Department of Pathology, Hôtel Dieu, Centre Hospitalier Universitaire of Nantes, Nantes, France.
Department of Digestive Surgery, Hôtel Dieu, Centre Hospitalier Universitaire of Nantes, Nantes, France.
Mod Pathol. 2017 Aug;30(8):1177-1189. doi: 10.1038/modpathol.2017.18. Epub 2017 Apr 21.
The aim of this study was to interrogate the heterogeneity of colorectal mucinous adenocarcinomas. This study is based on hierarchical clustering approach combining clinicopathological and molecular patterns known to be relevant to oncogenesis and therapeutic management of patients with colorectal carcinoma, ie, microsatellite instability, O6-methylguanine-DNA methyltransferase (MGMT) status, KRAS, and BRAF mutations and wnt signaling pathway activation. Comparison of the study group of 60 mucinous adenocarcinomas defined according to World Health Organization classification with control group of 136 colorectal adenocarcinomas successively removed shows higher frequency of BRAF and KRAS mutations and microsatellite instability-high status and lower frequency of wnt signaling pathway activation in mucinous adenocarcinomas. Hierarchical clustering isolated three relevant clusters: (i) cluster of microsatellite stable mucinous adenocarcinomas (54%) with KRAS mutation, and frequent MGMT changes, more frequently located in the left colon, often associated with contiguous precursor adenoma; (ii) cluster of BRAF-mutated mucinous adenocarcinomas (28%) with either microsatellite instability-high or microsatellite stable status, occurring in elderly female patients, nearly all located in the right colon, having the signature of serrated pathway of carcinomas; and (iii) a heterogeneous cluster of microsatellite instability-high mucinous carcinomas (18%), including inherited colorectal carcinomas, displaying a high-grade histological pattern. Age, TNM stage, and BRAF mutation had prognostic value. Hierarchical clustering analysis led to the identification of several clinicopathological entities of colorectal mucinous adenocarcinomas with epidemiologic, prognostic, and therapy relevance. Both KRAS and BRAF mutations appear as drivers in the alternate oncogenetic pathways governing the development of sporadic colorectal mucinous adenocarcinomas.
本研究旨在探讨结直肠黏液腺癌的异质性。该研究基于层次聚类方法，结合已知与结直肠癌发生和治疗管理相关的临床病理和分子模式，即微卫星不稳定性、O6-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）状态、KRAS 和 BRAF 突变以及 Wnt 信号通路激活。将根据世界卫生组织分类定义的 60 例黏液腺癌研究组与连续切除的 136 例结直肠腺癌对照组进行比较，结果显示黏液腺癌中 BRAF 和 KRAS 突变以及微卫星不稳定性高状态的频率更高，Wnt 信号通路激活的频率更低。层次聚类分离出三个相关聚类：（i）微卫星稳定型黏液腺癌聚类（54%），KRAS 突变，MGMT 改变频繁，更常位于左半结肠，常与连续前体腺瘤相关；（ii）BRAF 突变型黏液腺癌聚类（28%），微卫星不稳定性高或微卫星稳定状态，发生在老年女性患者，几乎全部位于右半结肠，具有锯齿状癌通路的特征；（iii）微卫星不稳定性高的黏液腺癌异质性聚类（18%），包括遗传性结直肠癌，具有高级别组织学模式。年龄、TNM 分期和 BRAF 突变具有预后价值。层次聚类分析确定了几种具有流行病学、预后和治疗相关性的结直肠黏液腺癌临床病理实体。KRAS 和 BRAF 突变似乎是导致散发性结直肠黏液腺癌发生的不同致癌途径的驱动因素。
