Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations

Our plain-English summary of Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations, by R. Bueno, E.W. Stawiski, L.D. Goldstein, et al (Nature Genetics, 2016).

The study

• Authors: R. Bueno, E.W. Stawiski, L.D. Goldstein, S. Durinck, A. De Rienzo, Z. Modrusan, F. Gnad, T.T. Nguyen, B.S. Jaiswal, L.R. Chirieac, D. Sciaranghella, N. Dao, C.E. Gustafson, K.J. Munir, J.A. Hackney, A. Chaudhuri, R. Gupta, J. Guillory, K. Toy, C. Ha, Y.J. Chen, J. Stinson, S. Chaudhuri, N. Zhang, T.D. Wu, D.J. Sugarbaker, F.J. de Sauvage, W.G. Richards, S. Seshagiri
• Journal: Nature Genetics
• Published: 2016;48(4):407-16
• Type of article: Meta-analysis
• Cited by: 762 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.

In plain English

This laboratory genetics study analyzed tumor tissue from 216 people with malignant pleural mesothelioma whose tumors were surgically removed, compared with matched normal tissue. The authors measured gene activity (RNA) in 211 tumors and read protein-coding DNA in 202 tumors (99 fully, 103 for 460 selected genes). Using gene activity, they sorted tumors into four molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid and biphasic-sarcomatoid. Of 141 tumors classed as epithelioid under the microscope, the 88 that fell outside the epithelioid molecular group had lower overall survival (hazard ratio 2.5, 95% confidence interval 1.6 to 3.8). Ten genes were significantly mutated, including BAP1 (46 of 202 tumors), NF2 (38 of 202) and TP53 (17 of 202). TP53 mutations were absent from the epithelioid subtype, and across the study cohort, patients with TP53 mutations had lower overall survival than patients without them. The mutation pattern did not differ significantly between 69 tumors with known asbestos exposure and 17 without known exposure. A smoking-related pattern was not seen. The authors concluded that genomic analysis in patient care will help in developing individualized therapy.

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: Genomic sequencing study of surgically removed tumor samples and matched normal samples (laboratory analysis of RNA and DNA)
• Who was studied: 216 primary malignant pleural mesothelioma tumors, stored as fresh-frozen specimens, with matched normal samples, from patients undergoing extirpative (tumor-removing) surgery. An additional tumor was analyzed only by whole-genome sequencing. RNA was sequenced for 211 tumors, whole exomes for 99 and targeted exomes for 103. The article does not state the dates of collection.
• Exposure: This was not an exposure study. For the mutation-signature analysis, tumors were grouped by asbestos exposure: 69 with known asbestos exposure and 17 without known asbestos exposure. No fiber types, products, jobs or doses are given.
• Main results:
  • Using RNA data from 211 tumors, the authors identified four molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid and biphasic-sarcomatoid.
  • Of 141 tumors classified as epithelioid under the microscope, 53 (38%) fell into the epithelioid molecular cluster. The remaining 88 (62%) had lower overall survival, with a hazard ratio of 2.5 (95% confidence interval 1.6–3.8).
  • In the whole-exome data, tumors carried an average of 24 plus or minus 11 protein-coding alterations each. The authors described this as a low mutation rate compared with other cancers, apart from thyroid carcinoma and acute myeloid leukemia.
  • Ten genes were significantly mutated: BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51.
  • BAP1 was mutated in 23% (46/202) of tumors and NF2 in 19% (38/202).
  • TP53 was mutated in 8% (17/202) of tumors.
  • TP53 mutations were absent from the epithelioid subtype. Across the study cohort, patients with TP53 mutations (n = 17) had lower overall survival than those with wild-type TP53 (n = 185); the figure gives P = 0.0167.
  • The authors found no significant difference in mutational signature between tumors with known asbestos exposure (n = 69) and those without known asbestos exposure (n = 17).
  • The mutational signature associated with cigarette smoking, though predominant in lung cancer, was not observed in these mesotheliomas.
  • Recurrent mutations were found in SF3B1 (about 2%; 4/216) and TRAF7 (about 2%; 5/216).
  • The authors identified 43 gene fusions in 22 tumor samples. Many involved tumor suppressor genes such as NF2, BAP1 and SETD2.
  • 39% (83/211) of tumors were positive for PD-L1 as assessed by RNA sequencing.
• The authors' conclusion: The authors concluded that incorporating genomic analysis to detect actionable alterations as part of mesothelioma patient care will help in developing individualized therapy.
• Limitations the authors state:
  • The authors stated that their observations on SF3B1 were limited and that further study is needed to establish its role in mesothelioma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Sarcomatoid, Epithelioid, Biphasic Mesothelioma, BAP1.

Related studies

• Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing — A. Miyanaga, M. Masuda, et al. (2015)
• RNA sequencing identifies fusion of the EWSR1 and YY1 genes in mesothelioma with t(14;22)(q32;q12) — I. Panagopoulos, J. Thorsen, et al. (2013)
• A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions — P. Desmeules, P. Joubert, et al. (2017)
• Genomic profiling of malignant peritoneal mesothelioma reveals recurrent alterations in epigenetic regulatory genes BAP1, SETD2, and DDX3X — N.M. Joseph, Y.Y. Chen, et al. (2017)
• Splicing modulation as novel therapeutic strategy against diffuse malignant peritoneal mesothelioma — R. Sciarrillo, A. Wojtuszkiewicz, et al. (2019)
• Generation of human embryonic stem cell models to exploit the EWSR1-CREB fusion promiscuity as a common pathway of transformation in human tumors — F. Vanoli, B. Meskauskaite, et al. (2021)

Browse return to medical research.