文章：

结直肠癌的遗传易感性

Genetic predisposition to colorectal cancer

原文发布日期：2004-10-01

DOI: 10.1038/nrc1453

类型: Review Article

开放获取: 否

要点：

1. Cancer is a genetic disease. Most cancer-causing mutations are somatic, occurring in the affected tissue during the course of carcinogenesis; however, most cancers also have a hereditary component that is caused by predisposing mutations that affect the germline, are heritable and contribute to the initiation of carcinogenesis.
2. Colorectal cancer is probably the type of cancer for which the most is known about the genes affected by cancer-causing mutations, their normal functions and their carcinogenic effects when mutated.
3. High-penetrance mutations confer predisposition to colorectal cancer mainly in Lynch syndrome (which involves mutations in mismatch-repair genes) and in familial adenomatous polyposis (which involves mutations in the APC tumour suppressor). Together, these conditions account for 5% or less of all cases of colorectal cancer.
4. Determining carriership for the mutations that underlie these conditions is important in the management and prevention of cancer in these patients and their families.
5. Low-penetrance mutations account for a high proportion of all the attributable risk of colorectal cancer, in both familial and sporadic cases. These mutations are more difficult to identify, but — mainly due to the implementation of association studies — are increasingly being detected and characterized.
6. The identification of both high- and low-penetrance mutations contributes significantly to our understanding of the molecular genetic processes occurring in cancer. This understanding facilitates the development of therapeutic drugs and preventive strategies.
7. Gene–gene and gene–environment interactions have a significant influence on susceptibility to colorectal cancer. Our current understanding of these interactions is limited, and concerted research efforts in this area will be important for a full understanding of predisposition to this cancer.

要点翻译：

1. 癌症是一种遗传性疾病。大多数致癌突变是体细胞突变，发生在癌变过程中受累组织内；然而，大多数癌症也具有遗传成分，由影响生殖系、可遗传并参与癌变启动的易感突变引起。
2. 结直肠癌可能是目前对致癌突变所影响基因、其正常功能及突变后致癌效应了解最为深入的一种癌症。
3. 高外显率突变主要导致林奇综合征（涉及错配修复基因突变）和家族性腺瘤性息肉病（涉及APC肿瘤抑制基因突变）中的结直肠癌易感性。这些情况合计占所有结直肠癌病例的5%或更少。
4. 确定这些疾病相关突变携带状态对于患者及其家庭的癌症管理和预防至关重要。
5. 在家族性和散发性结直肠癌病例中，低外显率突变占所有可归因风险的比例很高。这些突变较难识别，但主要得益于关联研究的实施，正日益被检测和表征。
6. 高外显率和低外显率突变的鉴定极大地促进了我们对癌症中分子遗传过程的理解。这种理解有助于治疗药物和预防策略的开发。
7. 基因-基因和基因-环境相互作用对结直肠癌易感性具有显著影响。我们目前对这些相互作用的理解有限，在该领域开展协同研究对于全面理解这种癌症的易感性至关重要。

英文摘要：

High-penetrance mutations in several genes have been identified that contribute to hereditary colorectal cancer. The role of these mutations in cancer pathogenesis is well understood and their detection is successfully used in clinical diagnosis. In stark contrast, our understanding of the influence of low-penetrance mutations that account for most of the remaining familial cases of colorectal cancer, as well as an unknown proportion of sporadic cases, is far less advanced. Extensive ongoing research into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease aetiology and developing new diagnostic, preventive and therapeutic strategies.

摘要翻译： 

对肿瘤抑制因子p53的关注已使人们在癌症发生过程中对其功能和调控的复杂性有了大量了解。然而，关于p53翻译后修饰在癌症发生和预防中的作用，我们的认识仍存在空白。深入理解p53将极有助于开发新的癌症治疗和预防策略，包括恢复p53功能以及选择性杀灭携带TP53突变的肿瘤。

原文链接：

Genetic predisposition to colorectal cancer