Background: The histologic classification of thymic epithelial tumors (TETs) is based on the description of both epithelial cell morphology and relative abundance of lymphocytes. Here, we used a computational biological model (CBM) approach on The Cancer Genome Atlas (TCGA) dataset to identify molecular subtypes of TETs and associated predicted therapeutic options. Method: Whole exome sequencing and gene expression data from the TCGA TET dataset (n ¼ 102) along with the IUTAB-1 cell line was input into CBM software (Cellworks Group, San Jose, CA) to build an unsupervised classification model beyond molecular subtypes previously reported (Loehrer PJ ASCO 2017). The CBM generated a disease specific protein network map using PubMed and other online resources. Using computer simulation, disease biomarkers unique to each tumor were identified within the protein network maps. Among the tumors simulated, 6 molecular clusters were identified (TH1-TH6). The CBM digital drug library was tested against these molecular subtypes and the cell growth score (i.e. cell proliferation, viability, and apoptosis) was analyzed. Result: The CBM identified 6 molecular subtypes among 102 TET patients. Among subtypes with a GTF2I mutation, TH1, TH4, and TH6 also had chromosomal aberrations in chromosome 22 and 9. Deletion of chromosome 22 was present in TH1, deletion of chromosome 9 in TH4 and TH6, and also amplification of chromosome 22q in TH4. Among GTF2I wild type subtypes, chromosome 22q deletion and complex cytogenetics were present in TH2, trisomy of chromosome 1 in TH3, and HRAS mutations and chromosome 2 amplification in TH5. The IUTAB-1 cell line had a GTF2I mutation and mapped to the TH4 molecular subtype. The CBM predictions of sensitivity of TH4 subtype to Nelfinavir (AKT inhibitor) and Panobinostat (histone deacetylase inhibitor) along with resistance to Everolimus (MTOR inhibitor) were validated in vitro. There were two molecular subtypes for which Everolimus was predicted to be sensitive, TH1 and TH6. Conclusion: We present an updated classification of TETs based on a CBM approach and associated potential novel therapeutic options that could be further validated in clinical trials. Keywords: thymic epithelial tumor, The Cancer Genome Atlas, computational biological model
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