Whole-proteome analysis of mesonephric-derived cancers describes new potential biomarkers

Evan Gibbard; Dawn R Cochrane; Jennifer Pors; Gian Luca Negri; Shane Colborne; Angela S Cheng; Christine Chow; David Farnell; Basile Tessier-Cloutier; Jessica N McAlpine; Gregg B Morin; Dietmar Schmidt; Stefan Kommoss; Friedrich Kommoss; Jacqueline Keul; Blake Gilks; David G Huntsman; Lynn Hoang

doi:10.1016/j.humpath.2020.10.005

Whole-proteome analysis of mesonephric-derived cancers describes new potential biomarkers

Hum Pathol. 2021 Feb:108:1-11. doi: 10.1016/j.humpath.2020.10.005. Epub 2020 Oct 26.

Authors

Evan Gibbard¹, Dawn R Cochrane², Jennifer Pors³, Gian Luca Negri⁴, Shane Colborne⁵, Angela S Cheng⁶, Christine Chow⁶, David Farnell³, Basile Tessier-Cloutier³, Jessica N McAlpine⁷, Gregg B Morin⁸, Dietmar Schmidt⁹, Stefan Kommoss¹⁰, Friedrich Kommoss¹¹, Jacqueline Keul¹², Blake Gilks¹³, David G Huntsman¹⁴, Lynn Hoang¹⁵

Affiliations

¹ Department of Medical Genetics, The University of British Columbia, Vancouver, BC, V6H 3N1, Canada; Molecular Oncology, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
² Molecular Oncology, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
³ Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
⁴ Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, V6T 2B5, Canada; Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4S6, Canada.
⁵ Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4S6, Canada.
⁶ Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada.
⁷ Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, The University of British Columbia, Vancouver, BC, V6Z 2K8, Canada.
⁸ Department of Medical Genetics, The University of British Columbia, Vancouver, BC, V6H 3N1, Canada; Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4S6, Canada.
⁹ MVZ of Histology, Cytology and Molecular Diagnostics, Trier, 54296, Germany.
¹⁰ Department of Obstetrics and Gynecology, University of Tübingen, Tübingen, 72076, Germany.
¹¹ Institute of Pathology, Medizin Campus Bodensee, Friedrichshafen, 88048, Germany.
¹² Department of Women's Health, Tübingen University Hospital, Tübingen, 72076, Germany.
¹³ Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, V6T 2B5, Canada; Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada; Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, BC, V5Z 1M9, Canada.
¹⁴ Department of Medical Genetics, The University of British Columbia, Vancouver, BC, V6H 3N1, Canada; Molecular Oncology, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, V6T 2B5, Canada; Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada.
¹⁵ Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, V6T 2B5, Canada; Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada; Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, BC, V5Z 1M9, Canada. Electronic address: Lien.Hoang@vch.ca.

PMID: 33121982
DOI: 10.1016/j.humpath.2020.10.005

Abstract

Mesonephric carcinomas (MEs) and female adnexal tumors of probable Wolffian origin (FATWO) are derived from embryologic remnants of Wolffian/mesonephric ducts. Mesonephric-like carcinomas (MLCs) show identical morphology to ME of the cervix but occur in the uterus and ovary without convincing mesonephric remnants. ME, MLC, and FATWO are challenging to diagnose due to their morphologic similarities to Müllerian/paramesonephric tumors, contributing to a lack of evidence-based and tumor-specific treatments. We performed whole-proteomic analysis on 9 ME/MLC and 56 endometrial carcinomas (ECs) to identify potential diagnostic biomarkers. Although there were no convincing differences between ME and MLC, 543 proteins showed increased expression in ME/MLC relative to EC. From these proteins, euchromatic histone lysine methyltransferase 2 (EHMT2), glutathione S-transferase Mu 3 (GSTM3), eukaryotic translation elongation factor 1 alpha 2 (EEF1A2), and glycogen synthase kinase 3 beta were identified as putative biomarkers. Immunohistochemistry was performed on these candidates and GATA3 in 14 ME/MLC, 8 FATWO, 155 EC, and normal tissues. Of the candidates, only GATA3 and EHMT2 were highly expressed in mesonephric remnants and mesonephric-derived male tissues. GATA3 had the highest sensitivity and specificity for ME/MLC versus EC (93% and 99%) but was absent in FATWO. EHMT2 was 100% sensitive for ME/MLC & FATWO but was not specific (65%). Similarly, EEF1A2 was reasonably sensitive to ME/MLC (92%) and FATWO (88%) but was the least specific (38%). GSTM3 performed intermediately (sensitivity for ME/MLC and FATWO: 83% and 38%, respectively; specificity 67%). Although GATA3 remained the best diagnostic biomarker for ME/MLC, we have identified EHMT2, EEF1A2, and GSTM3 as proteins of interest in these cancers. FATWO's cell of origin is uncertain and remains an area for future research.

Keywords: Biomarkers; Diagnosis; Female adnexal tumors of probable Wolffian origin; Mesonephric carcinoma; Mesonephric ducts; Proteomics.

Publication types

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

MeSH terms

Biomarkers, Tumor / analysis*
Female
Glutathione Transferase / analysis*
Histocompatibility Antigens / analysis*
Histone-Lysine N-Methyltransferase / analysis*
Humans
Mesonephroma / diagnosis*
Peptide Elongation Factor 1 / analysis*
Proteomics / methods

Substances

Biomarkers, Tumor
EEF1A2 protein, human
Histocompatibility Antigens
Peptide Elongation Factor 1
EHMT2 protein, human
Histone-Lysine N-Methyltransferase
GSTM3 protein, human
Glutathione Transferase