequencing, of which 312 individuals had GEJ adenocarcinoma. Genomic profiles and clinico-pathologic features were analyzed for the GEJ adenocarcinomas. Silencing of ATM and ATR was performed using validated short-interfering RNA species in GEJ, esophageal, and gastric adenocarcinoma cell lines. All statistical tests were 2-sided. Results Pathogenic or likely pathogenic ATM variants were identified in 18 of 312 patients (5.8%), and bi-allelic inactivation of ATM through loss of heterozygosity of the wild-type allele was detected in all (16 of 16) samples with sufficient tumor content. Germline ATM-mutated GEJ adenocarcinomas largely lacked somatic mutations in TP53, were more likely to harbor MDM2 amplification, and harbored statistically significantly fewer somatic single nucleotide variants (2.0 mutations/Mb vs 7.9 mutations/Mb; P < .001). A statistically significantly higher proportion of germline ATM-mutated than ATM-wild-type GEJ adenocarcinoma patients underwent a curative resection (10 [100%] vs 92 [86.8%], P = .04; Fisher's exact test.), A synthetic lethal interaction between short-interfering RNA silencing of ATM and ATR was observed in the models analyzed. Conclusions Our results indicate that germline pathogenic variants in ATM drive oncogenesis in GEJ adenocarcinoma and might result in a distinct clinical phenotype. Given the high prevalence of germline ATM-mutated GEJ adenocarcinomas, genetic testing for individuals with GEJ adenocarcinomas may be considered to better inform prognostication, treatment decisions, and future cancer risk.
Keywords:	gene; phosphorylation; carcinoma; esophageal; mutations; breast-cancer; impact; inhibition; tp53; rising incidence
Journal Title:	JNCI: Journal of the National Cancer Institute
Volume:	114
Issue:	5
ISSN:	0027-8874
Publisher:	Oxford University Press
Date Published:	2022-05-01
Start Page:	761
End Page:	770
Language:	English
ACCESSION:	WOS:000765951000001
DOI:	10.1093/jnci/djac024
PROVIDER:	wos
PMCID:	PMC9086803
PUBMED:	35078243
Notes:	Article -- Source: Wos