Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of cancer
Novel NBS1 heterozygous germ line mutation causing MRE11-binding domain loss predisposes to common types of cancer
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DOI：
10.1158/0008-5472.can-07-1749
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发表时间：
2007-12-01
期刊：
影响因子：
11.2
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
--
作者：
Ebi, Hiromichi;Matsuo, Keitaro;Takahashi, Takashi
DNA损伤反应（DDR）途径维持基因组的稳定性。一个657 de 15突变的NBS 1，一个关键的DDR组件，导致罕见的癌症易感性奈梅亨断裂综合征已报告几乎完全在斯拉夫人群。在这项研究中，我们描述了第一次鉴定在日本人口的一个前所未有的类型的杂合NBS 1突变体，称为IIVS 11 + 2 insT，缺乏MRE 11-和ATM-结合位点的COOH末端。在与MRE 11、MDC 1、BRCA 1和野生型NBS 1的关键结合方面存在严重缺陷，该突变体在杂合状态下对低剂量照射的反应导致ATM磷酸化受损。重要的是，尽管IVS 11 + 2 insT仅在2例中发现，在2,348例正常对照组中，2%（2/96）的胃癌杂合子中检出，0.8%（2/96）的胃癌杂合子中检出，（3/376）结直肠癌患者，0.4%（2/532），这与已知赋予癌症易感性的其他DDR相关基因报告的频率相当。杂合IVS 11 + 2 insT突变的存在似乎与胃肠道癌风险增加相关，比值比为12.6，95%置信区间（95%CI）为2.05至132.1（P = 0.0001）。胃癌和结直肠癌的比值比分别为25.0（95%CI，1.78-346.0）和9.43（95%CI，1.08-113.1）。这些研究结果表明，IVS 11 + 2 insT与某些类型的常见癌症的发展风险增加有关，这将促进未来的研究，包括杂合子中发病年龄和发病率的详细表型表征，以及其他种族群体的筛查。
DNA damage response (DDR) pathways maintain genomic stability. A 657de15 mutation of NBS1, a key DDR component, causing the rare cancer-predisposing Nijmegen breakage syndrome has been reported nearly exclusively in Slavic populations. In this study, we describe the first identification in a Japanese population of an unprecedented type of heterozygous NBS1 mutant, termed IIVS11+2insT, lacking the MRE11- and ATM-binding site at the COOH terminus. Profoundly defective in crucial binding to MRE11, MDC1, BRCA1, and wild-type NBS1, the mutant caused impaired ATM phosphorylation in response to low-dose irradiation in a heterozygous state. Importantly, whereas IVS11+2insT was found in only 2 (0.09%) of 2,348 control subjects, it was identified in 2% (2 of 96) of heterozygotes with gastric cancer, 0.8% (3 of 376) of those with colorectal cancer, and 0.4% (2 of 532) of those with lung cancer, which were comparable to frequencies reported for other DDR-related genes known to confer cancer susceptibility. The presence of the heterozygous IVS11+2insT mutation seemed to be associated with an increased risk for gastrointestinal cancers, with an odds ratio of 12.6 and 95% confidence interval (95% CI) of 2.05 to 132.1 (P = 0.0001). The odds ratios separately calculated for gastric and colorectal cancers were 25.0 (95% CI, 1.78-346.0) and 9.43 (95% CI, 1.08-113.1), respectively. These findings suggest that IVS11+2insT is associated with an increased risk for the development of certain types of common cancers, warranting future investigation including detailed phenotypic characterization of age of onset and penetrance in heterozygotes, as well as screening in other ethnic groups.