CHEK2 variant I157T may be associated with increased breast cancer risk

Int J Cancer. 2004 Sep 10;111(4):543-7. doi: 10.1002/ijc.20299.

Abstract

Cell cycle checkpoint kinase 2 (CHEK2) is a transducer of cellular responses to DNA damage. The CHEK2 1100delC has previously been shown to be a low-penetrance breast cancer susceptibility allele. We have evaluated the role of another CHEK2 variant, I157T in the FHA domain of the gene, for association with breast cancer. I157T was found at a significantly higher frequency in the population-based series of breast cancer patients (77/1035, 7.4%, odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.06-1.95, p = 0.021) than among population controls (100/1885, 5.3%). The frequency in the familial breast cancer patients was not elevated (28/507, 5.5%, OR = 1.04, 95% CI = 0.68-1.61). The I157T protein, that undermines cellular responses to ionizing radiation and shows deficiency in substrate recognition in vivo, was expressed at normal level in tumor tissues as well as in cultured cells. The I157T protein was stable and it dimerized with the wild-type CHEK2 co-expressed in human cells. These functional properties of the I157T protein suggest that this variant may have negative effect on the pool of normal CHEK2 protein in heterozygous carrier cells by formation of heterodimers with wild-type CHEK2. The I157T variant may be associated with breast cancer risk, but the risk is lower than for 1100delC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / etiology*
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • Checkpoint Kinase 2
  • DNA Damage
  • DNA Replication
  • Female
  • Genes, Tumor Suppressor
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Humans
  • Immunohistochemistry
  • Odds Ratio
  • Protein-Serine-Threonine Kinases / genetics*
  • Radiation Tolerance

Substances

  • Checkpoint Kinase 2
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases