N-Glycomic Profiling of Microsatellite Unstable Colorectal Cancer

SIMPLE SUMMARY: All human cells possess a complex glycan coating, and alterations in cell surface glycans play a role in cancer progression and immune suppression. Colorectal cancer is a heterogenous disease that can be classified into several molecular subtypes, with major variances in prognosis and therapy responses. Two important molecular markers in this regard are microsatellite instability and BRAF gene mutation, which have been largely ignored in previous glycomics studies. We analyzed the N-glycan profiles of local and advanced colorectal cancers consisting of different molecular subtypes to identify possible explanations for their differing behaviors. Our results show that the studied molecular subgroups of colorectal cancer exhibit characteristic glycan profiles, which may explain their tumorigenic properties. ABSTRACT: Aberrant glycosylation affects cancer progression and immune evasion. Approximately 15% of colorectal cancers (CRCs) demonstrate microsatellite instability (MSI) and display major differences in outcomes and therapeutic responses, as compared to corresponding microsatellite stable (MSS) tumors. We compared the N-glycan profiles of stage II and IV MSI CRC tumors, further subdivided into BRAF(V600E) wild-type and mutated subgroups (n = 10 in each subgroup), with each other and with those of paired non-neoplastic mucosal samples using mass spectrometry. Further, the N-glycans of BRAF(V600E) wild-type stage II MSI tumors were compared to corresponding MSS tumors (n = 9). Multiple differences in N-glycan profiles were identified between the MSI CRCs and control tissues, as well as between the stage II MSI and MSS samples. The MSI CRC tumors showed a lower relative abundance of high-mannose N-glycans than did the control tissues or the MSS CRCs. Among MSI CRC subgroups, acidic N-glycans showed tumor stage and BRAF mutation status-dependent variation. Specifically, the large, sulfated/phosphorylated, and putative terminal N-acetylhexosamine-containing acidic N-glycans differed between the MSI CRC subgroups, showing opposite changes in stages II and IV, when comparing BRAF mutated and wild-type tumors. Our results show that molecular subgroups of CRC exhibit characteristic glycan profiles that may explain certain carcinogenic properties of MSI tumors.