GALNT7 Stratifies dMMR/MSI Colorectal Cancer into Distinct Molecular Subsets Associated with Prognosis and PD-L1 Expression.

Abstract

Colorectal cancer with deficient mismatch repair (dMMR)/microsatellite instability (MSI) constitutes a distinct clinicopathologic and immunologic subtype, characterized by high sensitivity to immune checkpoint inhibitors. However, prognosis and therapeutic response vary considerably among dMMR/MSI colorectal cancers, underscoring the need for molecular markers to refine patient stratification. In this study, we systematically investigated cancer cell-intrinsic expression profiles of 188 glycosyltransferase genes by integrating single-cell, bulk, and cell line RNA sequencing datasets. This approach identified five glycosyltransferases, including GALNT7, expression of which differed consistently according to MSI status. The clinical and prognostic relevance of these glycosyltransferases was further analyzed across large-scale transcriptomic, proteomic, and IHC cohorts, comprising 662 dMMR/MSI and 3,483 proficient mismatch-repair (pMMR)/microsatellite-stable (MSS) colorectal cancers. A five-gene glycosyltransferase signature effectively distinguished MSI from MSS colorectal cancers across 18 datasets. Among the five genes, GALNT7 expression was robustly associated with favorable prognosis in four independent transcriptomic and IHC cohorts of dMMR/MSI colorectal cancers while showing little or no prognostic impact in pMMR/MSS colorectal cancers. Notably, GALNT7 expression was inversely correlated with PD-L1 expression at both the mRNA and protein levels in multiple datasets exclusively within dMMR/MSI colorectal cancers, but not in pMMR/MSS CRCs. Functional assays and lectin microarray analysis using MSI colorectal cancer cell lines revealed that GALNT7 knockdown enhanced IFNγ-induced PD-L1 expression without altering cell-surface glycosylation. In conclusion, GALNT7 expression stratified dMMR/MSI colorectal cancers into distinct subsets with differential tumor cell PD-L1 expression and diverse survival outcomes, highlighting its potential as a prognostic biomarker to guide treatment strategies.

Significance: We identified glycosyltransferases with altered expression depending on MMR/MSI status. Our findings indicate the existence of two molecularly defined subtypes within dMMR/MSI colorectal cancers based on GALNT7 expression, characterized by differential tumor cell PD-L1 levels and distinct survival outcomes.