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不符合阿姆斯特丹标准的家族性结直肠癌患者中突变体表型的特征分析

Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria.

作者信息

Kim Jin C, Lee Kang H, Ka In H, Koo Kum H, Roh Seon A, Kim Hee C, Yu Chang S, Kim Tae W, Chang Heung M, Gong Gyeong Y, Kim Jung S

机构信息

Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea.

出版信息

Clin Cancer Res. 2004 Sep 15;10(18 Pt 1):6159-68. doi: 10.1158/1078-0432.CCR-04-0651.

Abstract

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.

摘要

目的

尽管错配修复(MMR)系统的遗传和表观遗传改变等突变体表型在家族性结直肠癌中似乎很明显,但很少有综合研究涵盖整个突变途径。本研究旨在确定在不符合阿姆斯特丹标准的家族性结直肠癌患者中决定风险因素的整个突变途径。

实验设计

我们连续招募了134例有伴随癌症家族史的结直肠癌患者。排除符合阿姆斯特丹标准的遗传性非息肉病性结直肠癌患者、家族性腺瘤性息肉病患者或接受术前放疗的患者。通过检测24个标记物的微卫星不稳定性(MSI)、hMLH1启动子甲基化、MMR基因(hMLH1、hMSH2、hMSH6和hPMS2)的突变以及MMR蛋白(hMLH1、hMSH2、hMSH6、hPMS1和hPMS2)的免疫染色来评估突变体表型。

结果

在患者的一级和/或二级亲属的208例癌症中,结直肠癌和胃癌(81%)最为常见。在134例先证者结直肠癌中,23例(17%)为高水平微卫星不稳定性(MSI),32例(24%)为低水平MSI。在8例患者(6%)中鉴定出MMR改变,包括已知的多态性和剪接替代。通过hMLH1启动子甲基化和/或MMR蛋白表达缺失进一步鉴定出28例具有突变体表型的肿瘤。在51例肿瘤(38%)中,突变体表型与右半结肠癌(P<0.001)和发病年龄较轻(P=0.032)相关,但具有突变体表型的患者数量在伴随癌症的遗传模式方面没有差异,无论是连续还是水平传递(P=0.815)。家族影响值,其将亲属与所有伴随癌症的程度差异关联,有效地将高水平MSI与微卫星稳定/低水平MSI肿瘤区分开来。

结论

家族性结直肠癌可能与通过显性或隐性传递遗传的结直肠癌或伴随癌症的多次发生有关。然而,MMR基因突变与家族性结直肠癌的突变体表型相关性较小。

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