MSR1 – Barrett Esophagus

Germline variants in MSR1 have been implicated in susceptibility to Barrett esophagus (BE), a metaplastic precursor to esophageal adenocarcinoma. BE affects up to 10% of the general population and carries a substantial risk of progression to cancer. Identification of predisposing genes may refine risk stratification and inform surveillance strategies for patients and at-risk relatives.

A genome-wide linkage analysis in 21 concordant BE/adenocarcinoma sibling pairs followed by fine mapping in 176 patients and 200 controls nominated MSR1 among 12 candidate genes. Targeted sequencing in this series revealed germline MSR1 variants in 8 of 116 probands with BE/EAC (6.9%) (PMID:21791690). An independent validation cohort confirmed MSR1 mutations in 2 of 58 cases (3.5%) (PMID:21791690).

The predominant recurrent allele was c.877C>T (p.Arg293Ter), a truncating change seen in both discovery and validation cohorts. A second missense change, c.760C>G (p.Leu254Val), was also observed at lower frequency (PMID:21791690). No MSR1 mutations were detected in ancestry‐matched controls, supporting a role in disease predisposition.

Functional interrogation of MSR1 truncating alleles demonstrated up-regulation of CCND1 protein in peripheral cell lysates. Immunohistochemistry of BE tissues from MSR1 carriers showed increased nuclear CCND1 expression, consistent with dysregulated cell cycle control in the affected epithelium (PMID:21791690). These data support a haploinsufficiency mechanism driving clonal expansion.

To date, no large multigenerational families with clear segregation of MSR1 variants have been reported, limiting segregation evidence. Population frequencies of the truncating allele remain low, and additional studies are required to assess penetrance and modifier effects. There are no published refutations of the MSR1–BE association.

Overall, the association between MSR1 and Barrett esophagus is supported by multiple unrelated probands with recurrent truncating variants and concordant functional data. MSR1 genotyping may inform premorbid risk assessment in patients with familial BE. Further replication in larger cohorts and detailed segregation analyses will strengthen clinical recommendations.

References

• JAMA • 2011 • Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. PMID:21791690

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