Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis
Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis
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DOI：
10.1158/1078-0432.ccr-17-3533
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发表时间：
2018-09-15
影响因子：
11.5
通讯作者：
Kono, Koji
中科院分区：
文献类型：
--
作者：
Noda, Masaru;Okayama, Hirokazu;Kono, Koji
用途：我们的目的是发现糖基转移酶基因（糖基因）衍生的分子亚型的结直肠癌与患者outcome.Experimental设计：转录组和表观基因组数据集的非肿瘤，癌前病变，癌组织，细胞系与体细胞突变，错配修复状态，临床病理和生存信息进行了组装（n = 4，223）和糖基因谱进行了分析。在腺瘤和癌标本（n = 403）中进行了糖基因GALNT 6的IHC。通过体外功能丧失试验和凝集素微阵列分析进一步研究了其功能作用和细胞表面聚糖谱。结果：我们初步开发并验证了一个15-糖基因签名，该签名可以识别预后不良的亚型，该亚型与错配修复缺陷（dMMR）和GALNT 6下调密切相关。在肿瘤和细胞系的多个数据集中证实了GALNT 6减少与dMMR的关联，并通过IHC进一步概括，其中约15%的肿瘤表现出GALNT 6蛋白的丢失。GALNT 6 mRNA和蛋白在癌前/侵袭前病变中表达，但随后在一部分癌症中下调，可能是通过表观遗传沉默。通过多变量分析，GALNT 6降低与IHC队列和额外的微阵列荟萃队列中的不良预后独立相关，并且其生存的判别力在III期患者中特别显著。SW 480细胞中GALNT 6沉默促进了侵袭、迁移、化疗耐药性，并增加了癌相关截短O-聚糖、Tn-antigen.Conclusions的细胞表面表达：15-糖基因签名和GALNT 6 mRNA和蛋白的表达水平各自作为一种新的预后生物标志物，突出了糖基因失调在癌相关聚糖合成和不良预后中的作用。(C)2018年AACR。
Purpose: We aimed to discover glycosyltransferase gene (glycogene)-derived molecular subtypes of colorectal cancer associated with patient outcomes.Experimental Design: Transcriptomic and epigenomic datasets of nontumor, precancerous, cancerous tissues, and cell lines with somatic mutations, mismatch repair status, clinicopathologic and survival information were assembled (n = 4,223) and glycogene profiles were analyzed. IHC for a glycogene, GALNT6, was conducted in adenoma and carcinoma specimens (n = 403). The functional role and cell surface glycan profiles were further investigated by in vitro loss-of-function assays and lectin microarray analysis.Results: We initially developed and validated a 15-glycogene signature that can identify a poor-prognostic subtype, which closely related to deficient mismatch repair (dMMR) and GALNT6 downregulation. The association of decreased GALNT6 with dMMR was confirmed in multiple datasets of tumors and cell lines, and was further recapitulated by IHC, where approximately 15% tumors exhibited loss of GALNT6 protein. GALNT6 mRNA and protein was expressed in premalignant/preinvasive lesions but was subsequently downregulated in a subset of carcinomas, possibly through epigenetic silencing. Decreased GALNT6 was independently associated with poor prognosis in the IHC cohort and an additional microarray meta-cohort, by multivariate analyses, and its discriminative power of survival was particularly remarkable in stage III patients. GALNT6 silencing in SW480 cells promoted invasion, migration, chemoresistance, and increased cell surface expression of a cancer-associated truncated O-glycan, Tn-antigen.Conclusions: The 15-glycogene signature and the expression levels of GALNT6mRNAand protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis. (C) 2018 AACR.