title: Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features.
abstract: Purpose:To reconcile the heterogeneity of thymic epithelial tumors (TET) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors.Experimental Design:Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts.Results:Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2Igroup), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering ofGTF2Iwild-type tumors and represented TETs enriched in expression of genes associated with T-cell signaling (TS group; 33%). The remaining two groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in theGTF2Igroup and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression ofPD1mRNA and correlation ofPD1andCD8Ain the TS subgroup.Conclusions:Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging and in the discovery and development of rational treatment options for patients with TETs.Clin Cancer Res; 23(16); 4855-64. ©2017 AACR.
authors.affiliation: Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Rohan
authors.initials: R
authors.lastname: Shah
authors.affiliation: Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Yoon
authors.affiliation: Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hamaji
authors.affiliation: Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Ori
authors.initials: O
authors.lastname: Wald
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
authors.affiliation: Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Bryan.Burt@bcm.edu.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Burt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000145:classification / Q000235:genetics* / Q000473:pathology; D013953:Thymus Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D055815:Young Adult