[1916] Targeted Cancer Genome Sequencing in Thymic Epithelial Tumors

Andre L Moreira, McMillan Robert, Won Helen, Huang James, Riely J Gregory, Ladanyi Marc, Berger F Michael. Memorial Sloan-Kettering Cancer Center, New York, NY

Background: There have been very few studies dedicated to the understanding of the biology of thymomas and thymic carcinomas (TCA). An improved understanding of the molecular characteristics of thymoma and TCA may lead to a better comprehension of tumorigenesis, and more importantly lead to new therapeutic targets, thus opening new treatment options for these patients.
Design: Paired tissue (tumor and normal, paraffin-embedded) from 13 thymic carcinomas and 6 WHO type B3 thymomas were evaluated by exon capture of 275 cancer related genes (Agilent SureSelect Target Enrichment system), followed by next-generation sequencing (Illumina HiSeq). This approach identifies all sequence variants, small insertions and deletions, and copy number alterations involving the target genes.
Results: Mutations were identified in 11 of 13 (85%) TCA with a median of 1 mutation per tumor (range 0-26). All TCA were classified as squamous cell carcinoma; one with 26 mutations was a CD5 positive poorly-differentiated carcinoma. The most mutated genes were TP53 (n=3), SMAD4 (n=2) and CYLD (n=2); and chromatin remodeling genes KDM6A (n=3), SETD2 (n=2), MLL3 (N=2), and MLL2 (n=2). TP53 and KDM6A were seen as a single mutation in one tumor each. The most frequently amplified genes were APC and SOX2 (each n=5), MDM4, AKT3, IGFR1, and FBXW7 (each n=4). In this small sample, the 3 TCA with TP53 mutation appeared to exhibit more aggressive behavior: all 3 patients presented as Masaoka stage 4 and received neoadjuvant therapy. Two patients with TP53-mutated TCA died of disease (mean survival 2.2 years). In contrast 2 other stage 4 patients without TP53 mutations are alive with disease and 2 others died of unrelated causes. All other TCA patients were Masaoka stage 1 to 3 at diagnosis and are alive. Among the B3 thymomas, mutations were identified in 4 of 6 tumors. Mutations in BCOR (BCL6 co-repressor) were seen in 3 thymomas and MLL3 (involved in histone methylation) in one tumor. The most frequently amplified genes were DDR2, AKT3, CDC73 (each n=4), PIK3R1, ABL2, IKBKE, and FH (each n=3).
Conclusions: Exon capture sequencing of cancer genes in thymic epithelial tumors revealed a low frequency of mutation and gene amplifications. However, there is a different pattern of molecular alterations between TCA and B3 thymomas. TCA have more mutations in TP53 gene whereas B3 thymomas may have a higher frequency of mutations in the BCOR gene.
Category: Pulmonary

Tuesday, March 5, 2013 1:15 PM

Proffered Papers: Section D, Tuesday Afternoon

 

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