Hereditary non-polyposis colorectal cancer (HNPCC):: Phenotype-genotype correlation between patients with and without indentified mutation
Hereditary non-polyposis colorectal cancer (HNPCC):: Phenotype-genotype correlation between patients with and without indentified mutation
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DOI：
10.1002/humu.10083
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发表时间：
2002-01-01
期刊：
影响因子：
3.9
通讯作者：
Nielsen, FC
中科院分区：
文献类型：
--
作者：
Bisgaard, ML;Jäger, AC;Nielsen, FC
遗传性非息肉病性结直肠癌（HNPCC）家族的受影响成员在早期（平均45岁）发生结直肠癌，并经常发生结肠外癌症，特别是子宫，尿路和小肠。如果在第一次手术时没有接受结肠次全切除术治疗，他们患上多种原发性结直肠癌的风险很高，并且与散发性结直肠癌患者相比，右侧结肠癌的发生率更高，而直肠癌的发生率更低。我们通过直接测序筛选了31个符合阿姆斯特丹标准的家庭和54个结直肠癌聚集但不符合MLH 1和MSH 2突变阿姆斯特丹标准的家庭，并在61%的阿姆斯特丹阳性家庭中检测到突变，但仅在15%的阿姆斯特丹阴性家庭中检测到突变。基因型-表型相关性进行了比较141个受影响的个人与一个确定的突变和78个受影响的个人从阿姆斯特丹阳性家庭中的突变是无法识别的MLH 1或MSH 2。在受影响的人与确定的突变，所有预期的表型性状的代表，而受影响的人，其中没有检测到突变分为两个明显不同的亚组。未发现突变的次要亚组通常具有与已确定突变的受影响人员相同的特征。主要亚组在临床特征上有显著差异，表现出与晚发型家族相似的表型特征，包括直肠癌的丰度，少数HNPCC相关癌症，多发性结直肠癌的频率较低，以及发病年龄较晚。最后，对于6个错义突变和1个单密码子缺失，通过结构域定位、lod评分计算或分离分析（如果可能）以及突变诱导的生化变化来评估致病潜力。结果表明，大多数错义突变是致病性的，但在预测性检测程序中实施之前，需要通过功能测定进行进一步表征。
Affected members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at an early age (mean 45 yr) and frequently get extracolonic cancers particularly in the uterus, urinary tract, and small intestine. They have a high risk of developing more than one primary colorectal cancer if not treated with subtotal colectomy at first operation and have more frequent right-sided colon cancers and less frequent rectum cancers, compared to patients with sporadic colorectal cancer. We have screened 31 families fulfilling the Amsterdam criteria and 54 families with a colorectal cancer clustering but not fulfilling the Amsterdam criteria for mutations in MLH1 and MSH2 by direct sequencing, and detected a mutation in 61% of the Amsterdam positive families but only in 15% of the Amsterdam negative families. Genotype-phenotype correlation was compared between 141 affected individuals with an identified mutation and 78 affected individuals from Amsterdam positive families in which a mutation was not identifiable in MLH1 or MSH2. In the affected persons with identified mutations, all expected phenotypic traits were represented, whereas affected persons in whom no mutation was detected fell into two clearly distinguishable subgroups. The minor subgroup, in which no mutation was identified, generally had the same characteristics as found in affected persons with identified mutations. The major subgroup differed significantly in clinical features and exhibited phenotypic traits similar to those found in late-onset families, including abundance of rectal cancer, few HNPCC-related cancers, lower frequency of multiple colorectal cancers, and later age at onset. Finally, for six missense mutations and one single codon deletion, the pathogenic potential was evaluated by domain localization, lod score calculation or segregation analysis when possible, and mutation-induced biochemical change. The results indicate that the majority of missense mutations are pathogenic, although further characterization by functional assays is necessary before implementation in predictive testing programs.