TGFBR2 and BAX mononucleotide tract mutations, microsatellite instability, and prognosis in 1072 colorectal cancers

Background: Mononucleotide tracts in the coding regions of the TGFBR2 and Bax genes are commonly mutated in microsatellite instability-high (MSI-high) colon cancers. The receptor TGFBR2 plays an important role in the TGFB1 (transforming growth factor-β, TGF-β) signaling pathway, and Bax plays a key role in Apoptosis. However, a role of TGFBR2 or Bax mononucleotide mutation in colorectal Cancer as a prognostic biomarker remains uncertain.

Methodology/principal findings: We utilized a database of 1072 rectal and colon cancers in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study). COX proportional hazards model was used to compute mortality hazard ratio (HR), adjusted for clinical, pathological and molecular features including the CpG island methylator phenotype (CIMP), LINE-1 methylation, and KRAS, BRAF and PIK3CA mutations. MSI-high was observed in 15% (162/1072) of all colorectal cancers. TGFBR2 and Bax mononucleotide mutations were detected in 74% (117/159) and 30% (48/158) of MSI-high tumors, respectively. In Kaplan-Meier analysis as well as univariate and multivariate COX regression analyses, compared to microsatellite stable (MSS)/MSI-low cases, MSI-high cases were associated with superior colorectal cancer-specific survival [adjusted HR, 0.34; 95% confidence interval (CI), 0.20-0.57] regardless of TGFBR2 or Bax mutation status. Among MSI-high tumors, TGFBR2 mononucleotide mutation was associated with CIMP-high independent of Other variables [multivariate odds ratio, 3.57; 95% CI, 1.66-7.66; p = 0.0011].

Conclusions: TGFBR2 or Bax mononucleotide mutations are not associated with the patient survival outcome in MSI-high colorectal Cancer. Our data do not support those mutations as prognostic biomarkers (beyond MSI) in colorectal carcinoma.