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1.
Nat Genet ; 48(4): 407-16, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26928227

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.


Subject(s)
Lung Neoplasms/genetics , Mesothelioma/genetics , Oncogene Proteins, Fusion/genetics , Pleural Neoplasms/genetics , Alternative Splicing , Cell Line, Tumor , DNA Mutational Analysis , Exome , Humans , Kaplan-Meier Estimate , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Mesothelioma/metabolism , Mesothelioma/mortality , Mesothelioma, Malignant , Mutation , Oncogene Proteins, Fusion/metabolism , Phosphoproteins/genetics , Phosphoproteins/metabolism , Pleural Neoplasms/metabolism , Pleural Neoplasms/mortality , Polymorphism, Single Nucleotide , Proportional Hazards Models , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA Splicing Factors , Ribonucleoprotein, U2 Small Nuclear/genetics , Ribonucleoprotein, U2 Small Nuclear/metabolism
2.
Cancer Res ; 76(2): 319-28, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26554828

ABSTRACT

Malignant pleural mesothelioma (MPM) is an aggressive cancer that occurs more frequently in men, but is associated with longer survival in women. Insight into the survival advantage of female patients may advance the molecular understanding of MPM and identify therapeutic interventions that will improve the prognosis for all MPM patients. In this study, we performed whole-genome sequencing of tumor specimens from 10 MPM patients and matched control samples to identify potential driver mutations underlying MPM. We identified molecular differences associated with gender and histology. Specifically, single-nucleotide variants of BAP1 were observed in 21% of cases, with lower mutation rates observed in sarcomatoid MPM (P < 0.001). Chromosome 22q loss was more frequently associated with the epithelioid than that nonepitheliod histology (P = 0.037), whereas CDKN2A deletions occurred more frequently in nonepithelioid subtypes among men (P = 0.021) and were correlated with shorter overall survival for the entire cohort (P = 0.002) and for men (P = 0.012). Furthermore, women were more likely to harbor TP53 mutations (P = 0.004). Novel mutations were found in genes associated with the integrin-linked kinase pathway, including MYH9 and RHOA. Moreover, expression levels of BAP1, MYH9, and RHOA were significantly higher in nonepithelioid tumors, and were associated with significant reduction in survival of the entire cohort and across gender subgroups. Collectively, our findings indicate that diverse mechanisms highly related to gender and histology appear to drive MPM.


Subject(s)
Lung Neoplasms/genetics , Mesothelioma/genetics , Pleural Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Case-Control Studies , Female , Humans , Lung Neoplasms/pathology , Male , Mesothelioma/pathology , Mesothelioma, Malignant , Middle Aged , Pleural Neoplasms/pathology , Sex Factors , Young Adult
3.
Biochem Biophys Res Commun ; 423(4): 763-9, 2012 Jul 13.
Article in English | MEDLINE | ID: mdl-22705549

ABSTRACT

In cells exposed to environmental stress, inhibition of translation initiation conserves energy for the repair of cellular damage. Untranslated mRNAs that accumulate in these cells move to discrete cytoplasmic foci known as stress granules (SGs). The assembly of SGs helps cells to survive under adverse environmental conditions. We have analyzed the mechanism by which hydrogen peroxide (H(2)O(2))-induced oxidative stress inhibits translation initiation and induces SG assembly in mammalian cells. Our data indicate that H(2)O(2) inhibits translation and induces the assembly of SGs. The assembly of H(2)O(2)-induced SGs is independent of the phosphorylation of eIF2α, a major trigger of SG assembly, but requires remodeling of the cap-binding eIF4F complex. Moreover, H(2)O(2)-induced SGs are compositionally distinct from canonical SGs, and targeted knockdown of eIF4E, a protein required for canonical translation initiation, inhibits H(2)O(2)-induced SG assembly. Our data reveal new aspects of translational regulation induced by oxidative insults.


Subject(s)
Cytoplasmic Granules/metabolism , Eukaryotic Initiation Factor-2/metabolism , Hydrogen Peroxide/metabolism , Oxidative Stress , Protein Biosynthesis , Animals , Cell Line, Tumor , Eukaryotic Initiation Factor-2/genetics , Gene Knockdown Techniques , Humans , Hydrogen Peroxide/pharmacology , Mice , Phosphorylation , RNA, Small Interfering/genetics , RNA, Untranslated/metabolism
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