Genetic Testing Recommended for Patients With Esophageal Adenocarcinoma

The risk of progression from Barrett's esophagus (BE) to adenocarcinoma is less than 1% per year and isn't fully accounted for by clinical factors such as age, sex, obesity, smoking, presence of hiatal hernia, and length of BE.

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Researchers at Massachusetts General Hospital have found that a substantial fraction of individuals whose BE progresses to adenocarcinoma harbor pathogenic germline mutations in cancer-predisposing genes. Minyi Lee, a PhD candidate at Boston University and research associate in the Mass General Division of Gastroenterology, Manish K. Gala, MD, a gastroenterologist in the Division and instructor in Medicine at Harvard Medical School, and colleagues published the details in Gastroenterology.

Discovery Cohorts

The researchers examined data on 640 individuals with esophageal adenocarcinoma who were enrolled in large cohorts analyzed with whole-genome or whole-exome sequencing (the International Cancer Genome Consortium Project Accelerating Research in Genomic Oncology, Cancer Genome Atlas Pan-Cancer Cohort, Broad Institute Esophageal Adenocarcinoma Cohort or Memorial Sloan Kettering Prospective Clinical Cohort).

They discovered pathogenic germline mutations in 59 individuals (9.2%). The most frequently mutated genes were ATM (in 1.6% of individuals) and CHEK2 (1.25%). Five individuals (0.8%) had germline mutations in TP53.

Validation Cohort

To validate the results, the team performed germline whole-exome sequencing on three prospective cohorts at Mass General:

• Patients with BE that had progressed to high-grade dysplasia or intramucosal carcinoma (n=102)
• Patients with BE that had not progressed to dysplasia over ≥10 years (n=75)
• Healthy nonagenarians without any known history of gastrointestinal neoplasia (n=100)

Again, germline ATM mutations were the most frequent pathogenic mutation, detected in 2% of progressors and 2.7% of non-progressors. Immunohistochemistry demonstrated loss of ATM staining among progressors and retained expression among non-progressors, implying epigenetic mechanisms for loss of heterozygosity.

The Role of TP53

Somatic TP53 alterations are a key driver of the progression of nondysplastic BE to dysplasia, and germline TP53 mutations were overrepresented among progressors (0.7%). However, 25% to 30% of esophageal adenocarcinomas lacked somatic alterations in TP53. These TP53 wild-type tumors were significantly enriched for pathogenic germline mutations compared with TP53-mutant cancers (15.9% vs. 6.6%; OR, 2.7; P = 4.2 x 10⁻⁴).

Clinical Implications

The overall enrichment for pathogenic germline mutations suggests they facilitate the progression of BE to adenocarcinoma. Cancer onset in individuals with inherited mutations occured throughout the age spectrum, implying the development of BE and additional environmental factors are required for esophageal carcinogenesis.

Genetic testing has been recommended for all individuals diagnosed with pancreatic adenocarcinoma, who have a 7% to 10% prevalence of germline mutations. Given the similar prevalence detected in this study, universal genetic testing should also be considered for patients diagnosed with esophageal adenocarcinoma.

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