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: Yisong Wang, Anish Thomas, Christopher Lau, Arun Rajan, Yuelin Zhu, J Keith Killian, Iacopo Petrini, Trung Pham, Betsy Morrow, Xiaogang Zhong, Paul S Meltzer, Giuseppe Giaccone
• Journal: Scientific reports (Sci Rep) Vol. 4 Pg. 7336 (Dec 08 2014) ISSN: 2045-2322 [Electronic] England
• PMID: 25482724 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Topics

• Adult
• Aged
• Aged, 80 and over
• Amino Acid Substitution
• Carcinoma (genetics, mortality, pathology)
• Chromatin Assembly and Disassembly
• Epigenesis, Genetic
• Exome
• Female
• Gene Expression Regulation, Neoplastic
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• Middle Aged
• Mutation
• Mutation Rate
• Neoplasm Grading
• Neoplasm Staging
• Neoplasms, Glandular and Epithelial (genetics, pathology)
• Thymus Neoplasms (genetics, mortality, pathology)
• Young Adult