Oldenburg Rogier A, Kroeze-Jansema Karin, Kraan Jaennelle, Morreau Hans, Klijn Jan G M, Hoogerbrugge Nicoline, Ligtenberg Marjolein J L, van Asperen Christi J, Vasen Hans F A, Meijers Carel, Meijers-Heijboer Hanne, de Bock Truuske H, Cornelisse Cees J, Devilee Peter
Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
Cancer Res. 2003 Dec 1;63(23):8153-7.
The frame-shifting mutation 1100delC in the cell-cycle-checkpoint kinase 2 gene (CHEK2) has been reported to be associated with familial breast cancer in families in which mutations in BRCA1 and BRCA2 were excluded. To investigate the role of this variant as a candidate breast cancer susceptibility allele, we determined its prevalence in 237 breast cancer patients and 331 healthy relatives derived from 71 non-BRCA1/BRCA2 multiple-case early onset breast cancer families. Twenty-seven patients (11.4%) were carrying the CHEK21100delC variant. At least one carrier was found in 15 of the 71 families (21.1%). There was no evidence of cosegregation between the variant and breast cancer, but carrier patients developed breast cancer earlier than did noncarriers. We studied CHEK2 protein expression in 111, and loss of heterozygosity at CHEK2 in 88 breast tumors from these patients. Twelve of 15 tumors from carriers showed absent protein expression as opposed to 3 of 76 tumors from noncarriers (P < 0.001). CHEK2 loss of heterozygosity was associated with absence of protein expression but not with 1100delC carrier status. Thus, selecting for breast cancer cases with a strong familial background not accounted for by BRCA1 or BRCA2 strongly enriches for carriers of CHEK21100delC. Our results support a model in which CHEK2*1100delC interacts with an as yet unknown gene (or genes) to increase breast cancer risk.
细胞周期检查点激酶2基因（CHEK2）中的移码突变1100delC已被报道与排除了BRCA1和BRCA2突变的家族性乳腺癌相关。为了研究该变异作为候选乳腺癌易感等位基因的作用，我们在来自71个非BRCA1/BRCA2多病例早发性乳腺癌家族的237例乳腺癌患者和331名健康亲属中确定了其患病率。27例患者（11.4%）携带CHEK21100delC变异。在71个家族中的15个家族（21.1%）中发现了至少一名携带者。没有证据表明该变异与乳腺癌之间存在共分离现象，但携带该变异的患者患乳腺癌的时间比非携带者更早。我们研究了111例患者的CHEK2蛋白表达，并在这些患者的88个乳腺肿瘤中检测了CHEK2的杂合性缺失。携带者的15个肿瘤中有12个显示蛋白表达缺失，而非携带者的76个肿瘤中有3个显示蛋白表达缺失（P < 0.001）。CHEK2杂合性缺失与蛋白表达缺失相关，但与1100delC携带者状态无关。因此，选择具有强烈家族背景且不能用BRCA1或BRCA2解释的乳腺癌病例，会使CHEK21100delC携带者显著富集。我们的结果支持一种模型，即CHEK2*1100delC与一个或多个未知基因相互作用，以增加患乳腺癌的风险。
