Germline Mutations in MSR1, ASCC1, and CTHRC1 in Patients With Barrett Esophagus and Esophageal Adenocarcinoma

The incidence of esophageal adenocarcinoma (EAC) in the United States and Europe has increased 350% since 1970, with uncertain etiology.1 Although early-stage EAC is curable, most cases are detected at an advanced stage with poor survival. Esophageal adenocarcinoma is believed to be preceded by Barrett esophagus (BE), a premalignant metaplasia caused by chronic gastroesophageal reflux disease (GERD).2–6 GERD-related inflammation and the transforming growth factor β (TGFB) pathway have been implicated in sporadic BE and EAC, just as the role of inflammation has become prominent in a range of human cancers.7 Although acknowledged, the role of inflammation in BE and EAC has not been thoroughly studied.8 Barrett esophagus is common in the general population, estimated to occur in 1% to 10%6; it develops in 12% to 15% of patients with GERD.5 The risk of EAC in patients with BE is approximately 0.4% per year.9 Although most BE and EAC are believed to be sporadic, genetic (heritable) etiologies have been supported by observation of familial clustering of cases noted over several decades, although few large families co-segregating BE/EAC have been reported.10,11 In 1 referral series, clinical epidemiologic analyses suggest 7% of individuals with BE, EAC, or both have at least 1 affected blood relative.12 Although shared environmental factors may contribute to such familial aggregation, an autosomal dominant mode of inheritance with incomplete penetrance is consistent with most published studies, and rare reported cases are consistent with autosomal recessive inheritance.10 The discovery of germline mutations in a gene or genes that predispose to BE/EAC may have ramifications regarding cancer risk assessment, genetic counseling, premorbid diagnosis, and targeted surveillance and management, and also add to the fundamental understanding of the pathophysiology of sporadic BE and EAC. We therefore sought to identify a gene or genes associated with BE/EAC predisposition.