MTAP Loss Correlates With Favorable Prognosis in HPV-independent, p16-negative Oropharyngeal Squamous Cell Carcinoma

Human papillomavirus (HPV)-independent oropharyngeal squamous cell carcinoma (OPSCC) is an aggressive cancer without established molecular prognosis. CDKN2A (encoding p16) deletion is a common genetic event in HPV-independent OPSCC. CDKN2A homozygous deletion is recognized as a poor prognostic factor in various tumors, such as gliomas, and methylthioadenosine phosphorylase (MTAP) immunostaining serves as a surrogate marker for it. Because MTAP is related to the methionine salvage pathway, various cancer cell lines with MTAP deletion have been reported to exhibit increased sensitivity to the pyrimidine analog 5-fluorouracil (5-FU). This study aimed to clarify the prognostic effect of the expressions and homozygous deletions of CDKN2A ( p16 ) and MTAP in 177 patients with OPSCC (106 HPV-positive and 71 HPV-negative) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). MTAP loss by IHC was observed in 25.3% (16/63) of HPV-negative/p16-negative OPSCCs, and FISH confirmed homozygous deletions of both CDKN2A and MTAP . All HPV-negative/p16-positive (n=8) and HPV-positive (n=106) OPSCCs did not exhibit MTAP deficiency. The prognosis of the HPV-negative/MTAP - loss group (n=16) was significantly better than that of the HPV-negative/MTAP-retained group (n=47) and was as favorable as that of the HPV-positive group (n=106). A similar trend was confirmed in patients with HPV-negative OPSCC who received pyrimidine-based chemotherapy (n=46). MTAP deficiency is closely associated with homozygous CDKN2A and MTAP deletions in HPV-negative/p16-negative OPSCCs. Furthermore, MTAP loss may be a favorable prognostic factor in HPV-negative OPSCC, and this paradoxical phenomenon might be explained by the enhanced efficacy of chemotherapy with pyrimidine analogs.