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中华结直肠疾病电子杂志 ›› 2018, Vol. 07 ›› Issue (05) : 412 -419. doi: 10.3877/cma.j.issn.2095-3224.2018.05.003

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青年专家论坛

结直肠癌的分子分型及精准医学时代展望
孙玉琳1,(), 赵晓航1   
  1. 1. 100021 北京,国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院分子肿瘤学国家重点实验室
  • 收稿日期:2017-05-19 出版日期:2018-10-25
  • 通信作者: 孙玉琳
  • 基金资助:
    国家重点基础研究发展计划(No.2014CBA0200202); 自然科学基金面上项目(No.81572840)

The molecular subtypes and their clinical relevance of colorectal cancer

Yulin Sun1,(), Xiaohang Zhao1   

  1. 1. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
  • Received:2017-05-19 Published:2018-10-25
  • Corresponding author: Yulin Sun
  • About author:
    Corresponding author: Sun Yulin, Email:
引用本文:

孙玉琳, 赵晓航. 结直肠癌的分子分型及精准医学时代展望[J]. 中华结直肠疾病电子杂志, 2018, 07(05): 412-419.

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.

结直肠癌(CRC)的发生发展是一个多步骤、多阶段演进的复杂过程,近30年来,随着现代科学技术的飞跃发展,人们发现除了经典的"腺瘤——癌序贯"模型外,还有15%的病例通过"锯齿状"通路癌变。结直肠癌具有高度的异质性,微卫星不稳定、染色体不稳定、CpG岛甲基化等遗传学和表观遗传学特征可以以各种组合形式共存于肿瘤细胞中。因此随着个体化精准医学的发展,对结直肠癌精准分子分型的需求也日益迫切。本文将就结直肠癌的基因和蛋白分子分型体系及其临床意义展开探讨。

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.

表1 CRC分子特征共识分型(CMS)的生物学和临床病理特征
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Treg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
表2 CRC蛋白质组分型的生物学和临床病理特征
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