CTHRC1 – Barrett Esophagus

Germline analysis in 116 white Barrett esophagus (BE) and esophageal adenocarcinoma (EAC) cases versus 200 ancestry-matched controls identified a single missense variant in CTHRC1, c.131A>C (p.Gln44Pro), in 1 of 116 cases and absent in controls (PMID:21791690). No additional CTHRC1 variants were found in the independent validation series of 58 cases, and no segregation data are available. These findings support an autosomal dominant predisposition model with limited genetic evidence for CTHRC1 in BE.

Although CTHRC1 is implicated in extracellular matrix remodeling and pro-proliferative signaling, BE-specific functional studies are lacking. In hepatocellular carcinoma, CTHRC1 hypomethylation drives Hep3B2.1 cell proliferation, migration, and invasion (PMID:39134747), and in murine bone models, Phlpp1 deficiency upregulates Cthrc1 to enhance osteoblast mineralization (PMID:31189651). However, these data are not BE-specific, and no rescue or in vivo BE models have been reported.

Key take-home: Current evidence is insufficient to establish CTHRC1 as a monogenic risk gene for Barrett esophagus, and further genetic and functional studies are required to clarify its role.

References

• JAMA • 2011 • Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. PMID:21791690
• Discover oncology • 2024 • CTHRC1 modulates cell proliferation and invasion in hepatocellular carcinoma by DNA methylation. PMID:39134747
• The Journal of biological chemistry • 2019 • Deficiency in the phosphatase PHLPP1 suppresses osteoclast-mediated bone resorption and enhances bone formation in mice. PMID:31189651

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