Hypoxia-Inducible Factor-2-Altered Urothelial Carcinoma: Clinical and Genomic Features

• Published in: Current oncology (Toronto) Vol. 29; no. 11; pp. 8638 - 8649
• Main Authors: Vlachostergios, Panagiotis J, Tamposis, Ioannis A, Anagnostou, Maria, Papathanassiou, Maria, Mitrakas, Lampros, Zachos, Ioannis, Thodou, Eleni, Samara, Maria, Tzortzis, Vassilios
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.11.2022; MDPI
• Subjects: Basic Helix-Loop-Helix Transcription Factors - genetics; BCG; BCG vaccines; bladder cancer; Cancer; Carcinoma; Carcinoma, Transitional Cell - pathology; DNA Copy Number Variations; EPAS1; Gene expression; Genes; Genetic aspects; genomic landscape; Genomics; Humans; Hypoxia; hypoxia-inducible factor 2; Neovascularization, Pathologic; prognosis; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Urinary Bladder Neoplasms - genetics; urothelial carcinoma; Vascular endothelial growth factor; genomic landscape; immune; urothelial carcinoma; EPAS1; bladder cancer; hypoxia-inducible factor 2; prognosis
• ISSN: 1718-7729; 1198-0052; 1718-7729
• DOI: 10.3390/curroncol29110681

Hypoxia is recognized as a key feature of cancer growth and is involved in various cellular processes, including proliferation, angiogenesis, and immune surveillance. Besides hypoxia-inducible factor 1-alpha (HIF-1α), which is the main mediator of hypoxia effects and can also be activated under normoxic conditions, little is known about its counterpart, HIF-2. This study focused on investigating the clinical and molecular landscape of HIF-2-altered urothelial carcinoma (UC). Publicly available next-generation sequencing (NGS) data from muscle-invasive UC cell lines and patient tumor samples from the MSK/TCGA 2020 cohort ( = 476) were interrogated for the level of expression (mRNA, protein) and presence of mutations, copy number variations, structural variants in the gene encoding HIF-2, and findings among various clinical (stage, grade, progression-free and overall survival) and molecular (tumor mutational burden, enriched gene expression) parameters were compared between altered and unaltered tumors. 19% (7/37) of UC cell lines and 7% (27/380) of patients with muscle-invasive UC display high mRNA and protein expression or/and EPAS1 alterations. -altered tumors are associated with higher stage, grade, and lymph node metastasis as well as with shorter PFS (14 vs. 51 months, = 0.01) and OS (15 vs. 55 months, = 0.01). mRNA expression is directly correlated with that of its target-genes, including ( < 0.001). While there is a slightly higher tumor mutational burden in -altered tumors (9.9 vs. 4.9 mut/Mb), they are enriched in and associated with genes promoting immune evasion, including , and , respectively ( < 0.001). : HIF-2-altered UC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-promoting genes.