Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Spain; Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain.
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Mol Aspects Med. 2019 Oct;69:10-26. doi: 10.1016/j.mam.2019.03.001. Epub 2019 Mar 18.
The present article summarizes recent developments in the characterization of genetic predisposition to colorectal cancer (CRC). The main themes covered include new hereditary CRC and polyposis syndromes, non-CRC hereditary cancer genes found mutated in CRC patients, strategies used to identify novel causal genes, and review of candidate genes that have been proposed to predispose to CRC and/or colonic polyposis. We provide an overview of newly described genes and syndromes associated with predisposition to CRC and polyposis, including: polymerase proofreading-associated polyposis, NTHL1-associated polyposis, mismatch repair gene biallelic inactivation-related adenomatous polyposis (including MSH3- and MLH3-associated polyposes), GREM1-associated mixed polyposis, RNF43-associated serrated polyposis, and RPS20 mutations as a rare cause of hereditary nonpolyposis CRC. The implementation of next generation sequencing approaches for genetic testing has exposed the presence of pathogenic germline variants in genes associated with hereditary cancer syndromes not traditionally linked to CRC, which may have an impact on genetic testing, counseling and surveillance. The identification of new hereditary CRC and polyposis genes has not deemed an easy endeavor, even though known CRC-related genes explain a small proportion of the estimated familial risk. Whole-genome sequencing may offer a technology for increasing this proportion, particularly if applied on pedigree data allowing linkage type of analysis. The final section critically surveys the large number of candidate genes that have been recently proposed for CRC predisposition.
本文总结了近年来对结直肠癌（CRC）遗传易感性特征的研究进展。主要涵盖了新的遗传性 CRC 和息肉综合征、在 CRC 患者中发现突变的非 CRC 遗传性癌症基因、用于鉴定新的因果基因的策略，以及对可能导致 CRC 和/或结肠息肉的候选基因的综述。我们概述了与 CRC 和息肉易感性相关的新描述的基因和综合征，包括：聚合酶校对相关息肉病、NTHL1 相关息肉病、错配修复基因双等位基因失活相关腺瘤性息肉病（包括 MSH3 和 MLH3 相关息肉病）、GREM1 相关混合息肉病、RNF43 相关锯齿状息肉病，以及 RPS20 突变作为一种罕见的遗传性非息肉病 CRC 的原因。下一代测序方法在遗传检测中的应用揭示了与传统上与 CRC 无关的遗传性癌症综合征相关基因中致病性种系变异的存在，这可能对遗传检测、咨询和监测产生影响。尽管已知的 CRC 相关基因仅能解释估计的家族风险的一小部分，但识别新的遗传性 CRC 和息肉基因并非易事。全基因组测序可能提供一种增加这一比例的技术，特别是如果应用于允许连锁分析的系谱数据。最后一部分批判性地综述了最近提出的大量用于 CRC 易感性的候选基因。
