A compelling link between S-methyl-5′-thioadenosine phosphorylase deficiency and aggressive urothelial carcinoma was highlighted in a recent study with implications that could impact both diagnosis and treatment.
The research, published in the Journal of Pathology Clinical Research, involved more than 2,700 cases and focused on the prognostic and therapeutic significance of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression loss, a condition closely associated with homozygous 9p21 deletion.
MTAP plays a critical role in recycling adenine, an essential building block for DNA and RNA synthesis. In tumors with homozygous 9p21 deletions, MTAP expression is entirely absent, rendering cells reliant on alternative adenine biosynthesis pathways. Researchers noted that this vulnerability can be exploited by targeted therapies. These deletions, common in many cancers, are also associated with loss of the CDKN2A gene, a key tumor suppressor.
The researchers used tissue microarray analysis to assess MTAP expression and 9p21 deletions across a broad spectrum of urothelial carcinomas. A complete loss of MTAP expression was found in 24% of tumors and strongly correlated with homozygous 9p21 deletions. A near-perfect concordance was observed, with 98.4% of MTAP-negative tumors harboring these deletions.
MTAP deficiency was more common in advanced-stage (pT2–4) and high-grade tumors, correlating with worse overall survival. The rate of homozygous 9p21 deletions increased with tumor stage, from 16.5% in pT2 to 31.2% in pT4. Additionally, MTAP-deficient tumors showed lower levels of immune cell infiltration, including CD8-positive T cells, CD4-positive T cells, and PD-L1–positive cells. This “noninflamed” microenvironment was associated with immune evasion and poor response to immune checkpoint inhibitors.
Multivariate analyses confirmed that both MTAP loss and 9p21 deletions independently predicted poorer outcomes, even after adjusting for tumor stage and nodal status. MTAP immunohistochemistry (IHC) emerged as a reliable method for identifying homozygous 9p21 deletions, with potential utility in diagnosing urothelial neoplasms. The researchers noted that MTAP IHC may assist in distinguishing cancerous from noncancerous urothelium, particularly in challenging cases such as flat dysplasia or cytologic specimens.
Therapeutically, MTAP deficiency opened avenues for targeted treatments. Tumors lacking MTAP are vulnerable to inhibitors of enzymes including PRMT5 and MAT2A, which are critical for alternative adenine biosynthesis. A recent phase I trial using a PRMT5 inhibitor, MRTX1719, showed promising tumor size reductions in MTAP-deficient cancers. Such therapies could provide a lifeline for patients with aggressive, immune-resistant tumors, the researchers noted.
While the study underscored MTAP deficiency’s role in tumor progression and immune evasion, it also highlighted its potential as a biomarker for therapeutic response. Routine MTAP IHC testing may help identify patients who could benefit from emerging targeted therapies while flagging those less likely to respond to immune checkpoint inhibitors.
