Glycosyltransferase Gene Expression Identifies a Poor Prognostic Colorectal Cancer Subtype Associated with Mismatch Repair Deficiency and Incomplete Glycan Synthesis

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Masaru NodaKoji Kono

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. D...Continue Reading

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Citations

Aug 8, 2019·Journal of Cellular and Molecular Medicine·Divya ThomasPrakash Radhakrishnan
Nov 23, 2019·Carcinogenesis·Daisuke UjiieKoji Kono
Mar 18, 2020·Journal of Cellular Physiology·Jun-Liang LiFang-Cheng Li
May 3, 2019·Scientific Reports·Mai AshizawaKoji Kono
Jul 28, 2020·Nature Reviews. Gastroenterology & Hepatology·Matthew R KudelkaAndrew S Neish
Dec 16, 2020·Glycobiology·Kaitlyn A DorsettSusan L Bellis
Jan 26, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Pankaj AhluwaliaGagandeep K Gahlay
Dec 3, 2020·International Journal of Molecular Sciences·Takuro MatsumotoKoji Kono
May 1, 2021·International Journal of Molecular Sciences·Michela PucciFabio Dall'Olio
Jun 3, 2021·International Journal of Molecular Sciences·Cecilia Fernández-PonceElkin Navarro Quiroz

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