ATM Germline Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics and Potential Therapeutic Implications
Menée à partir de l'analyse du profil génomique et des caractéristiques clinicopathologiques d'adénocarcinomes de la jonction oesogastrique issus de 312 patients ayant bénéficié d'un test génétique, cette étude identifie des variants constitutionnels au niveau du gène ATM, détermine le rôle de ces derniers dans l'oncogenèse et examine les implications thérapeutiques
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.
Journal of the National Cancer Institute , article en libre accès, 2021