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CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer.
Annals of Oncology ( IF 50.5 ) Pub Date : 2018-05-01 , DOI: 10.1093/annonc/mdy085
J Smeby 1 , A Sveen 2 , M A Merok 3 , S A Danielsen 2 , I A Eilertsen 2 , M G Guren 4 , R Dienstmann 5 , A Nesbakken 6 , R A Lothe 7
Affiliation  

Background The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups. Patients and methods Totally 1197 primary tumors from a Norwegian series of CRC stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups. Results BRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P < 0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P = 0.013). BRAFV600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E mutation versus wild-type: HR 7.73, P = 0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P = 0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group. Conclusions BRAFV600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.

中文翻译:

CMS依赖的KRAS和BRAFV600E突变对原发性结直肠癌的预后影响。

背景KRAS和BRAFV600E突变对原发性结直肠癌(CRC)的预后影响随微卫星不稳定性(MSI)状态的不同而不同。CRC的基于基因表达的共有分子亚型(CMSs)定义了分子和临床上不同的亚组,并代表了生物标志物分析中的新型分层框架。我们调查了这些突变在CMS组中的预后价值。患者和方法分析了来自挪威CRC系列I-IV期的1197例原发性肿瘤的MSI和突变状态,分别在KRAS(密码子12、13和61)和BRAF(密码子600)的热点中。分析了一个子集的基因表达并获得了317个样品的可信CMS分类。此研究对象扩大了临床和分子数据,包括CMS分类,从公开可用的数据集GSE39582中的514位患者中提取。与KRAS和BRAFV600E突变相关的基因表达特征被用于评估CMS组之间突变对基因表达的不同影响。结果BRAFV600E和KRAS突变均与仅在MSS肿瘤中的5年总体生存期较低有关(BRAFV600E突变与KRAS / BRAF野生型:危险比(HR)2.85,P <0.001; KRAS突变与KRAS / BRAF野生型:HR 1.30,P = 0.013)。BRAFV600E突变的MSS肿瘤在CMS1中大量富集并与转移性疾病相关,导致对该亚型的预后产生负面影响(OS:BRAFV600E突变与野生型:HR 7.73,P = 0.001)。相比之下,KRAS突变的不良预后仅限于具有CMS2 / CMS3上皮样基因表达谱的MSS肿瘤(OS:KRAS突变与野生型:HR 1.51,P = 0.011)。根据MSI状态和CMS组,BRAFV600E和KRAS突变对基因表达特征的差异影响证实了亚型特异性的预后关联。结论BRAFV600E突变在CMS1 MSS肿瘤中富集并与转移性疾病相关,导致该亚型的预后不良。KRAS突变与上皮(CMS2 / CMS3)MSS肿瘤的不良预后相关。结论BRAFV600E突变在CMS1 MSS肿瘤中富集并与转移性疾病相关,导致该亚型的预后不良。KRAS突变与上皮(CMS2 / CMS3)MSS肿瘤的不良预后相关。结论BRAFV600E突变在CMS1 MSS肿瘤中富集并与转移性疾病相关,导致该亚型的预后不良。KRAS突变与上皮(CMS2 / CMS3)MSS肿瘤的不良预后相关。
更新日期:2018-03-05
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