Transcriptomic Analysis of Papillary Thyroid Cancer: A Focus on Immune-Subtyping, Oncogenic Fusion, and Recurrence
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Objectives. Thyroid cancer is the most common endocrine tumor, with rapidly increasing incidence worldwide. However, its transcriptomic characteristics associated with immunological signatures, driver fusions, and recurrence markers remain unclear. We aimed to investigate the transcriptomic characteristics of advanced papillary thyroid cancer. Methods. This study included 282 papillary thyroid cancer tumor samples and 155 normal samples from Chungnam National University Hospital and Seoul National University Hospital. Transcriptomic quantification was determined by high-throughput RNA sequencing. We investigated the associations of clinical parameters and molecular signatures using RNA sequencing. We validated predictive biomarkers using the Cancer Genome Atlas database. Results. Through a comparison of differentially expressed genes, gene sets, and pathways in papillary thyroid cancer compared to normal tumor-adjacent tissue, we found increased immune signaling associated with cytokines or T cells and decreased thyroid hormone synthetic pathways. In addition, patients with recurrence presented increased CD8+ T-cell and Th1-cell signatures. Interestingly, we found differentially overexpressed genes related to immune-escape signaling such as CTLA4, IDO1, LAG3, and PDCD1 in advanced papillary thyroid cancer with a low thyroid differentiation score. Fusion analysis showed that the PI3K and mitogen-activated protein kinase (MAPK) signaling pathways were regulated differently according to the RET fusion partner genes (CCDC6 or NCOA4). Finally, we identified HOXD9 as a novel molecular biomarker that predicts the recurrence of thyroid cancer in addition to known risk factors (tumor size, lymph node metastasis, and extrathyroidal extension). Conclusion. We identified a high association with immune-escape signaling in the immune-hot group with aggressive clinical characteristics among Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for advanced papillary thyroid cancer
Abstract
Objectives. Thyroid cancer is the most common endocrine tumor, with rapidly increasing incidence worldwide. However, its transcriptomic characteristics associated with immunological signatures, driver fusions, and recurrence markers remain unclear. We aimed to investigate the transcriptomic characteristics of advanced papillary thyroid cancer. Methods. This study included 282 papillary thyroid cancer tumor samples and 155 normal samples from Chungnam National University Hospital and Seoul National University Hospital. Transcriptomic quantification was determined by high-throughput RNA sequencing. We investigated the associations of clinical parameters and molecular signatures using RNA sequencing. We validated predictive biomarkers using the Cancer Genome Atlas database. Results. Through a comparison of differentially expressed genes, gene sets, and pathways in papillary thyroid cancer compared to normal tumor-adjacent tissue, we found increased immune signaling associated with cytokines or T cells and decreased thyroid hormone synthetic pathways. In addition, patients with recurrence presented increased CD8+ T-cell and Th1-cell signatures. Interestingly, we found differentially overexpressed genes related to immune-escape signaling such as CTLA4, IDO1, LAG3, and PDCD1 in advanced papillary thyroid cancer with a low thyroid differentiation score. Fusion analysis showed that the PI3K and mitogen-activated protein kinase (MAPK) signaling pathways were regulated differently according to the RET fusion partner genes (CCDC6 or NCOA4). Finally, we identified HOXD9 as a novel molecular biomarker that predicts the recurrence of thyroid cancer in addition to known risk factors (tumor size, lymph node metastasis, and extrathyroidal extension). Conclusion. We identified a high association with immune-escape signaling in the immune-hot group with aggressive clinical characteristics among Korean thyroid cancer patients. Moreover, RET fusion differentially regulated PI3K and MAPK signaling depending on the partner gene of RET, and HOXD9 was found to be a recurrence marker for advanced papillary thyroid cancer
참고문헌 (49)
- Ahn HS, "Korea’s thyroid-cancer “epidemic”: screening and overdiagnosis", N Engl J Med, 371(19), pp.1765~1767 (2014)
- Morris LG, "The increasing incidence of thyroid cancer : the influence of access to care", Thyroid, 23(7), pp.885~891 (2013)
- Eung Koo Yeon, "Diagnostic Performance of a Combination of Shear Wave Elastography and B-Mode Ultrasonography in Differentiating Benign From Malignant Thyroid Nodules", Clinical and Experimental Otorhinolaryngology, 13(2), pp.186~193 (2020), 대한이비인후과학회[DOI]
- Giani F, "The possible role of cancer stem cells in the resistance to kinase inhibitors of advanced thyroid cancer", Cancers(Basel), 12(8), pp.2249~ (2020)
- Haas BJ, "Accuracy assessment of fusion transcript detection via read-mapping and de novo fusion transcript assembly-based methods", Genome Biol, 20(1), pp.213~ (2019)
- Aran D, "xCell : digitally portraying the tissue cellular heterogeneity landscape", Genome Biol, 18(1), pp.220~ (2017)
- Dobin A, "Optimizing RNA-Seq mapping with STAR", Methods Mol Biol, 1415, pp.245~262 (2016)
- 안순현, "The Effect of Prophylactic Central Neck Dissection During Hemithyroidectomy on Locoregional Recurrence in Patients With Papillary Thyroid Carcinoma: A Meta-Analysis", Clinical and Experimental Otorhinolaryngology, 13(2), pp.194~202 (2020), 대한이비인후과학회[DOI]
- Cancer Genome Atlas Research Network, "Integrated genomic characterization of papillary thyroid carcinoma", Cell, 159(3), pp.676~690 (2014)
- Yoo SK, "Comprehensive analysis of the transcriptional and mutational landscape of follicular and papillary thyroid cancers", PLoS Genet, 12(8), pp.e1006239~ (2016)
- Yoo SK, "Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer", Nat Commun, 10(1), pp.2764~ (2019)
- Salvatore D, "The importance of the RET gene in thyroid cancer and therapeutic implications", Nat Rev Endocrinol, 17(5), pp.296~306 (2021)
- Wirth LJ, "Efficacy of selpercatinib in RET-altered thyroid cancers", N Engl J Med, 383(9), pp.825~835 (2020)
- Santoro M, "Central role of RET in thyroid cancer", Cold Spring Harb Perspect Biol, 5(12), pp.a009233~ (2013)
- Kim HJ, "Iodine intake as a risk factor for BRAF mutations in papillary thyroid cancer patients from an iodine-replete area", Eur J Nutr, 57(2), pp.809~815 (2018)
- 김원배, "Unmet Clinical Needs in the Treatment of Patients with Thyroid Cancer", Endocrinology and Metabolism, 35(1), pp.14~25 (2020), 대한내분비학회
- Kim HJ, "Correlation of BRAF mutation of papillary thyroid carcinoma and urine iodine status in Korean population" (2021), Yonsei University Health System
- Dobin A, "STAR : ultrafast universal RNA-seq aligner", Bioinformatics, 29(1), pp.15~21 (2013)
- Trapnell C, "Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks", Nat Protoc, 7(3), pp.562~578 (2012)
- Liberzon A, "The Molecular Signatures Database(MSigDB)hallmark gene set collection", Cell Syst, 1(6), pp.417~425 (2015)
- Hanzelmann S, "GSVA : gene set variation analysis for microarray and RNA-seq data", BMC Bioinformatics, 14, pp.7~ (2013)
- Kuleshov MV, "Enrichr: a comprehensive gene set enrichment analysis web server 2016 update", Nucleic Acids Res, 44(W1), pp.W90~W97 (2016)
- Russo PS, "CEMiTool : a Bioconductor package for performing comprehensive modular co-expression analyses", BMC Bioinformatics, 19(1), pp.56~ (2018)
- Wang X, "Identification of an immune-related signature indicating the dedifferentiation of thyroid cells", Cancer Cell Int, 21(1), pp.231~ (2021)
- Cunha LL, "The immune landscape of the microenvironment of thyroid cancer is closely related to differentiation status", Cancer Cell Int, 21(1), pp.387~ (2021)
- de Groot JW, "RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors", Endocr Rev, 27(5), pp.535~560 (2006)
- Li AY, "RET fusions in solid tumors", Cancer Treat Rev, 81, pp.101911~ (2019)
- Paratala BS, "RET rearrangements are actionable alterations in breast cancer", Nat Commun, 9(1), pp.4821~ (2018)
- Santoro M, "RET gene fusions in malignancies of the thyroid and other tissues", Genes(Basel), 11(4), pp.424~ (2020)
- Park JL, "MicroRNA profile for diagnostic and prognostic biomarkers in thyroid cancer", Cancers(Basel), 13(4), pp.632~ (2021)
- 조관훈, "Clinical implications of anti-thyroglobulin antibody measurement before surgery in thyroid cancer", The Korean Journal of Internal Medicine, 33(6), pp.1050~1057 (2018), 대한내과학회[DOI]
- Randolph GW, "The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension", Thyroid, 22(11), pp.1144~1152 (2012)
- Wang O, "ZCCHC12, a novel oncogene in papillary thyroid cancer", J Cancer Res Clin Oncol, 143(9), pp.1679~1686 (2017)
- Ho WJ, "Systemic inhibition of PTPN22 augments anticancer immunity", J Clin Invest, 131(17), pp.e146950~ (2021)
- Cubas R, "Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy", J Immunother Cancer, 8(2), pp.e001439~ (2020)
- Ross MD, "Podocan, a novel small leucine-rich repeat protein expressed in the sclerotic glomerular lesion of experimental HIV-associated nephropathy", J Biol Chem, 278(35), pp.33248~33255 (2003)
- Duval S, "Shedding of cancer susceptibility candidate 4 by the convertases PC7", furin unravels a novel secretory protein implicated in cancer progression, 2020, pp.11(8), 665~
- Rotte A, "Combination of CTLA-4 and PD-1 blockers for treatment of cancer", J Exp Clin Cancer Res, 38(1), pp.255~ (2019)
- Nguyen LT, "Clinical blockade of PD1 and LAG3 : potential mechanisms of action", Nat Rev Immunol, 15(1), pp.45~56 (2015)
- Prendergast GC, "Inflammatory reprogramming with IDO1 inhibitors : turning immunologically unresponsive ‘cold’ tumors ‘hot’", Trends Cancer, 4(1), pp.38~58 (2018)
- Lin J, "Exportin-T promotes tumor proliferation and invasion in hepatocellular carcinoma", Mol Carcinog, 58(2), pp.293~304 (2019)
- Hojilla CV, "Matrix metalloproteinases and their tissue inhibitors direct cell fate during cancer development", Br J Cancer, 89(10), pp.1817~1821 (2003)
- Bublik DR, "Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival", Proc Natl Acad Sci U S A, 114(4), pp.E496~E505 (2017)
- Somanath PR, "Akt1 in endothelial cell and angiogenesis", Cell Cycle, 5(5), pp.512~518 (2006)
- Ding ZY, "Prognostic role of cyclin D2", D3 in multiple human malignant neoplasms : a systematic review and meta-analysis, 2019, pp.8(6), 2717~2729
- Lv X, "HOXD9 promotes epithelial-mesenchymal transition and cancer metastasis by ZEB1 regulation in hepatocellular carcinoma", J Exp Clin Cancer Res, 34, pp.133~ (2015)
- Zhu H, "HOXD9 promotes the growth, invasion and metastasis of gastric cancer cells by transcriptional activation of RUFY3", J Exp Clin Cancer Res, 38(1), pp.412~ (2019)
- Verzella D, "Life, death, and autophagy in cancer : NF-κB turns up everywhere", Cell Death Dis, 11(3), pp.210~ (2020)
- Dhawan P, "A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells", J Biol Chem, 277(10), pp.7920~7928 (2002)
