Frequency and coexistence of KRAS, NRAS, BRAF and PIK3CA mutations and occurrence of MMR deficiency in Danish colorectal cancer patients
Frequency and coexistence of KRAS, NRAS, BRAF and PIK3CA mutations and occurrence of MMR deficiency in Danish colorectal cancer patients
复制标题
DOI：
10.1111/apm.13091
复制
发表时间：
2020-11-06
期刊：
影响因子：
2.8
通讯作者：
Hogdall, Estrid
中科院分区：
文献类型：
--
作者：
Poulsen, Tim Svenstrup;de Oliveira, Douglas Vinicius Nogueira Perez;Hogdall, Estrid
MAPK信号基因KRAS、NRAS和BRAF以及PIK3CA基因在结直肠癌的诊断程序中经常被用于突变的研究。很少有研究报告这些基因与临床相关的共存突变，而一些以前被认为是相互排斥的。我们开始调查这些靶点的频率和共存突变，以及在丹麦结直肠癌的大量队列中错配修复缺陷(DMMR)的发生。作为我们诊断工作流程的一部分，我们使用下一代测序(NGS)对1000例结直肠肿瘤进行了KRAS、NRAS、BRAF和PIK3CA突变的测序，并通过免疫组织化学(IHC)分析了MMR蛋白、MLH1、PMS2、MSH2和MSH6的丢失。12名患者(1.2%)的共存突变是同一基因中的多个突变或跨多个基因(KRAS、NRAS和/或BRAF)发生的。除了BRAF突变的频率更高(18.0%)外，基因单一突变的频率与以前报道的相似。我们发现14.6%的病例存在dMMR，其中大多数同时缺乏MLH1和PMS2的表达。仅在涉及MLH1和/或PMS2的dMMR病例中存在BRAF突变。我们的发现表明，除了热点BRAF V600E与KRAS/NRAS突变互斥外，还存在共存突变。因此，评估这些基因中一个或多个基因的共同突变也应该被考虑在内，而不是MAPK信号的单个基因改变。这可能会影响未来的肿瘤治疗，应该在诊断工作流程中考虑。
The MAPK signalling genes KRAS, NRAS and BRAF and the PIK3CA gene are routinely investigated for mutations in the diagnostic routine of colorectal cancer. Few studies have reported co-existing mutations in these genes with clinical relevance, while some have been previously regarded as mutually exclusive. We set to investigate the frequency and co-occurrent mutations in these targets, and the occurrence of mismatch repair deficiency (dMMR) in a large cohort of Danish colorectal cancers. 1000 colorectal tumours were sequenced as part of our diagnostic workflow for KRAS, NRAS, BRAF and PIK3CA mutations using next-generation sequencing (NGS) and analysed by immunohistochemistry (IHC) for loss of the MMR proteins, MLH1, PMS2, MSH2 and MSH6. Co-existing mutations in 12 patients (1.2%) occurred as multiple mutations in the same gene or spread across several genes (KRAS, NRAS and/or BRAF). The frequency of single mutations in the genes occurred with a frequency similar to previously reported, except for a higher frequency of BRAF mutations (18.0%). We found dMMR in 14.6% of the cases with a majority lacking expression of both MLH1 and PMS2. BRAF mutations were only present in dMMR cases involving MLH1 and/or PMS2. Our findings suggest that co-existing mutations occur, except for the hotspot BRAF V600E, which is mutually exclusive with KRAS/NRAS mutations. Therefore, instead of single gene alterations from the MAPK signalling, assessing co-occurrence of mutations within one or more of those genes should also be accounted. This may impact future oncological treatments and should be considered in the diagnostic workflow.