SMO mutations confer poor prognosis in malignant pleural mesothelioma

Our plain-English summary of SMO mutations confer poor prognosis in malignant pleural mesothelioma, by D. Signorelli, C. Proto, L. Botta, et al (Translational Lung Cancer Research, 2020).

The study

• Authors: D. Signorelli, C. Proto, L. Botta, A. Trama, M. Tiseo, G. Pasello, G. Lo Russo, A. Fabbri, M. Imbimbo, A. Busico, A. Prelaj, R. Ferrara, G. Galli, A. De Toma, E. Tamborini, U. Pastorino, F. de Braud, G. Gatta, M.C. Garassino, M. Ganzinelli
• Journal: Translational Lung Cancer Research
• Published: 2020;9(5):1940-1951
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

2020 Translational Lung Cancer Research. All rights reserved.

In plain English

This retrospective pilot study examined tumor tissue from 56 people with malignant pleural mesothelioma treated at three Italian institutions between 2002 and 2014. Patients were split into 32 'normo survivors' (survival of 3 years or less) and 24 'long survivors' (more than 3 years). The authors tested 21 genes in the tumors and measured levels of the SMO protein. The article did not report the patients' asbestos exposure. Eighteen of the 56 patients (32%) had no mutations in the genes tested. SMO mutations were found only in normo survivors (15.6% of that group). The article's table gave a P value of 0.063 for this difference between the groups. SMO mutations were linked to shorter survival (hazard ratio 4.36, 95% CI 2.32 to 8.18). The link held after adjusting for sex, age, stage, tumor type and treatment (hazard ratio 9.2, 95% CI 3.0 to 28.4). Mutations in BAP1, NF2, TP53 and PTCH1 showed no significant link to survival. The authors concluded that SMO mutations were associated with worse prognosis. They noted that only 5 patients had SMO mutations and called for an adequately powered prospective trial.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective pilot study comparing tumor gene mutations (next generation sequencing) and SMO protein levels (immunohistochemistry) between shorter- and longer-surviving patients, with survival analysis
• Who was studied: 56 patients with malignant pleural mesothelioma from three Italian institutions (INT Milan, Istituto Oncologico Veneto-Padua, Azienda Ospedaliera-Parma), recruited 2002 to 2014. Of these, 32 were normo survivors (overall survival 3 years or less) and 24 were long survivors (more than 3 years). Patients were mainly male, with epithelioid histotype, diagnosed at stage III.
• Exposure: Asbestos exposure was not studied or reported. The factors studied were tumor mutations in a 21-gene panel (including BAP1, NF2, TP53, SMO, PTCH1, CDKN2A) and SMO protein expression.
• Main results:
  • 18 of 56 patients (32%) had no mutations in the genes tested: 12 normo survivors and 6 long survivors
  • SMO was mutated only in normo survivors (5 of 32, 15.6%), all with epithelioid histotype. The text states no significant differences in mutation frequency between the two groups, and Table 3 gives P=0.063 for SMO.
  • In univariate analysis, only SMO mutation was significantly associated with poor overall survival (HR 4.36, 95% CI 2.32 to 8.18, P less than 0.0001). BAP1, NF2, TP53 and PTCH1 mutations were not significantly associated with survival.
  • After adjustment for sex, age, stage, histology and treatment, SMO mutation remained associated with poor survival (HR 9.2, 95% CI 3.0 to 28.4, P=0.0001)
  • The SMO-mutated patients died within 13 months
  • Median survival was 21.6 months (range 0.6 to 32.4) in normo survivors and 53 months (range 37 to 86) in long survivors
  • SMO protein was tested in 53 patients. All 4 SMO-mutated patients with tissue available had high protein levels. Among normo survivors, median survival was 11.6 months with high SMO expression vs 19.6 months with low expression.
  • Five PTCH1 mutations were also found, bringing alterations in the Hedgehog pathway to 16% overall, but PTCH1 mutations showed no clear correlation with survival
• The authors' conclusion: The authors concluded that, for the first time to their knowledge, SMO mutations were associated with a worse prognosis in malignant pleural mesothelioma, and that SMO might be a potential therapeutic target
• Limitations the authors state:
  • Only 5 patients with SMO mutations were identified
  • Including all available long survivors gave the sample a higher share of long survivors than the 12% seen in the population. The authors addressed this by resampling to 12% for the survival analyses.
  • Patients came from expert centres, so the proportion who had surgery (52%) was higher than usual
  • The gene panel was not designed to detect large genetic losses, such as CDKN2A deletions
  • It is not known whether the SMO mutations are linked to a deregulated Hedgehog pathway
  • The authors stated that a prospective trial with adequate statistical power is needed to define mutation frequencies and their prognostic role

Topics

Medical terms in this study, explained in our Lexicon: Prognosis, Pleural Mesothelioma, Immunotherapy, Overall Survival, Immunohistochemistry, BAP1.

Related studies

• Epigenetic down-regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma — V. Laszlo, M.A. Hoda, et al. (2015)
• Treatment patterns among patients with malignant pleural mesothelioma: An Italian, population-based nationwide study — A. Trama, C. Proto, et al. (2020)
• Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy? — D. Signorelli, M. Macerelli, et al. (2016)
• High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy — S.C. Kao, N. Pavlakis, et al. (2010)
• B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis — A.S. Mansfield, A.C. Roden, et al. (2014)
• Tumor necrosis correlates with angiogenesis and is a predictor of poor prognosis in malignant mesothelioma — J.G. Edwards, D.E. Swinson, et al. (2003)

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