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Death receptor 4 variants and colorectal cancer risk

Bernd Frank1, Kalai Selvi Shanmugam, Lars Beckmann

  • 1Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. b.frank@dkfz.de

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology
|October 13, 2006
PubMed

Insights

The death receptor 4 (DR4) Thr(209)Arg polymorphism may decrease colorectal cancer risk, particularly in males and older adults. Conversely, the DR4 Glu(228)Ala variant shows increased risk in females and advanced cancer stages.

Area of Science:

  • Genetics and Cancer Epidemiology
  • Molecular Biology and Disease Mechanisms

Background:

  • The tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) pathway, involving death receptor 4 (DR4), is crucial for regulating apoptosis.
  • Aberrant apoptosis due to genetic variations in DR4, a candidate tumor suppressor gene, can lead to uncontrolled cell proliferation and increased cancer susceptibility.
  • Previous research has suggested associations between DR4 gene variants and cancer risk, necessitating further investigation.

Purpose of the Study:

  • To investigate the association between two specific DR4 polymorphisms, Thr(209)Arg (626C>G) and Glu(228)Ala (683A>C), and the risk of developing colorectal cancer.
  • To analyze the influence of these DR4 variants on colorectal cancer risk, considering factors such as sex, age, cancer subsite, and disease stage.

Main Methods:

  • Genotyping of 659 incident colorectal cancer cases and 607 healthy controls from the German population-based DACHS study.
  • Evaluation of the Thr(209)Arg and Glu(228)Ala polymorphisms in the DR4 gene.
  • Statistical analysis including odds ratios (OR), 95% confidence intervals (95% CI), stratification by sex and age, subsite analysis, and haplotype analysis.

Main Results:

  • The DR4 Glu(228)Ala polymorphism showed no significant association with colorectal cancer risk overall.
  • DR4 Thr(209)Arg heterozygotes exhibited a significantly decreased risk of colorectal cancer (OR, 0.73).
  • Further analysis revealed decreased risk for male heterozygotes and older individuals (≥65 years) carrying the Thr(209)Arg variant. Conversely, female carriers of the Glu(228)Ala variant showed an increased risk, particularly with advanced disease stages. Haplotype analysis indicated a potential increased risk associated with the 626C-683C haplotype.

Conclusions:

  • The DR4 Thr(209)Arg polymorphism appears to have a protective effect against colorectal cancer, especially in specific demographic groups.
  • The DR4 Glu(228)Ala polymorphism may be associated with an increased risk of colorectal cancer, particularly in females and advanced stages.
  • The 626C-683C DR4 haplotype might play a role in colorectal cancer predisposition, warranting further investigation.

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