林奇综合征（遗传性非息肉病性结直肠癌）的诊断

Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics.

作者信息

Lagerstedt Robinson Kristina, Liu Tao, Vandrovcova Jana, Halvarsson Britta, Clendenning Mark, Frebourg Thierry, Papadopoulos Nickolas, Kinzler Kenneth W, Vogelstein Bert, Peltomäki Päivi, Kolodner Richard D, Nilbert Mef, Lindblom Annika

机构信息

Department of Clinical Genetics, Karolinska University Hospital, S-17176 Stockholm, Sweden.

出版信息

J Natl Cancer Inst. 2007 Feb 21;99(4):291-9. doi: 10.1093/jnci/djk051.

DOI:10.1093/jnci/djk051

PMID:17312306

Abstract

BACKGROUND

Preventive programs for individuals who have high lifetime risks of colorectal cancer may reduce disease morbidity and mortality. Thus, it is important to identify the factors that are associated with hereditary colorectal cancer and to monitor the effects of tailored surveillance. In particular, patients with Lynch syndrome, hereditary nonpolyposis colorectal cancer (HNPCC), have an increased risk to develop colorectal cancer at an early age. The syndrome is explained by germline mutations in DNA mismatch repair (MMR) genes, and there is a need for diagnostic tools to preselect patients for genetic testing to diagnose those with HNPCC.

METHODS

Patients (n = 112) from 285 families who were counseled between 1990 and 2005 at a clinic for patients at high risk for HNPCC were selected for screening to detect mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 based on family history, microsatellite instability (MSI), and immunohistochemical analysis of MMR protein expression. Tumors were also screened for BRAF V600E mutations; patients with the mutation were considered as non-HNPCC.

RESULTS

Among the 112 patients who were selected for screening, 69 had germline MMR mutations (58 pathogenic and 11 of unknown biologic relevance). Sixteen of the 69 mutations (23%) were missense mutations. Among patients with MSI-positive tumors, pathogenic MMR mutations were found in 38 of 43 (88%) of patients in families who met Amsterdam criteria and in 13 of 22 (59%) of patients in families who did not. Among patients with MSI-negative tumors, pathogenic MMR mutations were found in 5 of 17 (29%) of families meeting Amsterdam criteria and in 1 of 30 (3%) of non-Amsterdam families with one patient younger than age 50 years. In three patients with MSI-negative tumors who had pathogenic mutations in MLH1 or MSH6, immunohistochemistry showed loss of the mutated protein.

CONCLUSION

Our findings suggest that missense MMR gene mutations are common in HNPCC and that germline MMR mutations are also found in patients with MSI-negative tumors.

摘要

背景

针对结直肠癌终生风险较高的个体的预防计划可能会降低疾病的发病率和死亡率。因此，识别与遗传性结直肠癌相关的因素并监测定制化筛查的效果非常重要。特别是，林奇综合征（遗传性非息肉病性结直肠癌，HNPCC）患者患结直肠癌的风险在早年就会增加。该综合征由DNA错配修复（MMR）基因的种系突变引起，因此需要诊断工具来预先选择患者进行基因检测，以诊断HNPCC患者。

方法

从1990年至2005年在一家针对HNPCC高危患者的诊所接受咨询的285个家庭中选取112例患者进行筛查，根据家族史、微卫星不稳定性（MSI）和MMR蛋白表达的免疫组化分析来检测MMR基因MLH1、MSH2、MSH6和PMS2中的突变。还对肿瘤进行BRAF V600E突变筛查；有该突变的患者被视为非HNPCC。

结果

在入选筛查的112例患者中，69例有种系MMR突变（58例为致病性突变，11例生物学相关性未知）。69例突变中有16例（23%）为错义突变。在MSI阳性肿瘤患者中，符合阿姆斯特丹标准的家族中43例患者中有38例（88%）检测到致病性MMR突变，不符合该标准的家族中22例患者中有13例（59%）检测到。在MSI阴性肿瘤患者中，符合阿姆斯特丹标准的家族中17例患者中有5例（29%）检测到致病性MMR突变，在一个有一名年龄小于50岁患者的非阿姆斯特丹家族的30例患者中有1例（3%）检测到。在3例MSI阴性肿瘤且MLH1或MSH6有致病性突变的患者中，免疫组化显示突变蛋白缺失。