MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease.
MSH6 germline mutations in early-onset colorectal cancer patients without family history of the disease.
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DOI：
10.1038/sj.bjc.6603318
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发表时间：
2006-09-18
影响因子：
8.8
通讯作者：
Teixeira, M R
中科院分区：
文献类型：
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作者：
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
生殖系MLH1和MSH2突变在具有阴性家族史的年轻结直肠癌患者中很少。为了评估生殖系MSH6突变对早发性结直肠癌的贡献，我们分析了38例45岁以前诊断患有这种疾病的患者的外周血，这些患者没有遗传性非息肉病性结直肠癌相关癌症的家族史。研究人员分析了108名健康志愿者的血液样本，以确定是否存在可能影响MSH6功能的基因改变。在发现的7个（18.4%）MSH6改变中，我们已经确定了3个新的种系突变，一个8 bp缺失导致截短的蛋白质和两个错义突变导致属于不同极性组的氨基酸取代。在MSH6缺失的患者中发现了高频微卫星不稳定性，但在其他27种分析的癌症中没有发现。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突变有助于早发性结直肠癌的一个子集。进一步的研究是必要的，以了解负责MSH6种系突变的可变渗透的遗传和环境因素，以及确定早发性结直肠癌的其他原因。
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.