CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer.
CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer.
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DOI：
10.1093/annonc/mdy085
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发表时间：
2018-05-01
期刊：
影响因子：
--
通讯作者：
Lothe RA
中科院分区：
文献类型：
--
作者：
Smeby J;Sveen A;Merok MA;Danielsen SA;Eilertsen IA;Guren MG;Dienstmann R;Nesbakken A;Lothe RA
KRAS和BRAFV 600 E突变对原发性结直肠癌（CRC）预后的影响因微卫星不稳定性（MSI）状态而异。CRC的基于基因表达的共有分子亚型（CMS）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分层框架。我们研究了CMS组中这些突变的预后价值。分析了来自挪威一系列CRC I-IV期的总共1197个原发性肿瘤的MSI和KRAS（密码子12、13和61）和BRAF（密码子600）热点中的突变状态。分析了一个子集的基因表达，并获得了317个样品的置信CMS分类。该队列扩展了临床和分子数据，包括CMS分类，来自临床可用数据集GSE 39582中的514例患者。使用与KRAS和BRAFV 600 E突变相关的基因表达特征来评估CMS组中突变对基因表达的差异影响。 BRAF V600 E和KRAS突变均与MSS肿瘤的5年总生存期（OS）较低相关（BRAFV 600 E突变与KRAS/BRAF野生型相比：风险比（HR）2.85，P < 0.001; KRAS突变与KRAS/BRAF野生型相比：HR 1.30，P = 0.013）。BRAFV 600 E突变的MSS肿瘤高度富集，并与CMS 1中的转移性疾病相关，导致该亚型的不良预后影响（OS：BRAFV 600 E突变vs野生型：HR 7.73，P = 0.001）。相反，KRAS突变的不良预后仅限于具有CMS 2/CMS 3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，BRAFV 600 E和KRAS突变对基因表达特征的差异效应证实了亚型特异性预后相关性。 BRAF V600 E突变在CMS 1 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（CMS 2/CMS 3）MSS肿瘤的不良结局相关。
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. 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. BRAF V600E 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. BRAF V600E 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.
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影响因子：
45.3
作者：
Popovici, Vlad;Budinska, Eva;Delorenzi, Mauro
通讯作者：
Delorenzi, Mauro
影响因子：
9.8
作者：
Mouradov, Dmitri;Domingo, Enric;Sieber, Oliver M.
通讯作者：
Sieber, Oliver M.
影响因子：
50.3
作者：
Singh A;Greninger P;Rhodes D;Koopman L;Violette S;Bardeesy N;Settleman J
通讯作者：
Settleman J
DOI：
10.1093/annonc/mds614
发表时间：
2013-05
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Merok MA;Ahlquist T;Røyrvik EC;Tufteland KF;Hektoen M;Sjo OH;Mala T;Svindland A;Lothe RA;Nesbakken A
通讯作者：
Nesbakken A
影响因子：
11.2
作者：
Samowitz, WS;Sweeney, C;Slattery, ML
通讯作者：
Slattery, ML