Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts

Abstract

The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a populationbased case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically-and geographically-selected populations. ' 2007 Wiley-Liss, Inc.Key words: CHEK2; susceptibility; breast; cancer; mutation The highly penetrant breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to 80% of familial breast cancer, 1,2 but to only 10% of cases without a strong family history. [3][4][5]

CHEK2*1100delC homozygosity in the Netherlands—prevalence and risk of breast and lung cancer

“…5,[13][14][15][16][17][18][19] For homozygous carriers, our observations indicate that (contralateral) breast cancer risk may be as high as to justify preventive mastectomy (or at least intensified screening), but longitudinal studies on more cases are needed to arrive at more accurate risk estimates.…”

“…3,[10][11][12][13] Breast cancer patients heterozygous for 1100delC also have an increased risk of developing contralateral breast cancer when compared with wild-type breast cancer patients. 5,[13][14][15][16][17][18][19][20] The contralateral breast cancer risk may be even higher when radiotherapy has been given to treat the first tumor. 15,19 It must be noted that in women who also carry a pathogenic BRCA1/2 mutation the 1100delC allele does not seem to modify breast cancer risk.…”

“…15,19 It must be noted that in women who also carry a pathogenic BRCA1/2 mutation the 1100delC allele does not seem to modify breast cancer risk. 3,14,21 An association of the 1100delC allele with increased colon cancer and prostate cancer risk has been described, while an association with melanoma could not be found. [22][23][24][25] Other variants in CHEK2 have been associated with lung cancer, but a possible association of 1100delC with lung cancer has never been investigated.…”

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

“…Reviews, editorials, meeting abstracts, and commentaries were excluded from our analysis. We also excluded studies that did not detect the CHEK2 1100delC allele in both cases and controls (Rajkumar et al, 2003;Song et al, 2006;Bell et al, 2007;Choi, 2008;Lee and Ang, 2008;Thirthagiri et al, 2009). …”

“…However, this widely discussed variant of CHEK2 -which seemed clearly associated with the predominance of breast cancer in western countries -was rarely detected in Asian populations, such as the Chinese (Song et al, 2006), Koreans (Choi, 2008), Japanese (Bell et al, 2007), Singaporeans (Lee and Ang, 2008), Malaysians (Thirthagiri et al, 2009) and South Indians (Rajkumar et al, 2003). With the influx of recent studies concerning these particular findings, a stricter meta-analysis with the recent data is necessary.…”