title: Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma.
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.
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. aderienzo@partners.org.
authors.forename: Assunta
authors.initials: A
authors.lastname: De Rienzo
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Archer
authors.affiliation: Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Beow Y
authors.initials: BY
authors.lastname: Yeap
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Nhien
authors.initials: N
authors.lastname: Dao
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniele
authors.initials: D
authors.lastname: Sciaranghella
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Antonios C
authors.initials: AC
authors.lastname: Sideris
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Center for Cancer Computational Biology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Holman
authors.affiliation: Center for Cancer Computational Biology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Yaoyu E
authors.initials: YE
authors.lastname: Wang
authors.affiliation: Departments of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Paola S
authors.initials: PS
authors.lastname: Dal Cin
authors.affiliation: Departments of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Center for Cancer Computational Biology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Renee
authors.initials: R
authors.lastname: Rubio
authors.affiliation: Malaysian Genomics Resource Centre, Kuala Lumpur, Malaysia.
authors.forename: Larry
authors.initials: L
authors.lastname: Croft
authors.affiliation: Center for Cancer Computational Biology, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Harvard School of Public Health, Boston, Massachusetts.
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Sugarbaker
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Kiara J
authors.initials: KJ
authors.lastname: Munir
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jesse R
authors.initials: JR
authors.lastname: Battilana
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Corinne E
authors.initials: CE
authors.lastname: Gustafson
authors.affiliation: Departments of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.affiliation: Malaysian Genomics Resource Centre, Kuala Lumpur, Malaysia.
authors.forename: Soo Meng
authors.initials: SM
authors.lastname: Ching
authors.affiliation: Malaysian Genomics Resource Centre, Kuala Lumpur, Malaysia.
authors.forename: James
authors.initials: J
authors.lastname: Wong
authors.affiliation: Malaysian Genomics Resource Centre, Kuala Lumpur, Malaysia.
authors.forename: Liang Chung
authors.initials: LC
authors.lastname: Tay
authors.affiliation: Malaysian Genomics Resource Centre, Kuala Lumpur, Malaysia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rudd
authors.affiliation: Malaysian Genomics Resource Centre, Kuala Lumpur, Malaysia.
authors.forename: Robert
authors.initials: R
authors.lastname: Hercus
authors.affiliation: Debakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: The Thoracic Surgery Oncology laboratory and the International Mesothelioma Program, Division of Thoracic Surgery and the Lung Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D012737:Sex Factors; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor