发现新型结直肠癌分层的分子标志物
创作:Sophia 审核:Lexi 2019年11月11日
  • 病理Wnt通路经下游信号转导激活,包括非配体依赖性(LI)突变和配体依赖性(LD)突变激活;
  • Wnt通路的不同驱动突变在结直肠息肉、结直肠癌和非结直肠癌中相互排斥;
  • Wnt通路的中断主要由R-Spondin配体在间质增生性基质中过度表达引起;
  • 关键的Wnt负调控基因在LD/LI肿瘤中有差异表达,一些基因(如AXIN2和NKD1)的靶向高甲基化发生在CIMPL阴性的LD癌中;
  • 差异表达负调节剂之一的AXIN2 mRNA表达可作为鉴别LD/LI肿瘤的分子标志物。
主编推荐语
Lexi
病理Wnt通路激活是结直肠癌(CRC)的一个保守标志。Wnt激活突变可分为两类:包括非配体依赖性(LI)突变和配体依赖性(LD)突变激活。非配体依赖(LI)的细胞内信号转导蛋白(如腺瘤性息肉病基因、β-catenin)的改变导致该信号通路持续激活;配体依赖性(LD)突变通过内源性Wnt信号跨膜转导的扩增影响协同的R-Spondin轴。来自Gut杂志的一项最新研究,旨在探索Wnt靶基因的差异表达,寻找结直肠癌分层的分子生物标志物。该研究利用突变数据将病变细分为LI/LD肿瘤亚群,比较各组间的转录、甲基化、形态学和临床特征差异,最后发现适当的Wnt负反馈环的表观遗传抑制在LD肿瘤中具有选择性优势,而AXIN2在LD/LI病变中的差异表达可作为鉴别LD/LI肿瘤的分子标志物。
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Gut [IF:17.943]

Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification

探索Wnt靶基因的差异表达,寻找结直肠癌分层的分子生物标志物

10.1136/gutjnl-2019-319126

2019-09-28, Article

Abstract & Authors:展开

Abstract:收起
Objective : Pathological Wnt pathway activation is a conserved hallmark of colorectal cancer. Wnt-activating mutations can be divided into: i) ligand-independent (LI) alterations in intracellular signal transduction proteins (Adenomatous polyposis coli, β-catenin), causing constitutive pathway activation and ii) ligand-dependent (LD) mutations affecting the synergistic R-Spondin axis (RNF43, RSPO-fusions) acting through amplification of endogenous Wnt signal transmembrane transduction. Our aim was to exploit differential Wnt target gene expression to generate a mutation-agnostic biomarker for LD tumours.
Design: We undertook harmonised multi-omic analysis of discovery (n=684) and validation cohorts (n=578) of colorectal tumours collated from publicly available data and the Stratification in Colorectal Cancer Consortium. We used mutation data to establish molecular ground truth and subdivide lesions into LI/LD tumour subsets. We contrasted transcriptional, methylation, morphological and clinical characteristics between groups.
Results : Wnt disrupting mutations were mutually exclusive. Desmoplastic stromal upregulation of RSPO may compensate for absence of epithelial mutation in a subset of stromal-rich tumours. Key Wnt negative regulator genes were differentially expressed between LD/LI tumours, with targeted hypermethylation of some genes (AXIN2, NKD1) occurring even in CIMP-negative LD cancers. AXIN2 mRNA expression was used as a discriminatory molecular biomarker to distinguish LD/LI tumours (area under the curve >0.93).
Conclusions : Epigenetic suppression of appropriate Wnt negative feedback loops is selectively advantageous in LD tumours and differential AXIN2 expression in LD/LI lesions can be exploited as a molecular biomarker. Distinguishing between LD/LI tumour types is important; patients with LD tumours retain sensitivity to Wnt ligand inhibition and may be stratified at diagnosis to clinical trials of Porcupine inhibitors.

First Authors:
Sam O Kleeman ‍‍

Correspondence Authors:
Simon J Leedham

All Authors:
Sam O Kleeman ‍‍,Viktor H Koelzer,Helen JS Jones,Ester Gil Vazquez,Hayley Davis ‍‍,James E East,Roland Arnold,Martijn AJ Koppens,Andrew Blake,Enric Domingo,Chris Cunningham,Andrew D Beggs ‍‍,Valerie Pestinger,Maurice B Loughrey,Lai-Mun Wang,Tamsin RM Lannagan,Susan L Woods ‍‍,Daniel Worthley,S:CORT Consortium Ian Tomlinson ‍‍,Philip D Dunne ‍‍,Timothy Maughan,Simon J Leedham

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