Association of two mutations in the CHEK2 gene with breast cancer

Abstract

The 1100delC mutation of the cell cycle checkpoint kinase 2 (CHEK2) gene confers an increased risk for breast cancer, but the clinical impact of other CHEK2 gene variants remains unclear. We determined the frequency of two functionally relevant CHEK2 gene mutations, I157T and IVS211G > A, in two large series of breast cancer cases and controls from two independent populations. Our first series consisted of a hospital-based cohort of 996 German breast cancer cases and 486 population controls, and the second series consisted of 424 breast cancer patients and 307 population controls from the Republic of Belarus. The missense substitution I157T was identified in 22⁄996 cases (2.2%) vs. 3⁄486 controls (0.6%; OR 5 3.6, 95% CI 1.1-12.2, p 5 0.044) in the German population and in 24⁄424 cases (5.7%) vs. 4⁄307 controls (1.3%; OR 5 4.5, 95% CI 1.6-13.2, p 5 0.005) in the Byelorussian cohorts. The splicing mutation IVS211G > A was infrequent in both populations, being observed in 3⁄996 German and 4⁄424 Byelorussian patients (0.3% and 0.9%, respectively) and in 1⁄486 German controls (0.2%; adjusted OR 5 4.0, 95% CI 0.5-30.8, p 5 0.273). Heterozygous CHEK2 mutation carriers tended to be diagnosed at an earlier age in both populations, but these differences did not reach statistical significance. Family history of breast cancer did not differ between carriers and noncarriers. Our data indicate that the I157T allele, and possibly the IVS211G > A allele, of the CHEK2 gene contribute to inherited breast cancer susceptibility. ' 2005 Wiley-Liss, Inc.Key words: breast cancer; CHEK2; Germany; Belarus Cell-cycle checkpoint kinase 2 (CHEK2) is a central mediator of cellular responses to DNA damage.1,2 Ionizing radiation activates the CHEK2 protein via ATM-mediated phosphorylation, 3,4 and activated CHEK2 kinase can phosphorylate several substrates, including Cdc25A, p53 and E2F1, which mediate cell cycle arrest and apoptosis.1,2,5 CHEK2 phosphorylation of the breast cancer susceptibility protein BRCA1 regulates DNA double-strand break repair, 6 and deletion of CHEK2 potentiates the incidence of mammary carcinomas in BRCA1 conditional mutant mice.7 A truncating variant of CHEK2, the 1100delC mutation, has been identified as a low-penetrance breast-cancer susceptibility allele. 8,9 Heterozygous 1100delC carriers have an approximately 2-fold increased risk for breast cancer.10 Furthermore, a potential association of the 1100delC mutation with colorectal and prostate cancers has been reported. 11-13The role of variants in CHEK2 other than 1100delC is less clear. Most studies have led to the conclusion that other CHEK2 mutations do not make a major contribution to breast cancer susceptibility.14-16 However, one more recent investigation suggests that the common I157T mutation may be associated with increased breast cancer risk. 17 Parallel work has provided evidence that the missense substitution I157T as well as the splicing mutation IVS211G>A may confer an elevated risk for prostate cancer. 13,18 To assess the role of these CHEK2 varia...

The CHEK2 gene and inherited breast cancer susceptibility

“…Sodha et al (2004) found the 1100delC in one out of 26 familial male breast cancer cases, and no other CHEK2 mutations were identified in these cases either. Although the number of cases have been relatively small in these studies, it is likely that a risk for male breast cancer, if any, is substantially smaller (Cybulski et al, 2004b) and among German (2.2% in cases vs 0.6% in controls) and Byelo-Russian patients (5.7% in cases vs 1.3% in controls) (Bogdanova et al, 2005). The estimated fraction of breast cancer attributable to this variant is also quite similar in these populations, with 2.2% in Finland, 1.9% in Poland and 1.6% in the German and 4.3% in the Byelorussian populations.…”

“…Among familial non-BRCA1/2 breast cancer patients in the UK, North America and the Netherlands, the variant was found only in 0.27% of patients and in 0.14% of controls, suggesting a negligible contribution in these populations (Schutte et al, 2003). Overall, lower risks have been observed for I157T than 1100delC and while I157T has been associated with breast cancer risk in the population, it has not exhibited a significant association with familial aggregation of breast cancer in the Finnish or German populations (Dufault et al, 2004;Kilpivaara et al, 2004;Bogdanova et al, 2005). However, among the Byelorussian population, a significantly elevated risk was observed among familial cases as well (Bogdanova et al, 2005), possibly suggesting the presence of other, perhaps population-specific susceptibility alleles, if confirmed in further studies.…”

Germline mutations in the CHEK2 kinase gene are associated with an increased risk of bladder cancer

“…6,8,[12][13][14][15][16][17][18][19][20] CHEK2 is phosphorylated and regulated by the Ataxia Telangiectasia Mutated (ATM) kinase, another crucial mediator of cell cycle checkpoint control. 15,17 Cell cycle checkpoint control mechanisms are essential for the maintenance of genomic integrity but there appear to be differences in the efficiency of this process due to polymorphic variation, which have been suggested to contribute to oncogenesis.…”

“…Germline CHEK2 mutations have been associated with an increased risk of breast, prostate, colon cancers, thyroid, kidney, low-grade ovarian cancers and lymphomas, but bladder cancer has not been studied extensively. 1,11,[12][13][14][15][16]19,21,24,25 Two previous reports suggest that individuals with mutations in the CHEK2 gene might be at increased risk of bladder cancer. 13,14 To confirm this hypothesis, we have genotyped 416 incident cases of bladder cancer and 3,313 controls for the 4 CHEK2 founder mutations present in the Polish population.…”

“…12 Activation of CHEK2 in response to DNA damage is a signal to downstream targets in the checkpoint control pathways that include p53, Cdc25A, Cdc25C, BRCA1, E2F1, Pml1, Plk3 and other substrates whose biological functions become modified resulting in cell cycle blockade, enhanced DNA repair or apoptosis. 7,[12][13][14][15][16][17]19,21,22 The first mutations in CHEK2 which were reported in sporadic and hereditary cancers indicated that CHEK2 defects might explain the tumor-prone phenotype in families with Li-Fraumeni syndrome (LFS). 1,12,13,15,17,18,23 To date CHEK2 mutations have been found in subset of human breast carcinomas, testicular tumors and lymphomas.…”