High-grade serous carcinoma of uterine adnexa (HGSC) is the most frequent histotype of epithelial ovarian cancer and has a poor 5-year survival rate due to late-stage diagnosis and the poor efficacy of standard treatments. Novel biomarkers of cancer outcome are needed to identify new targetable pathways and improve personalized treatments. Cell-surface screening of 26 HGSC cell lines by high-throughput flow cytometry identified junctional adhesion molecule 1 (JAM-A, also known as F11R) as a potential biomarker. Using a multi-labeled immunofluorescent staining coupled with digital image analysis, protein levels of JAM-A were quantified in tissue microarrays from three HGSC patient cohorts: a discovery cohort (n = 101), the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158), and the Canadian Cancer Trials Group OV16 cohort (n = 267). Low JAM-A level was associated with poorer outcome in the three cohorts by Kaplan–Meier (p = 0.023, p < 0.001, and p = 0.036, respectively) and was an independent marker of shorter survival in the COEUR cohort (HR = 0.517 (0.381–703), p < 0.001). When analyses were restricted to patients treated by taxane–platinum-based chemotherapy, low JAM-A protein expression was associated with poorer responses in the COEUR (p < 0.001) and OV16 cohorts (p = 0.006) by Kaplan–Meier. Decreased JAM-A gene expression was an indicator of poor outcome in gene expression datasets including The Cancer Genome Atlas (n = 606, p = 0.002) and Kaplan–Meier plotter (n = 1816, p = 0.024). Finally, we observed that tumors with decreased JAM-A expression exhibited an enhanced epithelial to mesenchymal transition (EMT) signature. Our results demonstrate that JAM-A expression is a robust prognostic biomarker of HGSC and may be used to discriminate tumors responsive to therapies targeting EMT.
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LC, MM, and FS were supported by the Selective Therapy Program from the TFRI and the Ontario Institute for Cancer Research. LC was supported by a post-doctoral fellowship from the Fond de recherche Québec—Santé (FRQS). MM was supported by Ovarian Cancer Canada’s Teal Heart Scholarship. A-MMM and DP are researchers of CRCHUM/ICM, which receive support from the FRQS and the Réseau de Recherche sur le cancer (RR cancer). We thank Jacqueline Chung for English editing. We thank Anne-Marie Fortier, Senthil Muthuswamy, and Shakeel Virk for helpful discussions and information. We thank the molecular pathology core facility of the CRCHUM for performing the discovery and COEUR TMA construction and tissue scanning. We thank the Department of Pathology and Molecular Biology at the Queen’s University for performing the OV16 TMA construction. Tumor banking for the discovery cohort was supported by the Banque de tissus et de données of the RR cancer of the FRQS affiliated with the Canadian Tumor Repository Network. Tumor banking for the OV16 cohort was performed by the CCTG Tumor Tissue Data Repository. This study uses resources provided by the COEUR biobank funded by the TFRI and managed and supervised by the CHUM. The Consortium acknowledges contributions to its COEUR biobank from Institutions across Canada (for a full list see www.tfri.ca/COEUR/members). We thank the generosity of patients included in this study.
Conflict of interest
AO is a consultant/advisory board member for Immunogen, AstraZeneca, Tesaro, and Clovis. The other authors declare that they have no conflict of interest.
Ethical approval for the study was obtained from the Centre hospitalier de l’Université de Montreal (CHUM) institutional ethics committee (Comité d’éthique de la Recherche du CHUM).
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Communal, L., Medrano, M., Sircoulomb, F. et al. Low junctional adhesion molecule-A expression is associated with an epithelial to mesenchymal transition and poorer outcomes in high-grade serous carcinoma of uterine adnexa. Mod Pathol 33, 2361–2377 (2020). https://doi.org/10.1038/s41379-020-0586-0