title: Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes.
abstract: We detected low levels of acetylation for histone H3 tail lysines in malignant mesothelioma (MM) cell lines resistant to histone deacetylase inhibitors. To identify the possible genetic causes related to the low histone acetylation levels, whole-exome sequencing was conducted with MM cell lines established from eight patients. A mono-allelic variant of BRD1 was common to two MM cell lines with very low acetylation levels. We identified 318 homozygous protein-damaging variants/mutations (18-78 variants/mutations per patient); annotation analysis showed enrichment of the molecules associated with mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes and co-activators that facilitate initiation of transcription. In seven of the patients, we detected a combination of variants in histone modifiers or transcription factors/co-factors, in addition to variants in mSWI/SNF. Direct sequencing showed that homozygous mutations in SMARCA4, PBRM1 and ARID2 were somatic. In one patient, homozygous germline variants were observed for SMARCC1 and SETD2 in chr3p22.1-3p14.2. These exhibited extended germline homozygosity and were in regions containing somatic mutations, leading to a loss of BAP1 and PBRM1 expression in MM cell line. Most protein-damaging variants were heterozygous in normal tissues. Heterozygous germline variants were often converted into hemizygous variants by mono-allelic deletion, and were rarely homozygous because of acquired uniparental disomy. Our findings imply that MM might develop through the somatic inactivation of mSWI/SNF complex subunits and/or histone modifiers, including BAP1, in subjects that have rare germline variants of these transcription regulators and/or transcription factors/co-factors, and in regions prone to mono-allelic deletion during oncogenesis.
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Ayuko
authors.initials: A
authors.lastname: Sato
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.forename: Taiichiro
authors.initials: T
authors.lastname: Otsuki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Fukuoka
authors.forename: Seiki
authors.initials: S
authors.lastname: Hasegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hashimoto-Tamaoki
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004268:DNA-Binding Proteins; D018095:Germ-Line Mutation; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008654:Mesothelioma / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006657:Histones; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; C400134:BAP1 protein, human; C102195:PBRM1 protein, human; C445179:SWI-SNF-B chromatin-remodeling complex; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins
keywords: mSWI/SNF; malignant mesothelioma; rare germline variant; somatic mutation; transcription regulator