KRAS G12C突变在消化系统恶性肿瘤中的分子特点

Molecular characterization of KRAS G12C mutation in the tumors of digestive system

目的:探究KRAS G12C突变在不同消化系统恶性肿瘤中的发生率及分子病理特点。方法:收集2017—2022年在中国医学科学院肿瘤医院诊断为消化系统恶性肿瘤且有肿瘤组织样本的1100例患者资料。使用二代测序的方法对1100例消化系统恶性肿瘤组织样本(包括结肠腺癌、直肠腺癌、回盲肠腺癌、十二指肠腺癌、胃腺癌、胆管腺癌和胰腺导管腺癌)的微卫星状态和肿瘤突变负荷(TMB),以及KRAS、NRAS、BRAF、PIK3CA突变进行检测。结果:微卫星高度不稳定(MSI-H)在不同消化系统肿瘤中存在差异,其中在十二指肠腺癌发生率最高(19%),其次为回盲肠腺癌(18%)和结肠腺癌(10.2%),但在100例胰腺导管腺癌中未检出MSI-H的肿瘤。不同消化系统恶性肿瘤的TMB值亦有差异,高TMB(≥10 mut/Mb)在回盲肠腺癌中最常见(24%),其次为十二指肠腺癌(22%)和胃腺癌(18.9%)。KRAS在总人群中的突变率为41.09%,其中在胰腺导管腺癌中突变率最高(85.0%),其次为十二指肠腺癌(56%)和回盲肠腺癌(53%),在胃腺癌中最低(7.3%)。KRAS G12C在总人群中的突变率为2.82%(31/1100),在所有KRAS突变的消化系统肿瘤中仅占6.9%(31/452),常见于回盲肠腺癌(2/9),其次为十二指肠腺癌(13%)和结肠腺癌(8.8%)。KRAS G12C突变和其他KRAS突变亚型患者的性别、年龄、MSI和TMB状态相近。结论:虽然近一半的消化系统恶性肿瘤患者携带有KRAS突变,但KRAS G12C突变发生率相对较低,只占KRAS突变人群的6.9%。KRAS G12C突变最常见于回盲肠腺癌、十二指肠腺癌和结肠腺癌,且与其他类型的KRAS突变相比未见明显的临床和分子病理特征差异。

Objective:To identified the molecular characteristics of KRAS G12C mutation in the tumors of digestive system.Methods:Data of 1100 patients diagnosed as digestive malignant tumor in Cancer Hospital of Chinese Academy of Medical Sciences from 2017 to 2022 were collected.The microsatellite status,tumor mutation burden(TMB)and KRAS,NRAS,BRAF and PIK3CA mutations were detected by next-generation sequencing in 1100 patients with tumors of digestive system,including colorectal adenocarcinoma,duodenal adenocarcinoma,cholangiocarcinoma,gastric adenocarcinoma,ileocecal adenocarcinoma and pancreatic ductal adenocarcinoma.Results:Microsatellite instability-high(MSI-H)tumors were most common in duodenal adenocarcinoma(19%),followed by ileocecal adenocarcinoma(18%)and colorectal adenocarcinoma(10.2%).However,no MSI-H tumors were detected in the 100 cases of pancreatic ductal adenocarcinoma.TMB values also varied among different tumors of digestive system.High-TMB(≥10 mut/Mb)tumors were most common in ileocecal adenocarcinoma(24%),followed by duodenal adenocarcinoma(22%)and gastric adenocarcinoma(18.9%).KRAS mutations were detected in 452 of 1100(41.09%)cases,among which the most common tumor was pancreatic ductal adenocarcinoma(85.0%),followed by duodenal adenocarcinoma(56%)and ileocecal adenocarcinoma(53%).However,KRAS mutations were identified in 7.3%of gastric adenocarcinoma.KRAS G12C mutation was detected in 2.82%of all the 1100 tumors,and only 6.9%(31/452)of all digestive tumors with KRAS mutations among which the most common tumor was ileocecal adenocarcinoma(2/9),followed by duodenal adenocarcinoma(13%)and colorectal adenocarcinoma(8.8%).However,no significant differences in gender,age,MSI and TMB status were observed between patients with KRAS G12C mutation and other KRAS mutation subtypes.Conclusions:Although nearly half of patients with digestive malignancies carry KRAS mutations,but only 6.9%of KRAS-mutant cases harbored KRAS G12C mutation subtype.KRAS G12C mutation was most common in ileocecal cancer,duodenal cancer and colorectal cancer.And no obvious difference in clinical and molecular pathological features compared with other types of KRAS mutations.