Limited relevance of the CHEK2 gene in hereditary breast cancer

Abstract

To establish the importance of CHEK2 mutations for familial breast cancer incidence in the German population, we have screened all 14 of the coding exons in 516 families negative for mutations in both the BRCA1 and BRCA2 genes. We found 12 distinct variants in 30 unrelated patients (5.81%), including 5 that are novel and an additional 4 found for the first time in breast cancer. These aberrations were evaluated in 500 healthy women aged over 50 years and in the case of the 2 exon 10 mutations, 1100delC and 1214del4bp, in 1315 randomized healthy controls. According to our results, a statistically significant association for the exon 10 mutations was observed (p ‫؍‬ 0.006). The prevalence of the 1100delC mutation in the German population, however, is significantly lower than those reported for other Caucasian populations both in familial breast cancer patients (1.6%) and controls (0.5%), and shows independent segregation with breast cancer in 2 of 4 families analyzed. The remaining 10 variants were more abundant in patients (21) compared to the controls (12) although the difference was not statistically significant. Interestingly, we found no increased breast cancer risk associated with the splice site mutation IVS2؉1G3 A or the most common missense mutation I157T, which account for more than half (12/21) of the variants observed in patients. The low prevalence and penetrance of the exon 10 deletion mutations together with no, or an uncertain elevation in risk for other CHEK2 mutations suggests a limited relevance for CHEK2 mutations in familial breast cancer. Further evaluation of the unique variants observed in breast cancer is required to determine if they may play a role in a polygenic model of familial breast cancer. Nevertheless, it seems premature to include CHEK2 screening in genetic testing.

Association of two mutations in the CHEK2 gene with breast cancer

“…4,17,22 However, previous studies have failed to establish an association of these genetic variants with breast cancer; thus, it was proposed that CHEK2 mutations other than 1100delC do not make a major contribution to breast cancer susceptibility. [14][15][16] The reasons for the discrepancies between these results and ours may be heterogeneous and could be due to a smaller cohort size, 14 a very low frequency of the I157T allele 15 or a sampling bias toward multiplecase families who were negative for BRCA1 and BRCA2 gene mutations. 15,16 While our results clearly demonstrate a role for the CHEK2 mutation I157T in inherited breast cancer susceptibility, we have not detected a further increase in the frequency of this allele in familial breast cancer.…”

“…[14][15][16] The reasons for the discrepancies between these results and ours may be heterogeneous and could be due to a smaller cohort size, 14 a very low frequency of the I157T allele 15 or a sampling bias toward multiplecase families who were negative for BRCA1 and BRCA2 gene mutations. 15,16 While our results clearly demonstrate a role for the CHEK2 mutation I157T in inherited breast cancer susceptibility, we have not detected a further increase in the frequency of this allele in familial breast cancer. Similarly, a study of Finnish breast cancer patients revealed some evidence for an association of FIGURE 1 -Identification and confirmation of the CHEK2 gene mutations IVS211G>A and I157T by screening of PCR products using restriction enzymes ScrFI and PstI (upper figure, S, size marker; P, heterozygous patient; C, wild-type control) and subsequent direct sequencing of PCR products from heterozygous patients (lower panel, sense strand with N designating the mutated position).…”

Breast cancer susceptibility: current knowledge and implications for genetic counselling

“…Mutations in these genes are extremely rare in most populations and, even more importantly, the clinical consequences are not yet clear, especially regarding the incomplete segregation of the known mutation with breast cancer in affected families. 37,38,40,51,72 It has to be considered that mutations, at least in some of these genes, are not specific for BRCA1/ BRCA2 mutation-negative familial cases, but can also occur in sporadic breast cancer cases (Bogdanova et al, 73 Erkko et al 74 and A Meindl, unpublished data). Therefore, it is likely that predisposing mutations with moderate penetrance in other genes will be identified in families with multiple cases.…”

“…Allele frequencies in other European countries, North America and Australia rarely exceed 0.1 or 0.2%, meaning 1 or 2 in 1000 alleles (Table 3). 39,50 In addition, screening of all 14 coding exons in 516 BRCA1/ BRCA2 mutation-negative hereditary breast cancer families displayed independent segregation of CHEK2 1100delC with breast cancer in two of four families analysed, 51 and the initially reported high risk for male breast cancer has not been confirmed. 39 However, CHEK2 1100delC carriers Breast cancer susceptibility T Ripperger et al seem to have both poorer disease-free and overall survival than non-carriers, and an increased risk of developing a second, mostly contralateral breast cancer has been observed in CHEK2 1100delC mutation carriers having received initial radiotherapy.…”

CHEK2 1100delC Variant and Breast Cancer Risk in Caucasians: A Meta-analysis Based on 25 Studies with 29,154 Cases and 37,064 Controls

“…After the BRCA1 and BRCA2 proteins were cloned and their association with family breast cancer was detected (Miki Y et al, 1994;Wooster R et al, 1995), greater emphasis was placed on the candidate gene of breast cancer. The cell cycle-checkpoint kinase 2 gene, or CHEK2, was widely researched as a strong candidate gene for breast cancer susceptibility (Vahteristo et al, 2002;Sodha et al, 2002;Offit et al, 2003;CHEK2 Breast Cancer Consortium, 2004;Dufault et al, 2004;Friedrichsen et al, 2004;Mateus Pereira et al, 2004;Baeyens et al, 2005;Kleibl et al, 2005;Rashid et al, 2005;Bernstein et al, 2006;Einarsdóttir et al, 2006;Cybulski et al, 2007;Weischer et al, 2007;Zhang et al, 2008;Fletcher et al, 2009;McInerney et al, 2010;Iniesta et al, 2010).…”