ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 P666 | DOI: 10.1530/endoabs.63.P666

Pan-cancer analysis of thyroid hormone signaling pathway reveals new possible targets for combinations therapy

Karolina Hanusek, Piotr Popławski & Agnieszka Piekiełko-Witkowska

Centre of Postgraduate Medical Education, Warsaw, Poland.

Introduction: Published studies suggest links between altered actions of thyroid hormones (TH) and cancer development and progression. It is not clear, however, whether these links are specific to cancer types or whether TH can globally affect cancerogenesis. Here, we performed PanCancer analysis of TH signaling pathway.

Material/methods: 79 genes linked with TH signaling pathway, including genes encoding proteins involved in TH synthesis, transport, receptors, as well as key TH-regulated genes were selected basing on KEGG data. Transcriptomic, genomic, and clinical data of 10,967 cancer patients, 32 cancer types were retrieved from TCGA (The Cancer Genome Atlas) and analyzed using cBioPortal, Firebrowse, starBase.

Results: The expression of 29 genes was statistically significantly (P<0.05; threshold: 30%) commonly increased while expression of 20 genes was commonly decreased in the vast majority of analyzed cancers when compared with non-tumoral control samples. Cancers with the highest number of genes with altered expression included: breast invasive carcinoma (64 genes), cholangiocarcinoma (66 genes), kidney renal clear cell carcinoma (62 genes), lung adenocarcinoma (58 genes) and squamous cell carcinoma (69 genes), thyroid carcinoma (58 genes), and uterine corpus endometrial carcinoma (58 genes). The genes of which the expression was prevalently decreased in analyzed cancer types included TSHB, SLC16A2, ABCB1, THRB, ITGB3, TAAR1, PIK3R1, NCOA1, RCAN1, PLN. The genes of which expression was prevalently increased in cancers included SLC3A2, AKT1, PLCB3, HRAS, SRC, SLC2A1. Strong expression correlations were found for the following pairs of genes: DUOX1/DUOX2 (in 19 cancer types), SLC3A2/SLC7A5 (14 cancer types), SLCO1A2/SLCO1B1 (9 cancer types), SLCO1B3/SLCO1B1 (13 cancer types). Altered expression of 29 genes correlated with poor survival of patients in at least four types of cancer, including, among others, SLC7A7, ITGAV, SLC2A1, SLC7A5, SLC5A5, SLC3A2, DIO1, THRA and DUOX1. Mutation analysis revealed that the queried genes were altered in 7334 (67%) of analyzed tumor samples. Top 10% most frequently altered genes included PIK3CA, TG, MYC, CCND1, CREBBP, NOTCH1, ARNT, NCOR1. The analysis of 3081 pairs between tested 79 genes revealed co-occurring or mutually exclusive alterations of which more than 2800 were statistically significant. Top significant co-occurring alterations in gene pairs included TG and MYC, SLCO1A2 and SLCO1B1, SLCO1C1 and SLCO1B3, SLCO1B1 and SLCO1B3, THRA and MED1.

Conclusion: The study reveals global links between altered TH signaling and cancer, possibly contributing to patients survival rate. Co-occurrence of alterations in TH pathway genes and classical oncogenes suggest possible targets for therapy combinations.

Supported by grant 501-1-25-01-18.

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