Pinto C, Veiga I, Pinheiro M, Mesquita B, Jeronimo C, Sousa O, Fragoso M, Santos L, Moreira-Dias L, Baptista M, Lopes C, Castedo S, Teixeira M R
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
Br J Cancer. 2006 Sep 18;95(6):752-6. doi: 10.1038/sj.bjc.6603318. Epub 2006 Aug 29.
Germline MLH1 and MSH2 mutations are scarce in young colorectal cancer patients with negative family history of the disease. To evaluate the contribution of germline MSH6 mutations to early-onset colorectal cancer, we have analysed peripheral blood of 38 patients diagnosed with this disease before 45 years of age and who presented no family history of hereditary nonpolyposis colorectal cancer-related cancers. Blood samples from 108 healthy volunteers were analysed for those genetic alterations suspected to affect the function of MSH6. Of the seven (18.4%) MSH6 alterations found, we have identified three novel germline mutations, one 8 bp deletion leading to a truncated protein and two missense mutations resulting in the substitution of amino acids belonging to different polarity groups. High-frequency microsatellite instability was found in the patient with the MSH6 deletion, but not in the other 27 carcinomas analysed. No MLH1 promoter methylation was detected in tumour tissue. Our findings suggest that germline MSH6 mutations contribute to a subset of early-onset colorectal cancer. Further studies are warranted to understand the genetic and environmental factors responsible for the variable penetration of MSH6 germline mutations, as well as to identify other causes of early-onset colorectal cancer.
在无结直肠癌家族病史的年轻结直肠癌患者中，生殖系MLH1和MSH2突变很少见。为了评估生殖系MSH6突变对早发性结直肠癌的影响，我们分析了38例45岁之前被诊断为此病且无遗传性非息肉病性结直肠癌相关癌症家族病史的患者的外周血。对108名健康志愿者的血样进行分析，以检测那些疑似影响MSH6功能的基因改变。在所发现的7种（18.4%）MSH6改变中，我们鉴定出3种新的生殖系突变，一种8 bp缺失导致蛋白质截短，两种错义突变导致属于不同极性基团的氨基酸替换。在MSH6缺失的患者中发现高频微卫星不稳定性，但在其他27例分析的癌组织中未发现。在肿瘤组织中未检测到MLH1启动子甲基化。我们的研究结果表明，生殖系MSH6突变促成了一部分早发性结直肠癌。有必要进一步开展研究，以了解导致MSH6生殖系突变可变外显率的遗传和环境因素，以及确定早发性结直肠癌的其他病因。
