Genomic and transcriptomic characteristics of metastatic thyroid cancers with exceptional responses to radioactive iodine therapy Journal Article
| Authors: | Boucai, L.; Saqcena, M.; Kuo, F.; Grewal, R. K.; Socci, N.; Knauf, J. A.; Krishnamoorthy, G. P.; Ryder, M.; Ho, A. L.; Ghossein, R. A.; Morris, L. G. T.; Seshan, V.; Fagin, J. A. |
| Article Title: | Genomic and transcriptomic characteristics of metastatic thyroid cancers with exceptional responses to radioactive iodine therapy |
| Abstract: | PURPOSE: The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness. EXPERIMENTAL DESIGN: Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio. RESULTS: ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity. CONCLUSIONS: ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy. ©2023 American Association for Cancer Research. |
| Keywords: | retrospective studies; case control study; genetics; case-control studies; pathology; retrospective study; phosphatidylinositol 3 kinase; radioactive iodine; iodine radioisotopes; genomics; thyroid neoplasms; transcriptome; thyroid tumor; phosphatidylinositol 3-kinases; humans; human |
| Journal Title: | Clinical Cancer Research |
| Volume: | 29 |
| Issue: | 8 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-04-15 |
| Start Page: | 1620 |
| End Page: | 1630 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-22-2882 |
| PUBMED: | 36780190 |
| PROVIDER: | scopus |
| PMCID: | PMC10106408 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding author is MSK author James A. Fagin -- Export Date: 1 May 2023 -- Source: Scopus |
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