The molecular subtypes and their clinical relevance of colorectal cancer

doi:10.3877/cma.j.issn.2095-3224.2018.05.003

Abstract

Abstract:

The stepwise development of colorectal cancer (CRC) is a complex carcinogenesis process. During the past three decades, the canonical ″Adenoma–carcinoma sequence model″ and the alternative ″Serrated pathway″ were successively proposed. The latter accounts for approximately 15% of CRC. Importantly, CRC is a heterogeneous disease. Microsatellite instability, chromosomal instability and CpG island methylator phenotype are the main genetic and epigenetic characteristics of CRC. Some tumors can exhibit features of multiple alterations. Along with the development of personalized precision medicine, it is urgent to perform the precision molecular subtypes of CRC based on genomic and proteomic data. To further illustrate this issue, therefore, we summarize and discuss the current molecular subtypes, clinical presentation and response to therapy.

Key words: Colorectal neoplasms, Tumorigenesis, Heterogeneity, Molecular subtypes, Clinicopathological features

Yulin Sun, Xiaohang Zhao. The molecular subtypes and their clinical relevance of colorectal cancer[J]. Chinese Journal of Colorectal Diseases(Electronic Edition), 2018, 07(05): 412-419.

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References 62

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项目	CMS1（MSI免疫型）	CMS2（经典型）	CMS3（代谢型）	CMS4（间质型）
所占比例（%）	14	37	13	23
遗传特征	MSI，高基因突变率，高频BRAF突变；低CIN（SCNAs）	MSS高频TP53突变高CIN（SCNAs），HNF4A扩增	约30%的肿瘤具有MSI高频KRAS突变中等CIN（SCNAs），PTEN纯合缺失	MSS高频TP53突变高CIN（SCNAs）
表观遗传特征	高CIMP	低CIMP	中等CIMP	低CIMP
microRNAs	-	miR-17-92簇上调	let-7家族下调	miR-200家族下调
活化转录组通路	JAK-STAT通路 Caspases通路	上皮分化表型Wnt和Myc通路EGFR和SRC通路高表达EGFR、ERBB2（Her2）、IGF2、IRS2、HNF4A和cyclins等癌基因	代谢重编程，包括谷氨酰胺分解和脂肪生成通路活化	上皮间叶转换（EMT）、TGF-β和整合素通路促血管生成（VEGF和VEGFR通路）细胞外基质重塑补体介导的炎症通路
基质-免疫微环境	肿瘤中有弥漫性免疫细胞浸润，主要为Th1细胞、细胞毒T细胞和NK细胞； CTLA4、PD1、PDL1等免疫检测点分子高表达，具有高免疫原性	低的免疫和炎症特征，PDL1阴性，免疫原性低	低的免疫和炎症特征，PDL1阴性，免疫原性低	基质细胞浸润，如肿瘤相关成纤维细胞（CAFs）；炎症性免疫细胞浸润（免疫抑制），主要为T_reg细胞、髓源性抑制细胞（MDSCs）、单核细胞和Th17细胞促转移免疫逃逸微环境
临床特征	女性更多见多位于右半结肠，直肠癌罕见	多位于左半结肠，直肠癌所占比例较高	多位于右半结肠	直肠癌所占比例较高诊断时多为III或IV期
病理特征	多为实性和/或管状或粘液型多表现为中、低分化可由无蒂锯齿状腺瘤进展而来	多为复杂管状结构多表现为中、高分化	多为乳头状多表现为中、高分化	多有高间质结缔组织增生反应，多表现为中、低分化，可由无蒂锯齿状腺瘤进展而来
预后意义	总生存和无复发生存均较好，但是一旦复发，预后非常差	总生存和无复发生存均较好，复发后的预后相对较好	总生存和无复发生存均较好	总生存和无复发生存均很差

项目	CMS1（MSI免疫型）	CMS2（经典型）	CMS3（代谢型）	CMS4（间质型）
所占比例（%）	14	37	13	23
遗传特征	MSI，高基因突变率，高频BRAF突变；低CIN（SCNAs）	MSS高频TP53突变高CIN（SCNAs），HNF4A扩增	约30%的肿瘤具有MSI高频KRAS突变中等CIN（SCNAs），PTEN纯合缺失	MSS高频TP53突变高CIN（SCNAs）
表观遗传特征	高CIMP	低CIMP	中等CIMP	低CIMP
microRNAs	-	miR-17-92簇上调	let-7家族下调	miR-200家族下调
活化转录组通路	JAK-STAT通路 Caspases通路	上皮分化表型Wnt和Myc通路EGFR和SRC通路高表达EGFR、ERBB2（Her2）、IGF2、IRS2、HNF4A和cyclins等癌基因	代谢重编程，包括谷氨酰胺分解和脂肪生成通路活化	上皮间叶转换（EMT）、TGF-β和整合素通路促血管生成（VEGF和VEGFR通路）细胞外基质重塑补体介导的炎症通路
基质-免疫微环境	肿瘤中有弥漫性免疫细胞浸润，主要为Th1细胞、细胞毒T细胞和NK细胞； CTLA4、PD1、PDL1等免疫检测点分子高表达，具有高免疫原性	低的免疫和炎症特征，PDL1阴性，免疫原性低	低的免疫和炎症特征，PDL1阴性，免疫原性低	基质细胞浸润，如肿瘤相关成纤维细胞（CAFs）；炎症性免疫细胞浸润（免疫抑制），主要为T_reg细胞、髓源性抑制细胞（MDSCs）、单核细胞和Th17细胞促转移免疫逃逸微环境
临床特征	女性更多见多位于右半结肠，直肠癌罕见	多位于左半结肠，直肠癌所占比例较高	多位于右半结肠	直肠癌所占比例较高诊断时多为III或IV期
病理特征	多为实性和/或管状或粘液型多表现为中、低分化可由无蒂锯齿状腺瘤进展而来	多为复杂管状结构多表现为中、高分化	多为乳头状多表现为中、高分化	多有高间质结缔组织增生反应，多表现为中、低分化，可由无蒂锯齿状腺瘤进展而来
预后意义	总生存和无复发生存均较好，但是一旦复发，预后非常差	总生存和无复发生存均较好，复发后的预后相对较好	总生存和无复发生存均较好	总生存和无复发生存均很差

病理特征	亚型A	亚型B	亚型C	亚型D	亚型E
基因组特征	CIN	高突变和MSI BRAF突变	高突变和MSI	CIN	TP53突变18 q缺失HNF4A扩增高CIN
表观基因组特征	-	高CIMP	低CIMP	-	-
临床病理特征	-	-	富集II期病例总生存和无复发生存均较差	-	-
功能富集分析	-	-	干细胞样特征创伤反应和蛋白激活级联通路上皮间叶转换（EMT）	-	RNA代谢加工通路

病理特征	亚型A	亚型B	亚型C	亚型D	亚型E
基因组特征	CIN	高突变和MSI BRAF突变	高突变和MSI	CIN	TP53突变18 q缺失HNF4A扩增高CIN
表观基因组特征	-	高CIMP	低CIMP	-	-
临床病理特征	-	-	富集II期病例总生存和无复发生存均较差	-	-
功能富集分析	-	-	干细胞样特征创伤反应和蛋白激活级联通路上皮间叶转换（EMT）	-	RNA代谢加工通路

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