Ewald J, Rodrigue C M, Mourra N, Lefèvre J H, Fléjou J-F, Tiret E, Gespach C, Parc Y R
Department of Digestive Surgery, Hôpital Saint-Antoine (AP/HP), Université Pierre et Marie Curie, Paris, France.
Br J Surg. 2007 Aug;94(8):1020-7. doi: 10.1002/bjs.5704.
Hereditary non-polyposis colorectal cancer (HNPCC) arises mostly from germline mutations of the mismatch repair genes MSH2 and MLH1. The diagnosis of HNPCC is based on a set of clinical criteria that may be too restrictive to identify all affected patients. Immunohistochemical staining (IHC) for the mismatch repair proteins, MutS homologue 2 (MSH2) and MutL homologue 1 (MLH1), reliably identifies the microsatellite instability phenotype. This study evaluated the ability of IHC to detect germline mutations in an unselected group of patients with colorectal cancer (CRC).
All patients with CRC operated on between July 2000 and March 2003, and demonstrating a loss of protein, were contacted. Following informed consent, searchs for germline mutation and methylation of the promoter were performed on normal and tumoral DNA.
Thirty patients agreed to participate, four of whom fulfilled the Amsterdam II criteria. Loss of expression of MLH1 was found in 20 patients, and loss of expression of MSH2 in ten patients. Four of the MLH1-deficient patients had a germline MLH1 point mutation (positive predictive value (PPV) 20 (95 per cent confidence interval (c.i.) 2 to 38 per cent) and 11 had promoter methylation. Seven of the MSH2-deficient patients had a germline MSH2 point mutation (PPV 70 (95 per cent c.i. 54 to 96 per cent), and none showed promoter methylation.
MLH1-deficient patients who are young or have a positive family history of cancer should be referred for genetic testing and counselling, whereas MSH2-deficient patients should be counselled in the same way as patients with HNPCC.
遗传性非息肉病性结直肠癌（HNPCC）大多由错配修复基因MSH2和MLH1的种系突变引起。HNPCC的诊断基于一组临床标准，这些标准可能过于严格，无法识别所有受影响的患者。错配修复蛋白MutS同源物2（MSH2）和MutL同源物1（MLH1）的免疫组织化学染色（IHC）可可靠地识别微卫星不稳定性表型。本研究评估了IHC在一组未经选择的结直肠癌（CRC）患者中检测种系突变的能力。
联系了2000年7月至2003年3月期间接受手术且显示蛋白缺失的所有CRC患者。在获得知情同意后，对正常和肿瘤DNA进行种系突变和启动子甲基化检测。
30名患者同意参与，其中4名符合阿姆斯特丹II标准。20名患者发现MLH1表达缺失，10名患者发现MSH2表达缺失。4名MLH1缺陷患者有MLH1种系点突变（阳性预测值（PPV）20（95%置信区间（c.i.）2至38%），11名有启动子甲基化。7名MSH2缺陷患者有MSH2种系点突变（PPV 70（95% c.i. 54至96%），且均未显示启动子甲基化。
年轻或有癌症家族史阳性的MLH1缺陷患者应转诊进行基因检测和咨询，而MSH2缺陷患者应与HNPCC患者接受相同的咨询。
