Tissue glycomics distinguish tumour sites in women with advanced serous adenocarcinoma

Merrina Anugraham; Francis Jacob; Arun V Everest-Dass; Andreas Schoetzau; Sheri Nixdorf; Neville F Hacker; Daniel Fink; Viola Heinzelmann-Schwarz; Nicolle H Packer

doi:10.1002/1878-0261.12134

Tissue glycomics distinguish tumour sites in women with advanced serous adenocarcinoma

Mol Oncol. 2017 Nov;11(11):1595-1615. doi: 10.1002/1878-0261.12134. Epub 2017 Sep 29.

Authors

Merrina Anugraham^{1

2}, Francis Jacob², Arun V Everest-Dass^{1

3

4}, Andreas Schoetzau⁵, Sheri Nixdorf⁶, Neville F Hacker⁷, Daniel Fink⁸, Viola Heinzelmann-Schwarz^{5

9}, Nicolle H Packer^{1

3

4}

Affiliations

¹ Department of Chemistry & Biomolecular Sciences, Biomolecular Discovery & Design Research Centre, Faculty of Science and Engineering, Macquarie University, North Ryde, NSW, Australia.
² Glyco-oncology, Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
³ Australian Research Council Centre of Excellence in Nanoscale Biophotonics, Macquarie University, North Ryde, NSW, Australia.
⁴ Glycomics Institute, Griffith University, Gold Coast, Queensland, Australia.
⁵ Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel, University of Basel, Switzerland.
⁶ Gynecological Research, Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, Australia.
⁷ Royal Hospital for Women, Gynecological Cancer Centre, School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
⁸ Department of Gynecology, University Hospital Zurich, Switzerland.
⁹ Hospital for Women, Department of Gynecology and Gynecological Oncology, University Hospital Basel, University of Basel, Switzerland.

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 1205.0^2- and m/z 1059.4^2- ) being associated with ovarian-derived cancer tissue and bisecting GlcNAc-type (m/z 994.9^2- ) and branched N-glycans (m/z 1294.0^2- and m/z 1148.4^2- ) 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.

Keywords: gene expression; glycans; mass spectrometry; ovarian cancer; peritoneal cancer; porous graphitized carbon.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cystadenocarcinoma, Serous / genetics*
Cystadenocarcinoma, Serous / pathology
Female
Glycomics*
Humans
N-Acetylgalactosaminyltransferases / genetics
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / pathology
Peritoneal Neoplasms / genetics*
Peritoneal Neoplasms / pathology
Polysaccharides / analysis*
Polysaccharides / genetics*
Tandem Mass Spectrometry / methods
Transcriptome*

Substances

Polysaccharides
N-Acetylgalactosaminyltransferases