A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer.

CHEK2 (previously known as "CHK2") is a cell-cycle-checkpoint kinase that phosphorylates p53 and BRCA1 in response to DNA damage. A protein-truncating mutation, 1100delC in exon 10, which abolishes the kinase function of CHEK2, has been found in families with Li-Fraumeni syndrome (LFS) and in those with a cancer phenotype that is suggestive of LFS, including breast cancer. In the present study, we found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer. This was slightly, but not significantly (P=.182), higher than the 1.4% frequency found among 1,885 population control subjects. However, a significantly elevated frequency was found among those 358 patients with a positive family history (11/358 [3.1%]; odds ratio [OR] 2.27; 95% confidence interval [CI] 1.11-4.63; P=.021, compared with population controls). Furthermore, patients with bilateral breast cancer were sixfold more likely to be 1100delC carriers than were patients with unilateral cancer (95% CI 1.87-20.32; P=.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 and BRCA2 mutations confirmed a significantly elevated frequency of 1100delC (28/507 [5.5%]; OR 4.2; 95% CI 2.4-7.2; P=.0002), compared with controls, with a high frequency also seen in patients with only a single affected first-degree relative (18/291 [6.2%]). Finally, tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations show reduced CHEK2 immunostaining. The results suggest that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer-including families with only two affected relatives, which are more common than families that include larger numbers of affected women.

[1]  A Sajantila,et al.  Identification of individuals by analysis of biallelic DNA markers, using PCR and solid-phase minisequencing. , 1993, American journal of human genetics.

[2]  O. Kallioniemi,et al.  Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: evidence for additional susceptibility genes. , 1997, Human molecular genetics.

[3]  S. Elledge,et al.  Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. , 1998, Science.

[4]  B. Ponder,et al.  A Systematic Review Of Genetic Polymorphisms and Breast Cancer Risk 1 , 2000 .

[5]  K. Isselbacher,et al.  Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. , 1999, Science.

[6]  T. Halazonetis,et al.  Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. , 2000, Genes & development.

[7]  Jong-Soo Lee,et al.  hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response , 2000, Nature.

[8]  H. Konishi,et al.  Histological type-selective, tumor-predominant expression of a novel CHK1 isoform and infrequent in vivo somatic CHK2 mutation in small cell lung cancer. , 2000, Cancer research.

[9]  S. Elledge,et al.  Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[10]  H. Nevanlinna,et al.  Familial breast cancer in southern Finland: how prevalent are breast cancer families and can we trust the family history reported by patients? , 2000, European journal of cancer.

[11]  K Holli,et al.  Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. , 2000, Journal of the National Cancer Institute.

[12]  Y Taya,et al.  The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. , 2000, Genes & development.

[13]  S. Elledge,et al.  The DNA damage response: putting checkpoints in perspective , 2000, Nature.

[14]  M. Kastan,et al.  The many substrates and functions of ATM , 2000, Nature Reviews Molecular Cell Biology.

[15]  Carl W. Miller,et al.  Analysis of the CHK2 Gene in Lymphoid Malignancies , 2001, Leukemia & lymphoma.

[16]  Jing Chen,et al.  Characterization of Tumor-associated Chk2 Mutations* , 2001, The Journal of Biological Chemistry.

[17]  D. Sgroi,et al.  Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. , 2001, Cancer research.

[18]  W. Hofmann,et al.  Mutation analysis of the DNA-damage checkpoint gene CHK2 in myelodysplastic syndromes and acute myeloid leukemias. , 2001, Leukemia research.

[19]  J. Bartek,et al.  Chk2 tumour suppressor protein in human spermatogenesis and testicular germ-cell tumours , 2001, Oncogene.

[20]  N E Day,et al.  Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population‐based study , 2001, Genetic epidemiology.

[21]  H. Nevanlinna,et al.  A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families , 2001, British Journal of Cancer.

[22]  N. Mailand,et al.  DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. , 2001, Cancer research.

[23]  J. Bartek,et al.  Chk2 kinase — a busy messenger , 2001, Nature Reviews Molecular Cell Biology.

[24]  L. Aaltonen,et al.  p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. , 2001, Cancer research.

[25]  Nazneen Rahman,et al.  Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations , 2002, Nature Genetics.

[26]  N E Day,et al.  A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes , 2002, British Journal of Cancer.

[27]  Carl W. Miller,et al.  Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors , 2002, Genes, chromosomes & cancer.

[28]  H. Nevanlinna,et al.  Risk of cancer in BRCA1 and BRCA2 mutation-positive and -negative breast cancer families (Finland) , 2001, Cancer Causes & Control.