title: Mutations of epigenetic regulatory genes are common in thymic carcinomas.
abstract: Genetic alterations and etiology of thymic epithelial tumors (TETs) are largely unknown, hampering the development of effective targeted therapies for patients with TETs. Here TETs of advanced-stage patients enrolled in a clinical trial of molecularly-guided targeted therapies were employed for targeted sequencing of 197 cancer-associated genes. Comparative sequence analysis of 78 TET/blood paired samples obtained from 47 thymic carcinoma (TC) and 31 thymoma patients revealed a total of 86 somatic non-synonymous sequence variations across 39 different genes in 33 (42%) TETs. TCs (62%; 29/47) showed higher incidence of somatic non-synonymous mutations than thymomas (13%; 4/31; p < 0.0001). TP53 was the most frequently mutated gene in TETs (n = 13; 17%), especially in TCs (26%), and was associated with a poorer overall survival (p < 0.0001). Genes in histone modification [BAP1 (n = 6; 13%), SETD2 (n = 5; 11%), ASXL1 (n = 2; 4%)], chromatin remodeling [SMARCA4 (n = 2; 4%)], and DNA methylation [DNMT3A (n = 3; 7%), TET2 (n = 2; 4%), WT1 (n = 2; 4%)] pathways were recurrently mutated in TCs, but not in thymomas. Our results suggest a potential disruption of epigenetic homeostasis in TCs, and a substantial difference in genetic makeup between TCs and thymomas. Further investigation is warranted into the roles of epigenetic dysregulation in TC development and its potential for targeted therapy.
authors.affiliation: 1] Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 [2] Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC 20007.
authors.forename: Yisong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Anish
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Arun
authors.initials: A
authors.lastname: Rajan
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Petrini
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Trung
authors.initials: T
authors.lastname: Pham
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Betsy
authors.initials: B
authors.lastname: Morrow
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC 20007.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.affiliation: 1] Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 [2] Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC 20007.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D059472:Exome; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D055815:Young Adult