Microsatellite stable colorectal cancers in clinically suspected hereditary nonpolyposis colorectal cancer patients without vertical transmission of disease are unlikely to be caused by biallelic germline mutations in MYH
Microsatellite stable colorectal cancers in clinically suspected hereditary nonpolyposis colorectal cancer patients without vertical transmission of disease are unlikely to be caused by biallelic germline mutations in MYH
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DOI：
10.2353/jmoldx.2006.050119
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发表时间：
2006-05-01
影响因子：
4.1
通讯作者：
Mueller, Annegret
中科院分区：
文献类型：
--
作者：
Goergens, Heike;Krueger, Stefan;Mueller, Annegret
微卫星分析和免疫组织化学是遗传性非息肉病性结直肠癌常用的初步筛查试验。然而，在符合贝塞斯达指南的患者中，大约有一半的肿瘤是微卫星稳定的。此外，这些肿瘤中正常的错配修复蛋白表达表明错配修复系统不太可能存在缺陷。由于双等位基因MYH突变发生在高和低数量腺瘤的患者中，我们假设MYH参与了微卫星稳定型结直肠癌的发生，这些患者没有疾病垂直传播，并且符合Bethesda指南。用全基因组DNA测序法对50例癌症患者和116例健康对照的MYH基因进行分析。未发现双等位基因种系突变。一名患者是p.G382D错义突变的杂合子携带者，另一名患者是新错义突变p.Q484H的杂合子携带者。我们确定了6个常见的变异体，其中3个在编码区(p.V22M、p.Q324H和p.S501F)，3个在邻近内含子区域(c.157+30A>；G、c.462+35G>；A和c.1435-40G>；C)。综上所述，MYH双等位基因种系突变不太可能在具有相同临床特征且无错配修复缺陷的遗传性非息肉病性结直肠癌家系的患者中导致结直肠癌，因此不能填补这一亚组Bethesda阳性患者的分子诊断空白。
Microsatellite analysis and immunohistochemistry are commonly used initial screening tests for hereditary nonpolyposis colorectal cancer. However, tumors in roughly one-half of the patients fulfilling the Bethesda guidelines are microsatellite stable. in addition, normal mismatch repair protein expression in these tumors suggests that a defect in the mismatch repair system is unlikely. Because biallelic MYH mutations occur in patients with both high and low numbers of adenomas, we hypothesized that MYH is involved in the tumorigenesis of microsatellite stable colorectal cancers in patients without vertical transmission of disease and who fulfill the Bethesda guidelines. MYH was analyzed in 50 cancer patients and 116 healthy controls by complete genomic DNA sequencing. No biallelic germline mutations were identified. One patient was a heterozygous carrier for the p.G382D missense mutation, and another patient was a heterozygous carrier for the novel missense mutation p.Q484H. We identified six common variants, three in the coding region (p.V22M, p.Q324H, and p.S501F) and three in adjacent intronic regions (c.157+30A > G, c.462+35G > A, and c.1435-40G > C). In summary, biallelic germline mutations of MYH are unlikely to cause colorectal cancer in patients sharing clinical features with hereditary nonpolyposis colorectal cancer families without mismatch repair defect and therefore cannot fill the molecular diagnostic gap in this subgroup of Bethesda-positive patients.