年轻结直肠癌患者及与遗传性非息肉病性结直肠癌相关的多肿瘤患者中错配修复基因突变的鉴定。
Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer.
作者信息
Niessen R C, Berends M J W, Wu Y, Sijmons R H, Hollema H, Ligtenberg M J L, de Walle H E K, de Vries E G E, Karrenbeld A, Buys C H C M, van der Zee A G J, Hofstra R M W, Kleibeuker J H
机构信息
Department of Gastroenterology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
出版信息
Gut. 2006 Dec;55(12):1781-8. doi: 10.1136/gut.2005.090159. Epub 2006 Apr 24.
BACKGROUND
Patients with early-onset colorectal cancer (CRC) or those with multiple tumours associated with hereditary non-polyposis colorectal cancer (HNPCC) raise suspicion of the presence of germline DNA mismatch repair (MMR) gene mutations.
AIM
To analyse the value of family history, microsatellite instability (MSI) analysis and MMR protein staining in the tumour to predict the presence of an MMR gene mutation in such patients.
METHODS
In 281 patients diagnosed with CRC before the age of 50 years or with CRC and at least one additional HNPCC-associated cancer, germline mutation analysis in MLH1, MSH2 and MSH6 was carried out with denaturing gradient gel electrophoresis and multiplex ligation-dependent probe amplification. MSI analysis with five consensus markers and MMR protein staining for MLH1, MSH2 and MSH6 were carried out in the tumours.
RESULTS
25 pathogenic mutations (8 in MLH1, 9 in MSH2 and 8 in MSH6) were found. MSI analysis missed three and immunohistochemistry (IHC) missed two mutation carriers. Sensitivities of family history, MSI analysis and IHC for the presence of a mutation were 76%, 82% and 88%, specificities were 64%, 70% and 84%, and positive predictive values were 19%, 23% and 38%, respectively. Multivariate analysis showed the highest odds ratio for IHC (38.3, 95% confidence interval 9.0 to 184). Prevalence of pathogenic germline MMR gene mutations in patients with CRC before the age of 50 years was 6% and in those with > or =2 HNPCC-associated tumours was 22%. In the second group, no mutation carriers were found among the 29 patients who were diagnosed with their first tumour after the age of 60 years.
CONCLUSION
Family history, MSI analysis and IHC are indicative parameters to select patients with CRC for MMR gene mutation analysis. The data show that IHC is the best single selection criterion.
背景
早发性结直肠癌（CRC）患者或患有与遗传性非息肉病性结直肠癌（HNPCC）相关的多发肿瘤患者，会让人怀疑存在种系DNA错配修复（MMR）基因突变。
目的
分析家族史、微卫星不稳定性（MSI）分析及肿瘤中MMR蛋白染色在预测此类患者MMR基因突变存在情况中的价值。
方法
对281例50岁前诊断为CRC或患有CRC且至少还有一种与HNPCC相关癌症的患者，采用变性梯度凝胶电泳和多重连接依赖探针扩增法对MLH1、MSH2和MSH6进行种系突变分析。对肿瘤进行5个一致性标志物的MSI分析以及MLH1、MSH2和MSH6的MMR蛋白染色。
结果
发现25个致病突变（MLH1中8个，MSH2中9个，MSH6中8个）。MSI分析漏检3名突变携带者，免疫组化（IHC）漏检2名突变携带者。家族史、MSI分析和IHC检测突变的敏感性分别为76%、82%和88%，特异性分别为64%、70%和84%，阳性预测值分别为19%、23%和38%。多因素分析显示IHC的优势比最高（38.3，95%置信区间9.0至184）。50岁前患CRC的患者中致病种系MMR基因突变的患病率为6%，患有≥2种与HNPCC相关肿瘤的患者中为22%。在第二组中，60岁后诊断出首例肿瘤的29例患者中未发现突变携带者。
结论
家族史、MSI分析和IHC是选择CRC患者进行MMR基因突变分析的指示性参数。数据表明IHC是最佳的单一选择标准。
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