SMO mutations confer poor prognosis in malignant pleural mesothelioma.

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor but approximately 12% of patients survive more than 3 years. The biological differences underlying better outcomes are not known. Several targeted agents and immunotherapy have been ineffective. Hedgehog (Hh) is one emerging pathway. We compared the biological profiles of patients with different survival, investigating the most frequently altered genes, including the Hh pathway.
Methods: We analyzed 56 MPM. A 36-month overall survival (OS) cut-off divided patients into 32 normo (NS) and 24 long (LS) survivors. We used next generation sequencing to test 21 genes, immunohistochemistry to evaluate SMO expression. Mutation differences between NS and LS and their associations with clinical features were analysed by Fisher's test, OS with the Kaplan-Meier method and its association with mutations by univariate and multivariate Cox proportional hazard models.
Results: Clinical features were similar in both groups. Eighteen out of 56 patients (32%) were wild-type for the genes analysed. At least five had mutations in BAP1 , NF2 , TP53 , SMO and PTCH1 with no significant differences between the groups except for SMO . SMO , a member of the Hh pathway, was mutated only in NS (15.6%) and only SMO mutations were significantly associated with poor prognosis at univariate (HR =4.36, 95% CI: 2.32-8.18, P<0.0001) and multivariate (HR =9.2, 95% CI: 3.0-28.4, P=0.0001) analysis. All SMO mutated patients expressed high protein levels.
Conclusions: SMO mutations were clearly associated with worse prognosis. SMO may be a therapeutic target but this needs to be confirmed in a prospective trial.
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-19-425). DS reports personal fees from Astra Zeneca, BMS, Lilly, Boehringer Ingelheim, non-financial support from Astra Zeneca, Roche, MSD, Pfizer outside the submitted work. CP reports personal fees from BMS, MSD outside the submitted work. MT reports personal fees from Astra Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, grants from Astra Zeneca, Boehringer Ingelheim outside the submitted work. MT serves as an unpaid editorial board member of Translational Lung Cancer Research from Dec 2019 to Nov 2021. GP reports ADVISOR/CONSULTANT: BOEHRINGER ING, AstraZeneca, Roche, BMS, MSD, LILLY ONC. GLR reports personal fees from BMS, MSD, Astra Zeneca outside the submitted work. AP reports personal fees from Roche, AstraZeneca, BMS outside the submitted work. FdB reports personal fees from TIZIANA LIFE SCIENCES, BMS, CELGENE, SERVIER, PHARMA RESEARCH, DAIICHI SANKYO, IGNYTA, NOVARTIS, AMGEN, PFIZER, OCTIMET ONCOLOGY, INCYTE, PIERRE FABRE, ELI LILLY, ROCHE, ASTRA ZENECA, GENTILI, DEPHAFORUM, NOVARTIS, MSD, BAYER, FONDAZIONE MENARINI, SANOFI outside the submitted work. Dr. G Gatta reports grants from AIRC during the conduct of the study. MCG reports grants and personal fees from Eli Lilly, Otsuka Pharma, Astra Zeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Bayer, MSD, GlaxoSmithKline S.p.A., Spectrum Pharmaceutcials, Blueprint Medicine, personal fees from Boehringer Ingelheim, Inivata, Takeda, Sanofi-Aventis, Seattle Genetics, Daiichi Sankyo, Jannesen, grants from Tiziana Sciences, Clovis, Merck Serono, UNITED THERAPEUTICS CORPORATION, Merck KGaA, TURNING POINT, IPSEN, Medlmmune, EXELISIS, non-financial support from MSD, Pfizer, Eli-Lilly outside the submitted work. MG reports grants from MOH, during the conduct of the study. The other authors have no conflicts of interest to declare.
(2020 Translational Lung Cancer Research. All rights reserved.)