Abstract Malignant pleural mesothelioma (MPM) is a rare malignant disease with a short prognosis and limited treatment options. However, at population level about 12% of all MPM survive more than three years. The aim of this pivotal study is to investigate whether a different gene profile could divide short versus long survivors. METHODS: A cut-off of 36 months of survival was chosen to divide patients with shorter and longer survival. Under this condition we retrospectively collected data on 32 short- and 25 long-survivors from three Italian Institutions. Paraffin-embedded tissue samples were tested for a customized panel of 21 genes (CDKN2, NF2, GSTM1, NAT2, BAP1, TERT, P53, PTCH1, SMO, LATS2, KEAP1, PI3K, KRAS, NRAS, STK11, WT1, FBXW7, CTNNB1, KIT, KDR and REV3). DNA was obtained upon manual microdissection to ensure at least 50% cancer cells. DNA was processed by PGM Ion Torrent. The major prognostic factors and mutations were described. The hazard risk of death was calculated with the Cox Model. RESULTS: The main prognostic factors were equally distributed among the two groups (age, sex, histotype, stage, and treatment). The most frequent mutations were BAP-1 (24,5%), NF-2 (17,5%), p53 (14%), SMO (8,7%) PITCH (8,8%), KEAP1 (7%) and TERT (5.3%) considering all 57 patients together. Wild-type patients for this gene panel were 31.6%. Median survival for short survivors was 13 months, while 47 for long survivors. No major differences in gene profile were observed between long and short survivors with the exception of SMO which was mutated only in short survivors (16%). SMO seems strongly associated with a poor prognosis (HR 8.01; CI95% 2.79-22.98 p <0.001). Also when considering only short survivors the negative prognostic effect remained statistically significant (HR 3.67, CI95% 1.28-10.48, p = 0.015). The median survival for SMO mutated patients was 7 months. CONCLUSIONS: SMO mutation was likely to identify a subset of MPM patients with worse prognosis. As SMO could be a promising target for specific inhibitors, further researches at clinical level in this subset of patients and also at preclinical level are ongoing. This study was granted by AIRC. Citation Format: Monica Ganzinelli, Claudia Proto, Diego Signorelli, Laura Botta, Giulia Pasello, Marcello Tiseo, Annalisa Trama, Gemma Gatta, Adele Busico, Alessandra Fabbri, Nadia Zaffaroni, Giuseppe Pelosi, Ugo Pastorino, Filippo De Braud, Milena Vitali, Marina C. Garassino. SMO mutation identifies a subgroup of malignant pleural mesothelioma (MPM) patients with a worse prognosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3113.