Jekimovs C R, Chen X, Arnold J, Gatei M, Richard D J, Spurdle A B, Khanna K K, Chenevix-Trench G
Division of Cancer and Cell Biology, Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, QLD 4029, Australia.
Br J Cancer. 2005 Feb 28;92(4):784-90. doi: 10.1038/sj.bjc.6602381.
A protein-truncating variant of CHEK2, 1100delC, is associated with a moderate increase in breast cancer risk. We have determined the prevalence of this allele in index cases from 300 Australian multiple-case breast cancer families, 95% of which had been found to be negative for mutations in BRCA1 and BRCA2. Only two (0.6%) index cases heterozygous for the CHEK2 mutation were identified. All available relatives in these two families were genotyped, but there was no evidence of co-segregation between the CHEK2 variant and breast cancer. Lymphoblastoid cell lines established from a heterozygous carrier contained approximately 20% of the CHEK2 1100delC mRNA relative to wild-type CHEK2 transcript. However, no truncated CHK2 protein was detectable. Analyses of expression and phosphorylation of wild-type CHK2 suggest that the variant is likely to act by haploinsufficiency. Analysis of CDC25A degradation, a downstream target of CHK2, suggests that some compensation occurs to allow normal degradation of CDC25A. Such compensation of the 1100delC defect in CHEK2 might explain the rather low breast cancer risk associated with the CHEK2 variant, compared to that associated with truncating mutations in BRCA1 or BRCA2.
CHEK2基因的一种截短型变异体1100delC与乳腺癌风险适度增加相关。我们已确定了该等位基因在300个澳大利亚多病例乳腺癌家族的索引病例中的流行情况，其中95%的家族被发现BRCA1和BRCA2基因无突变。仅鉴定出两例（0.6%）CHEK2突变杂合的索引病例。对这两个家族中所有可获得的亲属进行了基因分型，但未发现CHEK2变异体与乳腺癌之间存在共分离现象。从一名杂合携带者建立的淋巴母细胞系中，相对于野生型CHEK2转录本，CHEK2 1100delC mRNA约占20%。然而，未检测到截短的CHK2蛋白。对野生型CHK2的表达和磷酸化分析表明，该变异体可能通过单倍剂量不足起作用。对CHK2的下游靶点CDC25A降解的分析表明，发生了一些补偿作用以允许CDC25A正常降解。CHEK2中1100delC缺陷的这种补偿作用可能解释了与CHEK2变异体相关的乳腺癌风险相对较低的原因，与BRCA1或BRCA基因的截短突变相关的风险相比。
