Mesothelioma in the age of “Omics”: Before and after The Cancer Genome Atlas
2020; Elsevier BV; Volume: 160; Issue: 4 Linguagem: Inglês
10.1016/j.jtcvs.2020.02.141
ISSN1097-685X
AutoresDavid T. Severson, Assunta De Rienzo, Raphael Bueno,
Tópico(s)Pancreatic and Hepatic Oncology Research
ResumoCentral MessageNGS studies, including the 2018 TCGA publication on MPM, have improved our molecular and genetic understanding of the disease.This Invited Expert Opinion provides a perspective on the following paper: Cancer Discov. 2018;8(12):1548-1565. https://doi.org/10.1158/2159-8290.CD-18-0804.See Commentaries on pages 1084 and 1086. NGS studies, including the 2018 TCGA publication on MPM, have improved our molecular and genetic understanding of the disease. This Invited Expert Opinion provides a perspective on the following paper: Cancer Discov. 2018;8(12):1548-1565. https://doi.org/10.1158/2159-8290.CD-18-0804. See Commentaries on pages 1084 and 1086. Feature Editor's Introduction—Malignant pleural mesothelioma (MPM) is a highly fatal cancer of the pleura that has been defeating standard and investigational therapies since its first description. The efficacies of chemotherapy, radiotherapy, and surgical therapy are limited, and we have been writing for decades that improved therapies are needed. MPM is born of inflammation, and approximately 80% of cases are associated with the smoldering tissue inflammatory responses against the carcinogenic fibers of asbestos. Emerging data on the use of programmed cell death protein 1 immune checkpoint inhibitors were initially exciting, but response is less than 20% and these agents are finding their place on the list of approaches with narrow efficacy. Molecular targeted therapies have revolutionized the treatment of other cancers, commonly result in striking antitumor responses, and directly embody precision medicine. For an example, we prescribe drugs for some lung adenocarcinomas that target the secondary mutations that develop as a resistance mechanism to their initial targeted therapy. The discovery of molecular therapeutics for any tumor begins with identification of a target through investigation of the genomic, epigenomic, and transcriptomic drivers of its carcinogenesis. Such an advance could revolutionize the treatment of mesothelioma. A comprehensive dissection of MPM's molecular structure was recently published by 2 groups, the first from the Brigham and Women's Hospital and then from The Cancer Genome Atlas. In the Invited Expert Opinion article that follows, a practical account of the molecular underpinnings of MPM is eloquently presented by the Brigham group and will inspire the discovery and translation of novel molecular targets by mesothelioma investigators and practitioners. Bryan M. Burt, MD The –omics technologies have expanded widely because of advances in both mass spectrometry and nucleotide sequencing technology. Together, these approaches have led to numerous new insights in medicine and biology. In cancer, the developments in nucleotide sequencing have been transformative, allowing cancer biologists to characterize cancer-specific driver genes (genomics), identify altered gene expression (transcriptomics, methylomics, interactomics), and generate candidates for novel drug targets. Malignant pleural mesothelioma (MPM) research has also benefitted from those advances. In The Cancer Genome Atlas (TCGA) article "Integrative Molecular Characterization of Malignant Pleural Mesothelioma," published in Cancer Discovery in 2018, Hmeljak and colleagues1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar applied these technologies in an integrated fashion. Before further discussion of the article by TCGA, the history and fundamentals of both MPM and nucleotide sequencing technology merit some introduction. MPM is a deadly, but relatively rare malignancy caused by prior asbestos exposure. MPM is derived from malignant transformation of the mesothelium, the monolayer of epithelial cells lining the pleural lumen.2Yap T.A. Aerts J.G. Popat S. Fennell D.A. Novel insights into mesothelioma biology and implications for therapy.Nat Rev Cancer. 2017; 17: 475-488Crossref PubMed Scopus (222) Google Scholar Approximately 60% of MPMs are epithelioid, another 20% are sarcomatoid characterized by spindle cell morphology, and the remaining 20% are a mixed type called "biphasic mesothelioma."2Yap T.A. Aerts J.G. Popat S. Fennell D.A. Novel insights into mesothelioma biology and implications for therapy.Nat Rev Cancer. 2017; 17: 475-488Crossref PubMed Scopus (222) Google Scholar These histologic subtypes are prognostic. The ranges of median survival for patients presenting with sarcomatoid-, biphasic-, and epithelioid-type MPM are 7 to 18 months, 8 to 21 months, and 12 to 27 months, respectively.2Yap T.A. Aerts J.G. Popat S. Fennell D.A. Novel insights into mesothelioma biology and implications for therapy.Nat Rev Cancer. 2017; 17: 475-488Crossref PubMed Scopus (222) Google Scholar Despite the phenotypic and prognostic diversity of these 3 histologic subtypes, few specific differences in genetic etiology have been identified to date. Several investigations suggest that decades of chronic inflammation in the pleural microenvironment facilitate carcinogenesis.2Yap T.A. Aerts J.G. Popat S. Fennell D.A. Novel insights into mesothelioma biology and implications for therapy.Nat Rev Cancer. 2017; 17: 475-488Crossref PubMed Scopus (222) Google Scholar Asbestos exposure is the initiator of this chronic, carcinogenic proinflammatory milieu in the majority of MPM cases.3Peto J. Seidman H. Selikoff I. Mesothelioma mortality in asbestos workers: implications for models of carcinogenesis and risk assessment.Br J Cancer. 1982; 45: 124-135Crossref PubMed Scopus (208) Google Scholar Radiation may be implicated in a minority of cases.4van Kaick G. Dalheimer A. Hornik S. Kaul A. Liebermann D. The German thorotrast study: recent results and assessment of risks.Radiat Res. 1999; 152: S64Crossref PubMed Scopus (92) Google Scholar Variants in the gene BAP1 have also been associated with familiar and sporadic MPM.2Yap T.A. Aerts J.G. Popat S. Fennell D.A. Novel insights into mesothelioma biology and implications for therapy.Nat Rev Cancer. 2017; 17: 475-488Crossref PubMed Scopus (222) Google Scholar Because little is known about the pathogenesis of MPM, the identification of somatic mutations and subsequently altered pathways that drive mesothelial transformation are of great interest in the field. The various "–omics" technologies, especially transcriptomics and genomics, have contributed greatly to our understanding of relevant genetic alterations and pathway perturbations in MPM. The technology allowing whole genome and transcriptome study represents a convergence of numerous discoveries and innovations in molecular biology. In 1953 when Watson and Crick5Watson J.D. Crick F.H.C. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid.Nature. 1953; 171: 737-738Crossref PubMed Scopus (8367) Google Scholar identified the double-helix chemical structure of DNA, the inevitable quest to sequence and understand the genome began. Rapid, although low throughput, techniques such as Maxam and Gilbert's method6Maxam A. Gilbert W. A new method for sequencing DNA.Proc Natl Acad Sci. 1977; 74: 560-564Crossref PubMed Scopus (5442) Google Scholar and Sanger sequencing7Sanger F. Coulson A.R. A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase.J Mol Biol. 1975; 94: 441-448Crossref PubMed Scopus (1587) Google Scholar were essential to fulfilling this mission. The advent of polymerase chain reaction in 19888Saiki R. Gelfand D. Stoffel S. Higuchi R. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase.Science. 1988; 239: 487-491Crossref PubMed Scopus (13473) Google Scholar expedited the rate of gene discoveries, which culminated in 2004 when the entire human genome was finally sequenced.9International Human Genome Sequencing ConsortiumFinishing the euchromatic sequence of the human genome.Nature. 2004; 431: 931-945Crossref PubMed Scopus (3498) Google Scholar Soon after, technologies collectively called "next-generation sequencing" (NGS) became available for genome-wide study.10Tucker T. Marra M. Friedman J.M. Massively parallel sequencing: the next big thing in genetic medicine.Am J Hum Genet. 2009; 85: 142-154Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar These massively parallel sequencing technologies made possible the simultaneous sequencing of millions to trillions of parallel base pairs and dramatically decreased the time and cost of sequencing. The field accelerated as sequencing individual genomes became orders of magnitude cheaper and faster. The thousand genomes project was completed in 2012.11The 1000 Genomes Project ConsortiumAn integrated map of genetic variation from 1,092 human genomes.Nature. 2012; 491: 56-65Crossref PubMed Scopus (5677) Google Scholar NGS technology was also used to understand functional elements. Whole transcriptomes of tissue were analyzed by sequencing cDNA, so-called RNA sequencing.12Wang Z. Gerstein M. Snyder M. RNA-Seq: a revolutionary tool for transcriptomics.Nat Rev Genet. 2009; 10: 57-63Crossref PubMed Scopus (8463) Google Scholar In ChIP-seq, chromatin immune precipitation of histone modifications and transcription factors enriched for DNA associated with these macro-molecules and the resulting DNA was sequenced.13Mikkelsen T.S. Ku M. Jaffe D.B. Issac B. Lieberman E. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells.Nature. 2007; 448: 553-560Crossref PubMed Scopus (3235) Google Scholar The ENCODE project combined these functional approaches, and the project's phase 3 conclusion in 2011 represented a great leap forward in decoding the fundamental language of gene expression and regulation.14The ENCODE Project ConsortiumAn integrated encyclopedia of DNA elements in the human genome.Nature. 2012; 489: 57-74Crossref PubMed Scopus (11030) Google Scholar After these achievements, costs have continued to decline; individual genomes and transcriptomes are routinely sequenced (Figure 1). Multi-institutional teams such as TCGA, and even individual laboratories, can now afford to tackle individual biological problems by applying multiple NGS approaches to numerous samples. In this way, in the last few years the understanding of MPM has improved because of high-throughput studies. Numerous cytogenetic, molecular genetics, and high-density array methods have identified many of the specific chromosomal rearrangements, epigenetic alterations, and genes that are important in MPM.15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar Chromosomal abnormalities have long been recognized as important in MPM, and aneuploidy has been observed to be characterized by widespread chromosomal loss.15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar These losses frequently occur in regions 1p, 3p14-p21, whole chromosome 4, 6q, 9p, and 22q.15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar Notably, several tumor suppressor genes (TSGs) frequently mutated in MPM, cyclin-dependent kinase inhibitor 2A (CDKN2A), ubiquitin carboxyl-terminal hydroxylase (BAP1), and tumor protein p53 (TP53) are found within 9p21.3, 3p21, and 17p13, respectively.15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar In epigenetic studies, tumor suppressors CDKN2A and cyclin-dependent kinase inhibitor 2B (CDKN2B), among others, were hypermethylated in patients with MPM compared with asbestos-exposed patients who were in turn hypermethylated compared with nonexposed patients.15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar Loss of TSGs was found to be a common feature in MPM; specific mutations in known TSGs, such as neurofibromatosis type 2 (NF2), large tumor suppressor kinase 2 (LATS2), CDKN2A, CDKN2B, and TP53, were identified mutations in MPM.15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar,16Murakami H. Mizuno T. Taniguchi T. Fujii M. Ishiguro F. LATS2 is a tumor suppressor gene of malignant mesothelioma.Cancer Res. 2011; 71: 873-883Crossref PubMed Scopus (179) Google Scholar No oncogene has been identified in MPM to date.15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar Taken together, these observations suggest MPM is a malignancy resulting from inhibition of cellular mechanisms of tumor suppression rather than transformation by activation of oncogenes. In 2016, our group confirmed many of these findings using Illumina SNP arrays, whole exome, and targeted deep sequencing of 95, 99, and 103 tumors, respectively.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar Consistent with previous studies,15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar somatic copy number alterations (SCNAs) identified in the cohort of 95 MPMS were broadly characterized by copy number loss in TSGs (eg, BAP1, NF2, CDKN2B, and TP53).17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar A subset of MPMs were characterized by copy number neutral widespread loss of heterozygosity.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar The previously described tumor suppressors, NF2, BAP1, and TP53 were among the most frequently and significantly mutated in the MPM cohort.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar In addition to these, we observed several new significantly mutated genes including histone modifiers, such as SETD2, SETDB1, and SETD5, RNA helicase family members DDX3X and DDX51, a target of mTOR negative regulation ULK2, and a calcium channel component RYR2.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar Early work in MPM transcriptomics used microarray technology. In 2005, Gordon and colleagues18Gordon G.J. Rockwell G.N. Jensen R.V. Rheinwald J.G. Glickman J.N. Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling.Am J Pathol. 2005; 166: 1827-1840Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar identified 2 molecular phenotype groups and observed that these groups associated with histologic classification consistent with similar observations in a smaller cohort made by Hoang and colleagues in 2004.19Hoang C.D. D'Cunha J. Kratzke M.G. Casmey C.E. Frizelle S.P. Gene expression profiling identifies matriptase overexpression in malignant mesothelioma.Chest. 2004; 125: 1843-1852Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Although the histology of mesothelioma did not perfectly correlate with these molecular features, a spectrum of histologically associated molecular signatures was beginning to emerge. In 2014, de Reyniès and colleagues20de Reyniès A. Jaurand M.-C. Renier A. Couchy G. Hysi I. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition.Clin Cancer Res. 2014; 20: 1323-1334Crossref PubMed Scopus (95) Google Scholar profiled 38 MPM primary cell lines using microarray profiling. Clustering of these expression profiles identified 2 major groups.20de Reyniès A. Jaurand M.-C. Renier A. Couchy G. Hysi I. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition.Clin Cancer Res. 2014; 20: 1323-1334Crossref PubMed Scopus (95) Google Scholar These clusters were associated with, but not identical to, histology; both groups contained epithelioid samples, but all the sarcomatoid samples were found in cluster 2.20de Reyniès A. Jaurand M.-C. Renier A. Couchy G. Hysi I. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition.Clin Cancer Res. 2014; 20: 1323-1334Crossref PubMed Scopus (95) Google Scholar Furthermore, genes associated with epithelioid-mesenchymal transition (EMT) were differentially regulated between the 2 clusters, and cluster 2 exhibited a more mesenchymal phenotype.20de Reyniès A. Jaurand M.-C. Renier A. Couchy G. Hysi I. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition.Clin Cancer Res. 2014; 20: 1323-1334Crossref PubMed Scopus (95) Google Scholar This work suggested that a primary feature of MPM heterogeneity was related to EMT phenotype. By using a 3 gene molecular test based on the observed gene expression differences in the 2 clusters, the relationship between the EMT status and histology and survival was demonstrated in 108 MPM tumor samples.20de Reyniès A. Jaurand M.-C. Renier A. Couchy G. Hysi I. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition.Clin Cancer Res. 2014; 20: 1323-1334Crossref PubMed Scopus (95) Google Scholar Following this work, in 2016 our group published RNA-sequencing profiles of 211 MPM tumor samples.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar In our cohort, unsupervised consensus clustering identified 4 molecular clusters approximately associated with the spectrum from epithelioid to sarcomatoid histology.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar Analysis of genes differentially expressed between the 2 extreme clusters identified in our MPM cohort suggested these clusters appeared to be related to EMT consistent with the observations of de Reyniès and colleagues.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar,20de Reyniès A. Jaurand M.-C. Renier A. Couchy G. Hysi I. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition.Clin Cancer Res. 2014; 20: 1323-1334Crossref PubMed Scopus (95) Google Scholar Additionally, a simple ratio of 2 genes, CLDN15 and VIM, the ratio of CLDN15/VIM genes (C/V) score, significantly discriminated each molecular cluster.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar Hmeljak and colleagues1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar performed a comprehensive analysis of 74 MPM tumors as part of the effort by TCGA. Genomic, epigenomic, and transcriptomic profiles were generated using high-throughput array and NGS experiments. Specifically, copy-number arrays and exome sequencing characterized chromosomal and genetic aberrations. For gene expression analysis, TCGA performed total RNA sequencing including long noncoding RNA analysis. In addition, micro-RNA, DNA methylation, and protein level profiles were also obtained using micro-RNA sequencing, hybridization arrays, and reverse-phase protein arrays, respectively. The SCNA landscape of MPM tumors described in TCGA cohort was consistent with previous NGS results in MPM.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar,15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar,17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar Several focal and arm-level deletions, but no recurring amplifications, were observed in this cohort.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar Loss of regions containing TSGs previously described in MPM such as CDKN2A and NF2 were present in 41 (56%) and 55 (74%) of 74 MPM tumors, respectively.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar Intriguingly, genomic analysis revealed a subpopulation of MPM tumors (n = 3 in TCGA) with loss of heterozygosity across more than 80% of the genome.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar This subpopulation was also observed in our previous study.17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar To better describe this cohort, the 3 TCGA loss of heterozygosity samples were combined with 2 additional cases from the Japanese International Cancer Genome Consortium for a total of 5 (3%) samples of 154 MPM tumors examined.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar This subpopulation was defined as having "genomic–near haploidization," where homozygous deletion of SETDB1 was a common feature of this subgroup, but absent in all other samples.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar Interestingly, 4 of these samples were female and 4 of them had TP53 mutations.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar Genomic alterations at the single nucleotide level were also consistent with previous work.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar,15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar,17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar The TSGs, BAP1, NF2, TP53, LATS2, and SETD2 were mutated significantly above the background mutation rate in this cohort.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar Several mutations identified in previous NGS studies,17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar including SETDB1, DDX3X, DDX51, ULK2, and RYR2, were found to be recurrently mutated in this cohort, but did not rise to significance likely because of a lack of statistical power. As in previous MPM studies.15Jean D. Daubriac J. Pimpec-Barthes F. Galateau-Salle F. Jaurand M.-C. Molecular changes in mesothelioma with an impact on prognosis and treatment.Arch Pathol Lab Med. 2012; 136: 277-293Crossref PubMed Scopus (74) Google Scholar,17Bueno R. Stawiski E.W. Goldstein L.D. Durinck S. De Rienzo A. Modrusan Z. et al.Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.Nat Genet. 2016; 48: 407-416Crossref PubMed Scopus (544) Google Scholar these mutations in TSGs were characterized by inactivation. Although BAP1 genetic alterations displayed nonrandom patterns of co-occurrence with recurrently mutated genes (NF2, TP53, LATS2, SETD2, and MALAT1), the associations were not significant when multiple hypothesis testing was taken into account.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar Tumors with BAP1 homozygous mutation had significantly more arm stability when compared with wild-type tumors.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar In this study, SCNAs, gene expression, and epigenetic information were integrated using 2 previously published clustering algorithms, iCluster21Shen R. Olshen A.B. Ladanyi M. Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis.Bioinformatics. 2009; 25: 2906-2912Crossref PubMed Scopus (490) Google Scholar and PARADIGM.22Vaske C.J. Benz S.C. Sanborn Z.J. Earl D. Szeto C. Inference of patient-specific pathway activities from multi-dimensional cancer genomics data using PARADIGM.Bioinformatics. 2010; 26: i237-i245Crossref PubMed Scopus (532) Google Scholar Both algorithms identified 4 distinct groups of MPMs.1Hmeljak J. Sanchez-Vega F. Hoadley K.A. Shih J. Stewart C. Heiman D. et al.Integrative molecular characterization of malignant pleural mesothelioma.Cancer Discov. 2018; 8: 1548-1565Crossref PubMed Scopus (298) Google Scholar There was strong concordance in the grouping of samples between the 2 methods, especially f
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