Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability
Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability
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DOI：
10.1016/s0165-4608(03)00196-1
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发表时间：
2003-12-01
影响因子：
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通讯作者：
Tomlinson, IPM
中科院分区：
文献类型：
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作者：
Alam, NA;Gorman, P;Tomlinson, IPM
外切核酸酶1（EXO 1）是结直肠肿瘤易感性的候选基因，因为它被认为在错配修复中发挥作用。已经有几项研究调查了EXO 1 9在错配修复中的作用，但很少调查其在引起临床疾病中的作用。在最近的一项研究中，据报道，EXO 1的种系变异与遗传性非息肉病性结肠癌（HNPCC）表型相似的家族中的结直肠癌易感性相关。我们最近从两个患有多发性皮肤和子宫平滑肌瘤病的英国家族中鉴定出9名个体，这些个体独立出现1q42.3类似于q43的杂合生殖系缺失，不仅包括FH（多发性平滑肌瘤病相关基因），还包括几个侧翼基因，包括EXO 1。我们通过详细的问卷调查、访谈和检查EXO 1缺失皮肤平滑肌瘤的微卫星不稳定性（NISI），调查了这些家庭是否有患结直肠癌或其他HNPCC谱系癌症的易感性。这些家族中没有人患过结直肠癌或已知的结直肠腺瘤，也没有人有任何胃肠道或其他检查的症状。EXO 1-null肿瘤没有显示MSI的证据。这项研究质疑了以前报道的HNPC样家族中EXO 1变体的功能意义，并表明在人类中可能存在其他尚未发现的蛋白质，其核酸外切酶功能与EXO 1在DNA错配修复中的功能重叠。同样令人感兴趣的是，在任何缺失携带者中，除了多发性平滑肌瘤病之外，不存在表型异常，即使相邻基因RGS 7、KMO、CHML和OPN 3也被缺失。(C)2003年爱思唯尔公司All rights reserved.
Exonuclease 1 (EXO1) is a candidate gene for colorectal tumor susceptibility because it is believed to play a role in mismatch repair. There have been several studies investigating the role of EXO1 9 in mismatch repair but few investigating its role in causing clinical disease. In one recent study, germline variants of EXO1 were reported to be associated with predisposition to colorectal cancer in families with phenotypes similar to hereditary nonpolyposis colon cancer (HNPCC). We recently identified nine individuals from two British families with multiple cutaneous and uterine leiomyomatosis with independently arising heterozygous germline deletions of 1q42.3similar toq43 encompassing not only FH, the multiple leiomyomatosis-associated gene, but also several flanking genes, including EXO1. We investigated these families for any indication of predisposition to colorectal cancer or other HNPCC spectrum cancers by means of detailed questionnaires, interviews, and examination of EXO1-null skin leiomyomata for microsatellite instability (NISI). No individual in these families had developed colorectal cancer or known colorectal adenomas, and none had any symptoms warranting gastrointestinal or other investigation. EXO1-null tumors showed no evidence of MSI. This study questions the functional significance of previously reported variants of EXO1 reported in HNPCC-like families and suggests that in humans there may be other as yet undiscovered proteins that have exonuclease function overlapping with that of EXO1 in DNA mismatch repair. Also of interest is the absence of phenotypic abnormality apart from multiple leiomyomatosis in any deletion carrier even though the adjacent genes RGS7, KMO, CHML, and OPN3 were also deleted. (C) 2003 Elsevier Inc. All rights reserved.