The impact of methylthioadenosine phosphorylase (MTAP) deficiency in patients with upper tract urothelial carcinoma



'''Purpose:'''  Urothelial carcinomas (UCs) involve recurrent chromosome 9p deletions. Methylthioadenosine phosphorylase ''(MTAP)''  on 9p21.3is a proposed functional tumor suppressor gene. The role of MTAP in upper tract UC (UTUC) is unknown. We aimed to investigate MTAPs association with disease characteristics and oncologic outcomes in UTUC patients undergoing radical nephroureterectomy (RNU).      

'''Materials and Methods:'''  Using immunohistochemistry, we investigated MTAP expression in 340 UTUC patients treated with RNU from1996–2004, and correlated it with clinicopathologic characteristics and clinical outcomes. Univariate and multivariate Cox regression analyses evaluated the association of MTAP expression with disease-specific survival (DSS) and metastasis-free survival (MeFS).      

'''Results:'''  MTAP was deficient in 119 (35.0%) patients. MTAP deficiency was significantly associated with higher pathologic stage (p < 0.001), lymph node metastasis (p < 0.001), high grade (p = 0.008), vascular invasion (p = 0.001), perineural invasion (p = 0.001), and higher mitotic rate (p = 0.016).Sixty (17.6%) patients died of UTUC and 70 (20.6%) developed metastasis. MTAP-deficient patients demonstrated significantly worse DSS (58.1% vs.89.3%; p < 0.0001) and MeFS (54.7% vs.87.9%; p < 0.0001) at five years than those with intact expression. MTAP deficiency was independently associated with cancer-specific mortality (hazard ratio [HR]:2.213, p = 0.019; 95% confidence interval [CI]:1.141–4.293) and metastasis development (HR:2.867, p < 0.001; 95% CI:1.601–5.106).      

'''Conclusion:'''  MTAP deficiency is associated with aggressive cancer phenotype and unfavorable oncologic outcomes, suggesting it may be a new biomarker and provide additional prognostic information in UTUC patients undergoing RNU.