Wasielewski Marijke, Vasen Hans, Wijnen Juul, Hooning Maartje, Dooijes Dennis, Tops Carli, Klijn Jan G M, Meijers-Heijboer Hanne, Schutte Mieke
Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
Clin Cancer Res. 2008 Aug 1;14(15):4989-94. doi: 10.1158/1078-0432.CCR-08-0389.
The pathogenic CHEK2 1100delC variant is firmly established as a breast cancer susceptibility allele. Dutch CHEK2 1100delC breast cancer families frequently also include colorectal cancer cases, and the variant is particularly prevalent among breast cancer families with hereditary breast and colorectal cancer. Yet, it is still unclear whether CHEK2 1100delC also confers a colorectal cancer risk independent of its breast cancer risk.
CHEK2 1100delC was genotyped in the index cases of 369 Dutch colorectal cancer families that had been excluded for familial breast cancer. The cohort included 132 cases with familial adenomatous polyposis (FAP) and FAP-related disease, and 237 cases with hereditary nonpolyposis colorectal cancer (HNPCC) and HNPCC-related disease.
None of the FAP/FAP-related cases carried the CHEK2 1100delC variant. In contrast, CHEK2 1100delC was present in 10 of 237 (4.2%) HNPCC/HNPCC-related cases that was significantly more prevalent than the 1.0% Dutch population frequency (odds ratio, 4.3; 95% confidence interval, 1.7-10.7; P = 0.002). Nine of the 10 CHEK2 1100delC colorectal cancer cases met the revised Amsterdam and/or Bethesda criteria. The 10 CHEK2 1100delC colorectal cancer families had a high-risk cancer inheritance pattern, including 35 colorectal cancer cases, 9 cases with polyps, and 21 cases with other tumor types.
Our analysis provides strong evidence that the 1100delC variant of CHEK2 confers a colorectal cancer risk in HNPCC/HNPCC-related families, supporting the hypothesis that CHEK2 is a multiorgan cancer susceptibility gene.
致病性CHEK2 1100delC变异已被确认为乳腺癌易感等位基因。荷兰携带CHEK2 1100delC变异的乳腺癌家族中常出现结直肠癌病例，且该变异在遗传性乳腺癌和结直肠癌的乳腺癌家族中尤为普遍。然而，CHEK2 1100delC是否独立于其乳腺癌风险之外还会增加结直肠癌风险仍不清楚。
对369个已排除家族性乳腺癌的荷兰结直肠癌家族的先证者进行CHEK2 1100delC基因分型。该队列包括132例家族性腺瘤性息肉病（FAP）及FAP相关疾病患者，以及237例遗传性非息肉病性结直肠癌（HNPCC）及HNPCC相关疾病患者。
FAP/FAP相关疾病患者中均未携带CHEK2 1100delC变异。相比之下，237例HNPCC/HNPCC相关疾病患者中有10例（4.2%）携带CHEK2 1100delC变异，其患病率显著高于荷兰人群的1.0%（优势比，4.3；95%置信区间，1.7 - 10.7；P = 0.002）。10例携带CHEK2 1100delC变异的结直肠癌患者中有9例符合修订后的阿姆斯特丹和/或贝塞斯达标准。这10个携带CHEK2 1100delC变异的结直肠癌家族具有高风险癌症遗传模式，包括35例结直肠癌病例、9例息肉病例和21例其他肿瘤类型病例。
我们的分析提供了有力证据，表明CHEK2的1100delC变异会增加HNPCC/HNPCC相关家族患结直肠癌的风险，支持CHEK2是多器官癌症易感基因这一假说。
