biostudies-literatureUnknown9(5)Signorelli D<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 <i>BAP1</i>, <i>NF2</i>, <i>TP53</i>, <i>SMO</i> and <i>PTCH1</i> with no significant differences between the groups except for <i>SMO</i>. <i>SMO</i>, a member of the Hh pathway, was mutated only in NS (15.6%) and only <i>SMO</i> 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 <i>SMO</i> mutated patients expressed high protein levels.<h4>Conclusions</h4><i>SMO</i> mutations were clearly associated with worse prognosis. SMO may be a therapeutic target but this needs to be confirmed in a prospective trial.Translational lung cancer research1940-1951https://www.ebi.ac.uk/biostudies/studies/S-EPMC7653142biostudies-literature<i>SMO</i> mutations confer poor prognosis in malignant pleural mesothelioma.PMC7653142de Braud FGanzinelli MPastorino UTrama AGarassino MCProto CTamborini ESignorelli DTiseo MFerrara RPasello GBusico APrelaj AGalli GFabbri AGatta GLo Russo GImbimbo MBotta LDe Toma Afalse<i>SMO</i> mutations confer poor prognosis in malignant pleural mesothelioma.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 <i>BAP1</i>, <i>NF2</i>, <i>TP53</i>, <i>SMO</i> and <i>PTCH1</i> with no significant differences between the groups except for <i>SMO</i>. <i>SMO</i>, a member of the Hh pathway, was mutated only in NS (15.6%) and only <i>SMO</i> 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 <i>SMO</i> mutated patients expressed high protein levels.<h4>Conclusions</h4><i>SMO</i> mutations were clearly associated with worse prognosis. SMO may be a therapeutic target but this needs to be confirmed in a prospective trial.2020-01-01T00:00:00Z2020 Oct2025-04-19T23:40:02.15Z2025-04-19T23:40:02.15ZS-EPMC76531423320961410.21037/tlcr-19-425