A missense variant in PTPN12 associated with the risk of colorectal cancer by modifying Ras/MEK/ERK signaling

Cancer Epidemiol. 2019 Apr:59:109-114. doi: 10.1016/j.canep.2019.01.013. Epub 2019 Feb 4.

Abstract

Background: The classical protein tyrosine phosphatases (PTPs) have been widely reported to be associated with various human malignancies including colorectal cancer (CRC). However, there are few comprehensive analyses of the association between the classical PTP genes and CRC risk.

Methods: First, a bioinformatics analysis was performed to identify missense variants within the classical PTP gene family. Second, exome-wide association data and an independent population study were conducted to evaluate effects of candidate variants on CRC risk. Finally, functional assays based on signaling pathways were applied to uncover the potential pathogenic mechanism.

Results: We identified that PTPN12 rs3750050 G allele presented a 19% increase the risk of CRC, with an OR of 1.19 (95% CI = 1.09-1.30, P = 1.015×10-4) under an additive model in the combined analysis. Furthermore, biochemical assays illustrated that rs3750050 could impair the inhibitory effect of PTPN12 on Ras/MEK/ERK signaling by impeding SHC dephosphorylation, increase the expression of cyclin D1 and ultimately lead to aberrant cell proliferation, thus contributing to CRC pathogenesis.

Conclusion: Our study highlights that PTPN12 rs3750050 could increase CRC risk by modifying Ras/MEK/ERK signaling. This work provides a novel insight into the roles of genetic variants within PTP genes in the pathogenesis of CRC.

Keywords: Colorectal cancer (CRC); PTPN12; Phosphorylation; Protein tyrosine phosphatases (PTPs); rs3750050.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • MAP Kinase Signaling System
  • Male
  • Middle Aged
  • Mutation, Missense
  • Oncogene Protein p21(ras) / metabolism
  • Phosphorylation
  • Polymorphism, Single Nucleotide*
  • Protein Processing, Post-Translational*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12 / metabolism
  • Signal Transduction*

Substances

  • PTPN12 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 12
  • Oncogene Protein p21(ras)