Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling Amsterdam criteria
Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling Amsterdam criteria
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DOI：
10.1158/1078-0432.ccr-04-0651
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发表时间：
2004-09-15
影响因子：
11.5
通讯作者：
Kim, JS
中科院分区：
文献类型：
--
作者：
Kim, JC;Lee, KH;Kim, JS
目的：虽然突变表型，包括错配修复(MMR)系统的遗传和表观遗传改变，似乎在家族性疾病中是明显的。在结直肠癌中，几乎没有包含整个突变子通路的综合性研究。这项研究是为了确定决定不符合阿姆斯特丹标准的家族性结直肠癌患者的危险因素的整个突变子通路。实验设计：我们连续招募了134名有伴随癌症家族史的结直肠癌患者。符合阿姆斯特丹标准的遗传性非息肉病性结直肠癌、家族性腺瘤性息肉病或接受术前放射治疗的患者被排除在外。通过检测24个标记的微卫星不稳定性(MSI)、hMLH1启动子甲基化、MMR基因突变(hMLH1、hMSH2、hMSH6和hPMS2)以及MMR蛋白(hMLH1、hMSH2、hMSH6、hPMS1和hPMS2)的免疫染色来评估突变表型。134例结直肠癌先证者中，高水平MSI 23例(17%)，低水平MSI 32例(24%)。在8名患者(6%)中发现了MMR改变，包括已知的多态和剪接替换。通过hMLH1启动子甲基化和/或MMR蛋白表达缺失进一步鉴定了28例具有突变子表型的肿瘤。在51例肿瘤(38%)中，突变基因表型与右侧结肠癌(P<；0.001)和发病年龄较小(P=0.032)相关，但突变基因表型患者的数量与伴发癌症的遗传模式无关(无论是连续遗传还是水平传播)(P=0.815)。结论：家族性结直肠癌可能与多发显性或隐性遗传的结直肠癌或伴癌有关。然而，在家族性结直肠癌中，MMR基因突变与突变表型的相关性较小。
Purpose: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial. colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria.Experimental Design: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2).,Results: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P = 0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P = 0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors.Conclusion: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.