KRAS G12C 突变型结直肠癌和非小细胞肺癌的分子特征。

Molecular profile of KRAS G12C-mutant colorectal and non-small-cell lung cancer.

机构信息

Progenética, Grupo Pardini, Vespaziano, Brazil.

Research & Development Sector, Grupo Pardini, Vespaziano, Brazil.

出版信息

BMC Cancer. 2021 Feb 25;21(1):193. doi: 10.1186/s12885-021-07884-8.

DOI:10.1186/s12885-021-07884-8

PMID:33632153

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7905642/

Abstract

BACKGROUND

KRAS is the most frequently mutated oncogene in cancer, however efforts to develop targeted therapies have been largely unsuccessful. Recently, two small-molecule inhibitors, AMG 510 and MRTX849, have shown promising activity in KRAS G12C-mutant solid tumors. The current study aims to assess the molecular profile of KRAS G12C in colorectal (CRC) and non-small-cell lung cancer (NSCLC) tested in a clinical certified laboratory.

METHODS

CRC and NSCLC samples submitted for KRAS testing between 2017 and 2019 were reviewed. CRC samples were tested for KRAS and NRAS by pyrosequencing, while NSCLC samples were submitted to next generation sequencing of KRAS, NRAS, EGFR, and BRAF.

RESULTS

The dataset comprised 4897 CRC and 4686 NSCLC samples. Among CRC samples, KRAS was mutated in 2354 (48.1%). Most frequent codon 12 mutations were G12D in 731 samples (14.9%) and G12V in 522 (10.7%), followed by G12C in 167 (3.4%). KRAS mutations were more frequent in females than males (p = 0.003), however this difference was exclusive of non-G12C mutants (p < 0.001). KRAS mutation frequency was lower in the South and North regions (p = 0.003), but again KRAS G12C did not differ significantly (p = 0.80). In NSCLC, KRAS mutations were found in 1004 samples (21.4%). As opposed to CRC samples, G12C was the most common mutation in KRAS, in 346 cases (7.4%). The frequency of KRAS G12C was higher in the South and Southeast regions (p = 0.012), and lower in patients younger than 50 years (p < 0.001). KRAS G12C mutations were largely mutually exclusive with other driver mutations; only 11 NSCLC (3.2%) and 1 CRC (0.6%) cases had relevant co-mutations.

CONCLUSIONS

KRAS G12C presents in frequencies higher than several other driver mutations, and may represent a large volume of patients in absolute numbers. KRAS testing should be considered in all CRC and NSCLC patients, independently of clinical or demographic characteristics.

摘要

背景

KRAS 是癌症中最常发生突变的致癌基因，但开发靶向治疗的努力在很大程度上都没有成功。最近，两种小分子抑制剂 AMG 510 和 MRTX849 在 KRAS G12C 突变的实体瘤中显示出了有前景的活性。本研究旨在评估在临床认证实验室中检测到的结直肠癌（CRC）和非小细胞肺癌（NSCLC）中 KRAS G12C 的分子谱。

方法

对 2017 年至 2019 年间进行 KRAS 检测的 CRC 和 NSCLC 样本进行了回顾性研究。CRC 样本通过焦磷酸测序检测 KRAS 和 NRAS，而 NSCLC 样本则进行 KRAS、NRAS、EGFR 和 BRAF 的下一代测序。

结果

数据集包括 4897 例 CRC 和 4686 例 NSCLC 样本。在 CRC 样本中，2354 例（48.1%）发生了 KRAS 突变。最常见的密码子 12 突变是 731 例（14.9%）中的 G12D 和 522 例（10.7%）中的 G12V，其次是 167 例（3.4%）中的 G12C。女性中 KRAS 突变的频率高于男性（p=0.003），但这种差异仅存在于非 G12C 突变体中（p<0.001）。南、北部地区的 KRAS 突变频率较低（p=0.003），但 KRAS G12C 没有显著差异（p=0.80）。在 NSCLC 中，在 1004 例样本（21.4%）中发现了 KRAS 突变。与 CRC 样本不同，G12C 是 KRAS 中最常见的突变，在 346 例（7.4%）中发现了 G12C 突变。KRAS G12C 的频率在南部和东南部地区较高（p=0.012），而在 50 岁以下的患者中较低（p<0.001）。KRAS G12C 突变与其他驱动突变在很大程度上是相互排斥的；仅在 11 例 NSCLC（3.2%）和 1 例 CRC（0.6%）中发现了相关的共突变。