title: Whole exome and targeted deep sequencing identify genome-wide allelic loss and frequent SETDB1 mutations in malignant pleural mesotheliomas.
abstract: Malignant pleural mesothelioma (MPM), a rare malignancy with a poor prognosis, is mainly caused by exposure to asbestos or other organic fibers, but the underlying genetic mechanism is not fully understood. Genetic alterations and causes for multiple primary cancer development including MPM are unknown. We used whole exome sequencing to identify somatic mutations in a patient with MPM and two additional primary cancers who had no evidence of venous, arterial, lymphovascular, or perineural invasion indicating dissemination of a primary lung cancer to the pleura. We found that the MPM had R282W, a key TP53 mutation, and genome-wide allelic loss or loss of heterozygosity, a distinct genomic alteration not previously described in MPM. We identified frequent inactivating SETDB1 mutations in this patient and in 68 additional MPM patients (mutation frequency: 10%, 7/69) by targeted deep sequencing. Our observations suggest the possibility of a new genetic mechanism in the development of either MPM or multiple primary cancers. The frequent SETDB1 inactivating mutations suggest there could be new diagnostic or therapeutic options for MPM.
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.|Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Hio Chung
authors.initials: HC
authors.lastname: Kang
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.|Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hong Kwan
authors.initials: HK
authors.lastname: Kim
authors.affiliation: CureSeq Inc, Brisbane, CA, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Mendez
authors.affiliation: CureSeq Inc, Brisbane, CA, USA.
authors.forename: James Wansoo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Gavitt
authors.initials: G
authors.lastname: Woodard
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Jun-Hee
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Kuang-Yu
authors.initials: KY
authors.lastname: Jen
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Li Tai
authors.initials: LT
authors.lastname: Fang
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Kirk
authors.initials: K
authors.lastname: Jones
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.|Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.|Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Il-Jin
authors.initials: IJ
authors.lastname: Kim
mesh_terms: D015153:Blotting, Western; D059472:Exome / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics*; D008654:Mesothelioma / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010997:Pleural Neoplasms / Q000235:genetics*; D011379:Prognosis; D011496:Protein Methyltransferases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
chemical_list: D012333:RNA, Messenger; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human
keywords: SETDB1; exome sequencing; genome-wide allelic loss; malignant pleural mesothelioma; multiple primary cancer
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