State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.
Department of Molecular Diagnosis, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China.
Cancer Commun (Lond). 2020 Nov;40(11):620-632. doi: 10.1002/cac2.12093. Epub 2020 Sep 10.
Inherited susceptibility accounts for nearly one-third of colorectal cancer (CRC) predispositions and has an 80%-100% lifetime risk of this disease. However, there are few data about germline mutations of hereditary CRC-related genes in Chinese patients with CRC. This study aimed to assess the prevalence of gene mutations related to cancer susceptibility among Chinese patients with CRC, differences between Chinese and Western patients, and the phenotype-genotype correlation.
We retrospectively collected tumor samples from 526 patients with CRC under 70 years old who underwent hereditary CRC genetic testing. A series of bioinformatic analyses, as well as statistical comparisons, were performed.
We found that 77 patients (14.6%) harbored functional variants of the 12 genes. The mutation frequencies of the top 5 mutated genes were 6.5% for MutL homolog 1 (MLH1), 5.1% for MutS homolog 2 (MSH2), 1.0% for MSH6, 0.8% for PMS1 homolog 2 (PMS2), and 0.8% for APC regulator of the WNT signaling pathway (APC). Our data showed much higher rates of mutations of MSH6 and PMS2 genes among all mismatch repair (MMR) genes as compared with those in Western populations. Mutations in MLH1, MSH2, and MSH6 were found to be mutually exclusive. Patients with MLH1 or MSH2 mutations had higher frequencies of personal history of cancer (MLH1: 20.6% vs. 8.7%; MSH2: 25.9% vs. 8.6%) and family history of cancer than those without these mutations (MLH1: 73.5% vs. 48.4%; MSH2: 70.4% vs. 48.9%), and the lesions were more prone to occur on the right side of the colon than on the left side (MLH1: 73.5% vs. 29.3%; MSH2: 56.0% vs. 31.0%). The proportion of stage I/II disease was higher in patients with MLH1 mutations than in those without MLH1 mutations (70.6% vs. 50.7%), and the rate of polyps was higher in patients with APC mutations than in those with wild-type APC (75.0% vs. 17.4%).
These results provide a full-scale landscape of hereditary susceptibility over 12 related genes in CRC patients and suggest that a comprehensive multi-gene panel testing for hereditary CRC predisposition could be a helpful analysis in clinical practice.
遗传性易感性占结直肠癌（CRC）易感性的近三分之一，终生患该病的风险为 80%-100%。然而，关于中国 CRC 患者中与遗传性 CRC 相关基因的种系突变的数据很少。本研究旨在评估中国 CRC 患者中与癌症易感性相关的基因突变的流行率、中国与西方患者之间的差异，以及表型-基因型相关性。
我们回顾性收集了 526 名年龄在 70 岁以下接受遗传性 CRC 遗传检测的 CRC 患者的肿瘤样本。进行了一系列生物信息学分析和统计比较。
我们发现 77 名患者（14.6%）携带 12 个基因的功能变异。前 5 个突变基因的突变频率为：MutL 同源物 1（MLH1）为 6.5%，MutS 同源物 2（MSH2）为 5.1%，MSH6 为 1.0%，PMS1 同源物 2（PMS2）为 0.8%，Wnt 信号通路 APC 调节剂（APC）为 0.8%。我们的数据显示，与西方人群相比，所有错配修复（MMR）基因中 MSH6 和 PMS2 基因的突变率要高得多。MLH1、MSH2 和 MSH6 的突变相互排斥。MLH1 或 MSH2 突变的患者比没有这些突变的患者有更高的癌症个人史（MLH1：20.6%比 8.7%；MSH2：25.9%比 8.6%）和癌症家族史（MLH1：73.5%比 48.4%；MSH2：70.4%比 48.9%），病变更倾向于发生在结肠右侧而不是左侧（MLH1：73.5%比 29.3%；MSH2：56.0%比 31.0%）。MLH1 突变患者的 I/II 期疾病比例高于无 MLH1 突变患者（70.6%比 50.7%），APC 突变患者的息肉率高于野生型 APC（75.0%比 17.4%）。
这些结果提供了 CRC 患者中与 12 个相关基因相关的遗传性易感性的全面概况，并表明对遗传性 CRC 易感性进行综合多基因面板检测可能有助于临床实践。
