Lage Pedro A, Albuquerque Cristina, Sousa Rita G, Cravo Marilia L, Salazar Maria, Francisco Inês, Maia Lara, Claro Isabel, Suspiro Alexandra, Rodrigues Paula, Raposo Hélder, Fidalgo Paulo A, Nobre-Leitão Carlos
Serviço de Gastrenterologia, Instituto Português de Oncologia de Lisboa, Rua Professor Lima Basto, 1099-023 Lisbon, Portugal.
Cancer. 2004 Jul 1;101(1):172-7. doi: 10.1002/cncr.20320.
Hereditary nonpolyposis colorectal carcinoma (HNPCC) significantly raises the risk of developing colorectal carcinoma (CRC) and other extracolonic tumors. It is defined by the Amsterdam Criteria and is associated with germline mutations in mismatch repair genes, primarily MLH1 and MSH2. The objectives of the current study were to evaluate the presence of CRC (Type I) and other extracolonic tumors (Type II) in families with HNPCC and to analyze the findings for correlations with germline mutations in the MLH1 and MSH2 genes.
Seventy families with an HNPCC diagnosis were analyzed. Denaturing gradient gel electrophoresis and direct sequencing were used for germline mutation analysis in the MLH1 and MSH2 genes.
Forty-three of 70 families (61%) presented with HNPCC Type II. In 21 of 30 families that had a complete genetic diagnosis, 16 pathogenic germline mutations (7 MLH1 mutations and 9 MSH2 mutations) and 5 mutations of unknown pathogenecity (all MLH1 mutations) were found. In the remaining nine families, no mutations were detected. Unequivocally pathogenic mutations were far more common in families with HNPCC Type II compared with families that had CRC only (P = 0.01). Families with endometrial carcinoma presented with the greatest probability of mutational detection (P = 0.005). MLH1 was only gene affected in families with HNPCC Type I, whereas mutations in both MLH1 and MSH2 were found in families with HNPCC Type II (P = 0.04). However, the MSH2 gene was more frequently involved in families with HNPCC in which endometrial carcinoma was present (P = 0.005).
CRC and endometrial carcinoma were associated with a greater probability of detecting pathogenic mutations in mismatch repair genes, with MSH2 involvement predominating. The results support specific mutational screening strategies, based on observed phenotypes, for families with HNPCC.
遗传性非息肉病性结直肠癌（HNPCC）显著增加了患结直肠癌（CRC）和其他结肠外肿瘤的风险。它由阿姆斯特丹标准定义，与错配修复基因的种系突变相关，主要是MLH1和MSH2。本研究的目的是评估HNPCC家族中CRC（I型）和其他结肠外肿瘤（II型）的存在情况，并分析这些发现与MLH1和MSH2基因种系突变的相关性。
对70个诊断为HNPCC的家族进行分析。采用变性梯度凝胶电泳和直接测序对MLH1和MSH2基因进行种系突变分析。
70个家族中有43个（61%）表现为HNPCC II型。在30个进行了完整基因诊断的家族中，发现了16个致病种系突变（7个MLH1突变和9个MSH2突变）以及5个致病性未知的突变（均为MLH1突变）。在其余9个家族中未检测到突变。与仅患有CRC的家族相比，明确的致病突变在HNPCC II型家族中更为常见（P = 0.01）。患有子宫内膜癌的家族检测到突变的可能性最大（P = 0.005）。MLH1是I型HNPCC家族中唯一受影响的基因，而在II型HNPCC家族中发现了MLH1和MSH2的突变（P = 0.04）。然而，MSH2基因在存在子宫内膜癌的HNPCC家族中更常受累（P = 0.005）。
CRC和子宫内膜癌与检测错配修复基因致病突变的可能性增加相关，其中MSH2受累占主导。研究结果支持基于观察到的表型，对HNPCC家族采取特定的突变筛查策略。
