While FISH is the gold standard for detecting CDKN2A deletions, it is costly and time-consuming. Immunohistochemistry (IHC) for the encoded protein, p16, may be used as a surrogate marker, though it has suboptimal performance. The MTAP tumor suppressor gene, located on chromosome 9p21.3 near CDKN2A, has been identified as an alternative IHC surrogate for CDKN2A FISH in mesothelioma and other tumors. In this study, we have retrospectively examined CDKN2A deletions and MTAP loss in MIBC and metastatic urothelial carcinomas, exploring their correlation with clinical, pathological, genomic features and patient outcomes.
In a cohort of 302 MIBCs, CDKN2A deletions were identified in 45.3% of tumors, with 30.3% exhibiting homozygous deletions linked to FGFR3 mutations and normal p53 IHC. MTAP loss, identified in nearly 28.8%% of tumors, was linked to FGFR3 mutations and demonstrated a high correlation with CDKN2A deletions and p53 wild-type/normal IHC. As a more time- and cost-effective alternative to FISH, MTAP IHC showed promise as a surrogate biomarker for CDKN2A homozygous deletions, with 84.0% sensitivity, 96.3% specificity, 92.3% negative and 91.9% positive predictive value. The luminal-URO MIBC subtype had the highest rates of CDKN2A deletions (68.9%) and MTAP loss (48.7%). In this subtype, distinguishing between MTAP-deficient and MTAP-proficient tumors may enhance risk assessment and inform future personalized therapies.
Additionally, this study demonstrated absolute (100%) concordance in MTAP expression between primary tumors and synchronous nodal metastases, suggesting that MTAP status can be reliably assessed from either site, highlighting its clinical relevance and potential for guiding the management of metastatic urothelial carcinoma, with emerging evidence supporting its role as a therapeutic target and predictive biomarker across various treatment modalities, including chemotherapy and immunotherapy. Ongoing early-stage clinical trials are investigating targeted strategies for MTAP-deficient solid tumors, including metastatic urothelial cancer. These trials will be crucial in establishing the clinical utility of MTAP as a biomarker and its role in the future of personalized cancer therapy.
Written by:
- Ekaterina Olkhov-Mitsel, PhD, Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Precision Diagnostics and Therapeutics Program, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
- Michelle R. Downes, MD, Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Precision Diagnostics and Therapeutics Program, Sunnybrook Health Sciences Centre, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada