Department of Digestive Surgery, Hôpital Saint Antoine (AP-HP), Paris VI University, Paris, France.
Fam Cancer. 2013 Mar;12(1):27-33. doi: 10.1007/s10689-012-9568-9.
Some patients happen to have a colorectal cancer with microsatellite instability (MSI), but without any alteration in Mismatch Repair (MMR) system (germline mutation/promoter methylation). We aimed to identify the mechanism of inactivation of MMR genes in those cases. We studied 18 patients with MSI CCR and loss of expression of a MMR protein. DNA was extracted from tumoral and normal colonic material. We studied the 3 main MMR genes in tumors, by sequencing and large rearrangement analysis, and looked for mosaicism. Seven patients lost expression of MLH1, we found 1 mutation in the tumor for 3 patients and 2 mutations in one. Eight patients lost expression of MSH2: we found 1 mutation in 2 patients and 2 mutations in four. In the 5 cases with 2 hits, MSI was due to double somatic hits (n = 3), mosaicism (n = 1) and missed germline mutation (n = 1). Mosaicism was confirmed by HRM analysis, and by finding a germline mutation in one patient's son. We could explain MSI in the tumors of 5 patients (27.8 %). Their follow up and family's surveillance could be adjusted, as the sporadic cases don't require intensive surveillance. We describe the first case of somatic mosaicism after de novo mutation in MSH2.
有些患者恰好患有微卫星不稳定（MSI）的结直肠癌，但错配修复（MMR）系统（种系突变/启动子甲基化）没有任何改变。我们旨在确定这些病例中 MMR 基因失活的机制。我们研究了 18 例 MSI CCR 伴 MMR 蛋白表达缺失的患者。从肿瘤和正常结肠组织中提取 DNA。我们通过测序和大片段重排分析研究了肿瘤中 3 个主要的 MMR 基因，并寻找嵌合体。7 例患者 MLH1 表达缺失，我们在 3 例患者的肿瘤中发现 1 个突变，在 1 例患者中发现 2 个突变。8 例患者 MSH2 表达缺失：我们在 2 例患者中发现 1 个突变，在 4 例患者中发现 2 个突变。在 5 例有 2 个突变的患者中，MSI 是由于双体细胞突变（n=3）、嵌合体（n=1）和漏检种系突变（n=1）所致。HRM 分析和在 1 名患者的儿子中发现一个种系突变证实了嵌合体的存在。我们可以解释 5 名患者（27.8%）肿瘤中的 MSI。他们的随访和家族监测可以进行调整，因为散发性病例不需要密集监测。我们描述了 MSH2 从头突变后体细胞嵌合体的首例病例。
