External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS
External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS
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DOI：
10.1186/s12885-019-5842-7
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发表时间：
2019-07-11
期刊：
影响因子：
3.8
通讯作者：
Hoffmeister, Michael
中科院分区：
文献类型：
--
作者：
Alwers, Elizabeth;Blaeker, Hendrik;Hoffmeister, Michael
背景已提出竞争性分子分类系统来补充TNM分期系统，以更好地预测结直肠癌（CRC）的生存率。然而，迄今为止缺乏验证研究。本研究的目的是验证和扩展以前发表的分子分类的CRC在一个大的独立队列的CRC patients.MethodsCRC患者被招募到一个以人群为基础的队列研究（DACHS）。分子亚型是根据三个先前公布的分类进行分类。Cox比例风险模型基于相同的患者组，并使用与原始研究报告相同的混杂因素，用于确定每种亚型的总体、癌症特异性或无复发生存期。风险比和置信区间，以及Kaplan-Meier图进行了比较，以那些报告的原始study.ResultsWe观察到类似的模式，更糟糕的生存微卫星稳定（MSS）/BRAF突变和MSS/KRAS突变亚型在我们的验证分析，其中包括在两个验证的分类。在两种MSI亚型中，一种是由额外存在的CIMP高和BRAF突变定义的，另一种是由CIMP、BRAF和KRAS突变阴性的肿瘤定义的，我们不能证实与其中一种分类所提示的更好预后的相关性。对于两个已发表的分类，我们能够提供额外的亚组不包括在原来的研究（男性，其他疾病阶段，其他locations）的结果。关于MSI亚型，其他患者特征（如肿瘤分期）可能会影响潜在的生存获益。需要进一步整合甲基化、遗传和免疫学信息，以开发和验证与临床实践相关的综合分类。
BackgroundCompeting molecular classification systems have been proposed to complement the TNM staging system for a better prediction of survival in colorectal cancer (CRC). However, validation studies are so far lacking. The aim of this study was to validate and extend previously published molecular classifications of CRC in a large independent cohort of CRC patients.MethodsCRC patients were recruited into a population-based cohort study (DACHS). Molecular subtypes were categorized based on three previously published classifications. Cox-proportional hazard models, based on the same set of patients and using the same confounders as reported by the original studies, were used to determine overall, cancer-specific, or relapse-free survival for each subtype. Hazard ratios and confidence intervals, as well as Kaplan-Meier plots were compared to those reported by the original studies.ResultsWe observed similar patterns of worse survival for the microsatellite stable (MSS)/BRAF-mutated and MSS/KRAS-mutated subtypes in our validation analyses, which were included in two of the validated classifications. Of the two MSI subtypes, one defined by additional presence of CIMP-high and BRAF-mutation and the other by tumors negative for CIMP, BRAF and KRAS-mutations, we could not confirm associations with better prognosis as suggested by one of the classifications. For two of the published classifications, we were able to provide results for additional subgroups not included in the original studies (men, other disease stages, other locations).ConclusionsExternal validation of three previously proposed classifications confirmed findings of worse survival for CRC patients with MSS subtypes and BRAF or KRAS mutations. Regarding MSI subtypes, other patient characteristics such as stage of the tumor, may influence the potential survival benefit. Further integration of methylation, genetic, and immunological information is needed to develop and validate a comprehensive classification that will have relevance for use in clinical practice.