Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility

Carcinogenesis. 2010 Sep;31(9):1612-9. doi: 10.1093/carcin/bgq146. Epub 2010 Jul 7.

Abstract

Genetic susceptibility accounts for approximately 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value < 10(-3)). The risk of CRC increased significantly with an increasing number of risk alleles in seven genes involved in MAPK signalling events (P(trend) = 2.2 x 10(-16), OR(per allele) = 1.34, 95% CI 1.11-1.61).

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / genetics*
  • European Continental Ancestry Group / genetics*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Germany / epidemiology
  • Humans
  • Mitogen-Activated Protein Kinases / genetics*
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide / genetics*
  • Prognosis
  • Risk Factors
  • Signal Transduction / genetics*

Substances

  • Mitogen-Activated Protein Kinases