J Natl Cancer Inst. 2022 Jan 25:djac024. doi: 10.1093/jnci/djac024. Online ahead of print.
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 (siRNA) species in GEJ, esophageal and gastric adenocarcinoma cell lines. All statistical tests were 2-sided.
RESULTS: Pathogenic/likely pathogenic ATM variants were identified in 18 of 312 patients (5.8%), and bi-allelic inactivation of ATM through loss of heterozygosity (LOH) 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 siRNA 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.
PMID:35078243 | DOI:10.1093/jnci/djac024
