Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Finland.
Int J Cancer. 2010 Dec 15;127(12):2974-80. doi: 10.1002/ijc.25529.
It is estimated that up to 35% of colorectal cancers (CRC) can be explained by hereditary factors. However, genes predisposing to highly penetrant CRC syndromes account for only a small fraction of all cases. Thus, most CRCs still remain molecularly unexplained. A recent systematic sequencing study on well-annotated human protein coding genes identified 280 somatically mutated candidate cancer genes (CAN genes) in breast and colorectal cancer. It is estimated that 8% of all reported cancer genes show both somatic and germline mutations. Therefore, the identified CAN genes serve as a distinct set of candidates for being involved in hereditary susceptibility. The aim of this study was to evaluate the role of colorectal CAN genes in familial CRC. Samples from 45 familial CRCs without known cancer predisposing mutations were screened for somatic and germline variants in 15 top-ranked CAN genes. Six of the genes were found to be somatically mutated in our tumor series. We identified 22 nonsynonymous somatic mutations of which the majority was of missense type. In germline, three novel nonsynonymous variants were identified in the following genes: CSMD3, EPHB6 and C10orf137, and none of the variants were present in 890 population-matched healthy controls. It is possible that the identified germline variants modulate predisposition to CRC. Functional validation and larger sample sets, however, will be required to clarify the role of the identified germline variants in CRC susceptibility.
据估计，多达 35%的结直肠癌（CRC）可以用遗传因素来解释。然而，导致高外显率 CRC 综合征的基因仅占所有病例的一小部分。因此，大多数 CRC 仍然在分子水平上无法解释。最近一项针对人类蛋白质编码基因进行的系统测序研究在乳腺癌和结直肠癌中鉴定了 280 个体细胞突变候选癌症基因（CAN 基因）。据估计，所有报道的癌症基因中有 8%同时存在体细胞和种系突变。因此，鉴定出的 CAN 基因是参与遗传性易感性的一组独特候选基因。本研究旨在评估结直肠 CAN 基因在家族性 CRC 中的作用。对 45 例无已知癌症易感突变的家族性 CRC 样本进行了 15 个排名靠前的 CAN 基因的体细胞和种系变异筛选。在我们的肿瘤系列中发现了 6 个基因发生了体细胞突变。我们鉴定了 22 个非同义体细胞突变，其中大部分为错义突变。在种系中，在以下基因中发现了 3 个新的非同义变体：CSMD3、EPHB6 和 C10orf137，而在 890 个与人群匹配的健康对照中均未发现这些变体。这些鉴定出的种系变体可能会调节 CRC 的易感性。然而，需要进行功能验证和更大的样本量研究，以阐明鉴定出的种系变体在 CRC 易感性中的作用。
