Tissue glycomics distinguish tumour sites in women with advanced serous adenocarcinoma

Abstract

In the era of precision medicine, the tailoring of cancer treatment is increasingly important as we transition from organ‐based diagnosis towards a more comprehensive and patient‐centric molecular diagnosis. This is particularly the case for high‐grade serous adenocarcinomas of the ovary and peritoneum, which are commonly diagnosed at an advanced stage, and collectively treated and managed similarly. We characterized the N‐ and O‐glycome of serous ovarian (OC) and peritoneal cancer (PC) tissues using PGC‐LC‐ESI‐IT‐MS/MS profiling and validated the discriminatory glycans and their corresponding glyco‐gene expression levels using cell lines and transcriptomic data from 232 patients. Overall, the N‐ and O‐glycan repertoires of both cancer types were found to comprise mostly of α2,6‐sialylated glycan structures, with the majority of N‐glycans displaying the biantennary mono‐ and disialylation as well as bisecting‐type biantennary glycans. The MS profiling by PGC‐LC also revealed several glycan structural isomers that corresponded to LacdiNAc‐type (GalNAcβ1‐4GlcNAc) motifs that were unique to the serous ovarian cancers and that correlated with elevated gene expression of B4GALNT3 and B4GALNT4 in patients with serous cancer. Statistical evaluation of the discriminatory glycans also revealed 13 N‐ and 3 O‐glycans (P < 0.05) that significantly discriminated tumour‐sampling sites, with LacdiNAc‐type N‐glycans (m/z 1205.02− and m/z 1059.42−) being associated with ovarian‐derived cancer tissue and bisecting GlcNAc‐type (m/z 994.92−) and branched N‐glycans (m/z 1294.02− and m/z 1148.42−) upregulated at the metastatic sites. Hence, we demonstrate for the first time that OC and PC display distinct molecular signatures at both their glycomic and transcriptomic levels. These signatures may have potential utility for the development of accurate diagnosis and personalized treatments.

MALDI Mass Spectrometry Imaging of Early‐ and Late‐Stage Serous Ovarian Cancer Tissue Reveals Stage‐Specific N‐Glycans

“…Sialylated N‐ glycan structures have previously been found to be glyco‐markers of tumorigenesis . (Hex) 2 (HexNAc) 2 (NeuAc) 1 + (Man) 3 (GlcNAc) 2 was discovered in our study to be predominantly in late‐stage OC relative to the early‐stage patients (Figure , Supporting Information).…”

“…isolated N‐ glycans from FF endometrioid, serous, and healthy OC tissue sections and discovered that bisecting N‐ glycan structures were elevated in the serous OC tissue as well as the glycosyltransferase enzyme, MGAT 3. More recently, the glycomes from cancer tissue originating from the ovaries and peritoneum were compared using PGC‐LC‐ESI‐MS/MS . This study reported high levels of α‐2‐6 sialylated and bisecting N‐ glycan structures from both cancers originating from the ovaries and peritoneum.…”

Glycomic Profiling Highlights Increased Fucosylation in Pseudomyxoma Peritonei

“…H5N5F1) (51), and potentially also Lac-diNAc (e.g. H3N6F1) (51). The proposed monosaccharide compositions were further validated with both MS/MS fragmentation analysis and exoglycosidase digestions.…”

“…H3N4F1) (21), bisecting GlcNAc (e.g. H5N5F1) (51), and potentially also Lac-diNAc (e.g. H3N6F1) (51).…”

Translating N‐Glycan Analytical Applications into Clinical Strategies for Ovarian Cancer

“…An investigation into the N‐ glycome of women with advanced serous adenocarcinoma identified α 2–6 sialylated structures in both OC and peritoneal cancer, with the majority displaying bi‐antennary mono‐ and di‐sialylation as well as bisecting . PGC–LC–ESI–MS/MS revealed that LacdiNAc motifs were unique to serous OC only and correlated with the elevated gene expression of the glycosyltransferases, B4GALNT3 and B4GALNT4, in patients.…”