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ORIGINAL RESEARCH article

Front. Endocrinol.
Sec. Thyroid Endocrinology
Volume 15 - 2024 | doi: 10.3389/fendo.2024.1440722

BRAFV600E/pTERT Double Mutated Papillary Thyroid Cancers Exhibit Immune Gene Suppression

Provisionally accepted
Ana-Maria Chindris Ana-Maria Chindris 1*Michael Rivera Michael Rivera 2Brian Necela Brian Necela 1Jennifer Kachergus Jennifer Kachergus 1John Casler John Casler 1Christopher Brett Christopher Brett 3Ana Marcella Rivas Ana Marcella Rivas 4Yaohua Ma Yaohua Ma 1Xue Wang Xue Wang 1Victor Bernet Victor Bernet 1John Copland John Copland 1Keith L Knutson Keith L Knutson 1E Aubrey Thompson E Aubrey Thompson 1Robert Smallridge Robert Smallridge 1
  • 1 Mayo Clinic Florida, Jacksonville, United States
  • 2 Mayo Clinic, Rochester, Minnesota, United States
  • 3 University of Tennessee Medical Center, Knoxville, Tennessee, United States
  • 4 CoxHealth Adult Medicine and Endocrinology Specialists, Springfield, Missouri, United States

The final, formatted version of the article will be published soon.

    Introduction: BRAFV600E mutation (BRAF mut ) is common in papillary thyroid cancer (PTC), and most patients have an excellent outcome. However, a TERT-promoter mutation (pTERT mut ) in the presence of BRAF mut (BRAF mut pTERT mut ) has been demonstrated to confer a more aggressive behavior to PTC. Lymphocytic infiltration is often present in PTC. In this study, we sought to decipher the relationship between the BRAF and TERT mutations and immune gene dysregulation in tumor samples from a cohort of 147 samples of PTC.The abundance of 770 immune gene transcripts was determined by multiprex capture/detection and digital counting of mRNA transcripts using the NanoString nCounter® PanCancer Immune Profiling Panel.We identified 40 immune transcripts differentially expressed in BRAF mut pTERT mut vs BRAF mut pTERT wildtype (pTERT wt ) (P<0.05). Transcripts induced by BRAF mut alone were significantly repressed in BRAF mut pTERT mut samples, such as genes expressed by lymphoid cells, antigen-presenting cells, and cytotoxic cells, including chemokines, cytokines, checkpoint control proteins, interferon downstream markers, TNF superfamily proteins and BMP markers. A validation analysis using 444 samples from The Cancer Genome Atlas (TCGA) PTC dataset yielded similar results. Deconvolution analysis confirmed differences in the immune cell populations such as increased presence of M2 macrophages in the BRAF mut TERT mut Mayo cohort and a lower abundance of M1 macrophages in the BRAF mut TERT mut TCGA cohort compared to BRAF mut pTERT wt . Most of the immune gene pathways were enriched in the BRAF mut pTERT wt tumors in both Mayo and TCGA cohorts but not in BRAF mut TERT mut . BRAF mut pTERT wt had higher stromal lymphocytes infiltration as compared to BRAF wt pTERT wt tumors, corroborating the transcriptomic findings.4 Discussion: To our knowledge this is the first report of a potential link between TERT and the immune microenvironment, offering a explanation for the aggressive nature of BRAF mut pTERT mut PTC.

    Keywords: Papillary Thyroid Cancer (PTC), BRAF mutation V600 E, TERT promoter mutation (pTERT), Immune genes, Lymphocytic infiltration

    Received: 29 May 2024; Accepted: 18 Nov 2024.

    Copyright: © 2024 Chindris, Rivera, Necela, Kachergus, Casler, Brett, Rivas, Ma, Wang, Bernet, Copland, Knutson, Thompson and Smallridge. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Ana-Maria Chindris, Mayo Clinic Florida, Jacksonville, United States

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