目的:遗传性结直肠癌(CRC)约占所有CRC病例的5%-10%。在中国人群中,尚未完全确定与CRC相关的种系突变的全谱和相应的体细胞突变谱。
方法:我们进行了首次人群研究,调查了1,000多名(n=1,923)中国CRC患者的种系突变状态,并检查了他们与体细胞突变景观的关系。用58基因的下一代测序小组检查了种系改变,和体细胞改变用605基因小组检查。
结果:在85例患者中发现了92个致病(P)突变,在62例患者中鉴定出81种可能的致病性(LP)种系突变,占所有患者的7.6%(147/1,923)。MSH2和APC是Lynch综合征和非Lynch综合征组中突变最多的基因,分别。P/LP突变患者的微卫星不稳定性比率明显增高,高度缺乏错配修复,CRC家族史,和较低的年龄。体细胞突变景观显示P组中的突变频率明显更高,而非P组中的拷贝数变异趋势更高。Lynch综合征组的突变频率和肿瘤突变负担明显高于非Lynch综合征组。聚类分析显示Notch信号通路在Lynch综合征组中具有独特的聚集性,MAPK和cAMP信号通路在非Lynch综合征组中具有独特的聚集性。人群风险分析表明,P组为11.13(95%CI:8.289-15.44),LP组为20.68(95%CI:12.89-33.18)。
结论:在中国患有种系突变的CRC患者中发现了明显的特征。Notch信号通路在Lynch综合征组中具有独特的聚集性,MAPK和cAMP信号通路在非Lynch综合征组中具有独特的聚集性。具有P/LP种系突变的患者表现出更高的CRC风险。
OBJECTIVE: Hereditary colorectal cancer (CRC) accounts for approximately 5%-10% of all CRC cases. The full profile of CRC-related germline mutations and the corresponding somatic mutational profile have not been fully determined in the Chinese population.
METHODS: We performed the first population study investigating the germline mutation status in more than 1,000 (n = 1,923) Chinese patients with CRC and examined their relationship with the somatic mutational landscape. Germline alterations were examined with a 58-gene next-generation sequencing panel, and somatic alterations were examined with a 605-gene panel.
RESULTS: A total of 92 pathogenic (P) mutations were identified in 85 patients, and 81 likely pathogenic (LP) germline mutations were identified in 62 patients, accounting for 7.6% (147/1,923) of all patients. MSH2 and APC was the most mutated gene in the Lynch syndrome and non-Lynch syndrome groups, respectively. Patients with P/LP mutations had a significantly higher ratio of microsatellite instability, highly deficient mismatch repair, family history of CRC, and lower age. The somatic mutational landscape revealed a significantly higher mutational frequency in the P group and a trend toward higher copy number variations in the non-P group. The Lynch syndrome group had a significantly higher mutational frequency and tumor mutational burden than the non-Lynch syndrome group. Clustering analysis revealed that the Notch signaling pathway was uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Population risk analysis indicated that the overall odds ratio was 11.13 (95% CI: 8.289-15.44) for the P group and 20.68 (95% CI: 12.89-33.18) for the LP group.
CONCLUSIONS: Distinct features were revealed in Chinese patients with CRC with germline mutations. The Notch signaling pathway was uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Patients with P/LP germline mutations exhibited higher CRC risk.