ATM Germline-Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics, and Potential Therapeutic Implications. (25th January 2022)

• Record Type: Journal Article
• Authors: El Jabbour, Tony; Misyura, Maksym; Cowzer, Darren; Zimmermann, Michal; Rimkunas, Victoria; Marra, Antonio; Derakhshan, Fatemeh; Selenica, Pier; Parilla, Megan; Setton, Jeremy S; Ceyhan-Birsoy, Ozge; Kemel, Yelena; Catchings, Amanda; Ranganathan, Megha; Ku, Geoffrey Y; Janjigian, Yelena Y; Zinda, Michael; Koehler, Maria; Stadler, Zsofia; Shia, Jinru; Reis-Filho, Jorge S; Mandelker, Diana
• Is Part Of: Journal of the National Cancer Institute. Volume 114:Number 5(2022)
• Page Start: 761
• Page End: 770
• Publication Date: 2022-01-25
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; 616.994
• DOI: 10.1093/jnci/djac024
• Languages: English
• ISSNs: 0027-8874

Abstract

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.