Solute carrier family 12 member 2 as a proteomic and histological biomarker of dysplasia and neoplasia in ulcerative colitis

Angela-Maria Merli; Sophie Vieujean; Charlotte Massot; Noella Blétard; Florence Quesada Calvo; Dominique Baiwir; Gabriel Mazzucchelli; Laurence Servais; Odile Wéra; Cécile Oury; Laurence de Leval; Christine Sempoux; Roberto Manzini; Sena Bluemel; Michael Scharl; Gerhard Rogler; Edwin De Pauw; C Coimbra Marques; Arnaud Colard; Anne Vijverman; Philippe Delvenne; Edouard Louis; Marie-Alice Meuwis

doi:10.1093/ecco-jcc/jjaa168

Solute carrier family 12 member 2 as a proteomic and histological biomarker of dysplasia and neoplasia in ulcerative colitis

J Crohns Colitis. 2020 Sep 13:jjaa168. doi: 10.1093/ecco-jcc/jjaa168. Online ahead of print.

Authors

Angela-Maria Merli¹, Sophie Vieujean^{1

2}, Charlotte Massot^{1

2}, Noella Blétard³, Florence Quesada Calvo¹, Dominique Baiwir⁴, Gabriel Mazzucchelli⁵, Laurence Servais⁶, Odile Wéra⁶, Cécile Oury⁶, Laurence de Leval⁷, Christine Sempoux⁷, Roberto Manzini⁸, Sena Bluemel⁸, Michael Scharl⁸, Gerhard Rogler⁸, Edwin De Pauw⁵, C Coimbra Marques⁹, Arnaud Colard¹⁰, Anne Vijverman¹¹, Philippe Delvenne³, Edouard Louis^{1

2

12}, Marie-Alice Meuwis^{1

2

12}

Affiliations

¹ Laboratory of Translational Gastroenterology, University of Liège, Liège, Belgium.
² Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium.
³ Pathological Anatomy and Cytology, University Hospital CHU of Liège, Liège, Belgium.
⁴ GIGA Proteomics Facility, University of Liège, Liège, Belgium.
⁵ Laboratory of Mass Spectrometry, University of Liège, Liège, Belgium.
⁶ Laboratory of Cardiology, GIGA-Cardiovascular Sciences, University of Liège, Liège, Belgium.
⁷ Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
⁸ Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁹ Abdominal Surgery Department, University Hospital CHU of Liège, Liège, Belgium.
¹⁰ Department of Gastroenterology, CHC Clinique Saint-Joseph, Liège, Belgium.
¹¹ Department of Gastroenterology, CHR Citadelle, Liège, Belgium.
¹² Equally contributed to this work.

PMID: 32920643
DOI: 10.1093/ecco-jcc/jjaa168

Abstract

Background and aims: Ulcerative colitis (UC) patients have a greater risk of developing colorectal cancer through inflammation-dysplasia-carcinoma sequence of transformation. The histopathological diagnosis of dysplasia is therefore of critical clinical relevance, but dysplasia may be difficult to distinguish from inflammatory changes.

Methods: A proteomic pilot study on 5 UC colorectal dysplastic patients highlighted proteins differentially distributed between paired dysplastic, inflammatory and normal tissues. The best candidate marker was selected and immunohistochemistry confirmation was performed on AOM/DSS mouse model lesions, 37 UC dysplasia, 14 UC cancers, 23 longstanding UC, 35 sporadic conventional adenomas, 57 sporadic serrated lesions and 82 sporadic colorectal cancers.

Results: Differential proteomics found 11 proteins significantly more abundant in dysplasia compared to inflammation, including Solute carrier family 12 member 2 (SLC12A2) which was confidently identified with 8 specific peptides and was below the limit of quantitation in both inflammatory and normal colon. SLC12A2 immunohistochemical analysis confirmed the discrimination of preneoplastic and neoplastic lesions from inflammatory lesions in mice, UC and in sporadic contexts. A specific SLC12A2 staining pattern termed "loss of gradient" reached 89% sensitivity, 95% specificity and 92% accuracy for UC-dysplasia diagnosis together with an inter-observer agreement of 95.24% (multirater κfree of 0.90; IC95%: 0.78 - 1.00). Such discrimination could not be obtained by Ki67 staining. This specific pattern was also associated with sporadic colorectal adenomas and cancers.

Conclusions: We found a specific SLC12A2 immunohistochemical staining pattern in precancerous and cancerous colonic UC-lesions which could be helpful for diagnosing dysplasia and cancer in UC and non-UC patients.

Keywords: SLC12A2; colorectal neoplasia; dysplasia associated to inflammation.