RRC ID 67139
Author Noda M, Okayama H, Tachibana K, Sakamoto W, Saito K, Thar Min AK, Ashizawa M, Nakajima T, Aoto K, Momma T, Katakura K, Ohki S, Kono K.
Title Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis.
Journal Clin Cancer Res
Abstract 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 GALNT6 mRNA and protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis. Clin Cancer Res; 24(18); 4468-81. ©2018 AACR.
Volume 24(18)
Pages 4468-4481
Published 2018-9-15
DOI 10.1158/1078-0432.CCR-17-3533
PII 1078-0432.CCR-17-3533
PMID 29844132
MeSH Brain Neoplasms / genetics Cell Proliferation / drug effects Colorectal Neoplasms / classification Colorectal Neoplasms / drug therapy Colorectal Neoplasms / genetics* Colorectal Neoplasms / pathology Disease-Free Survival Female Fluorouracil / pharmacology Gene Expression Regulation, Neoplastic HCT116 Cells Humans Male Microarray Analysis N-Acetylgalactosaminyltransferases / genetics* Neoplastic Syndromes, Hereditary / genetics Polysaccharides / biosynthesis Polysaccharides / genetics* Prognosis* RNA, Messenger / genetics Transcriptome / genetics
IF 10.107
Human and Animal Cells HCT116(RCB2979)