Abstract
As a common malignant tumor disease, thyroid cancer lacks effective preventive and therapeutic drugs. Thus, it is crucial to provide an effective drug selection method for thyroid cancer patients. The connectivity map (CMAP) project provides an experimental validated strategy to repurpose and optimize cancer drugs, the rationale behind which is to select drugs to reverse the gene expression variations induced by cancer. However, it has a few limitations. Firstly, CMAP was performed on cell lines, which are usually different from human tissues. Secondly, only gene expression information was considered, while the information about gene regulations and modules/pathways was more or less ignored. In this study, we first measured comprehensively the perturbations of thyroid cancer on a patient including variations at gene expression level, gene co-expression level and gene module level. After that, we provided a drug selection pipeline to reverse the perturbations based on drug signatures derived from tissue studies. We applied the analyses pipeline to the cancer genome atlas (TCGA) thyroid cancer data consisting of 56 normal and 500 cancer samples. As a result, we obtained 812 up-regulated and 213 down-regulated genes, whose functions are significantly enriched in extracellular matrix and receptor localization to synapses. In addition, a total of 33,778 significant differentiated co-expressed gene pairs were found, which form a larger module associated with impaired immune function and low immunity. Finally, we predicted drugs and gene perturbations that could reverse the gene expression and co-expression changes incurred by the development of thyroid cancer through the Fisher’s exact test. Top predicted drugs included validated drugs like baclofen, nevirapine, glucocorticoid, formaldehyde and so on. Combining our analyses with literature mining, we inferred that the regulation of thyroid hormone secretion might be closely related to the inhibition of the proliferation of thyroid cancer cells.
Highlights
Thyroid cancer is one of the most common malignancies of endocrine organs with enormous heterogeneity in terms of morphological features and prognosis [1]
It is known that the expression pattern of a gene or a pathway is closely related to the status of a patient and an effective drug could convert the abnormal gene expression in cancer patients to that of the healthy control subjects [3]
Giordano et al [22] inferred thyroid cancer associated point mutations in BRAF and RAS genes, which might be driven by the fusion of RET, NTRK1 and ALK
Summary
Thyroid cancer is one of the most common malignancies of endocrine organs with enormous heterogeneity in terms of morphological features and prognosis [1]. If a drug has the potential to reverse the gene expression changes and gene regulations of cancer patients to those of the healthy control subjects, this drug might be able to cure the cancer Based on this assumption, the connectivity map (CMAP) project [3] and its continuing project the Library of Integrated Network-based Cellular Signatures (LINCS) [5] have successfully repurposed a few useful drugs and identified several drug targets. Only single gene expression variations were modelled in CMAP and CCLE, the gene regulation/co-expression changes or gene network variations were ignored To this aim, Guney et al presented a network-based in silico drug efficacy prediction method, which maps drug targets and disease genes into a protein-protein interaction (PPI) network and measures their reachability by the shortest path. By combining the top predicted drugs and genes, we inferred potential biological mechanism underlying the inhibition of thyroid cancer cell proliferation
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