Abstract 95: MTAP deficiency closely correlates with p16 status in non-small cell lung cancer but is unrelated to tumor aggressiveness or patient prognosis

Abstract Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression is often caused by genomic deletions of chromosome 9p21 in non-small cell lung cancer (NSCLC). Complete MTAP loss results in a critical vulnerability of cancer cells towards drugs targeting adenine synthesis and the methionine cycle. To study the clinical impact and heterogeneity of MTAP expression in lung cancer, a tissue microarray containing 470 adenocarcinomas and 235 squamous cell carcinomas, and conventional whole sections from all (5-15, average 7.4) tumor-containing tissue blocks of 5 lung cancers were analyzed by for immunohistochemical (IHC) expression of MTAP. MTAP expression was lost (0+) in 13.2%, weak (1+) in 45.4% and strong (2+/3+) in 41.4% of 423 interpretable adenocarcinomas (ADC), and 0+ in 25.8%, 1+ in 46.4% and 2+/3+ in 27.8% of 209 interpretable squamous cell carcinomas (SQCC) of the lung. MTAP deficiency was unrelated to parameters of tumor aggressiveness, including pT status, pN status, histological grade, and patient survival, in ADC and in SQCC. In 40 analyzed mesotheliomas, a MTAP loss was seen in 45% (p<0.0001 for adenocarcinoma vs. mesothelioma). Among the 5 consecutive lung cancers from which a total of 37 whole sections were analyzed, MTAP was homogeneously deficient in 1 case, heterogeneously deficient in another case, and homogeneously retained in the remaining 3 cases. In conclusion, loss of MTAP expression occurs in 13% (ADC) to 25% (SQCC) of NSCLC irrespective of tumor extent or metastasis stage. These findings identify a potential application of MTAP IHC in NSCLC for diagnosis of malignancy and the identification of patients who might benefit from MTAP-based therapies. However, the possible therapeutic efficacy could be impaired in patients with heterogeneous MTAP loss. Citation Format: Natalia Gorbokon, Nina Schraps, Katharina Möller, Seyma Büyücek, Maximilian Lennartz, Florian Viehweger, Christoph Fraune, Christian Bernreuther, Elena Bady, Lisa Hornsteiner, Ronald Simon, Guido Sauter, Martin Reck, Till Olchers, Florian Lutz, Till S Clauditz, Martina Kluth, Stefan Steurer. MTAP deficiency closely correlates with p16 status in non-small cell lung cancer but is unrelated to tumor aggressiveness or patient prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 95.