Brett, Christopher1; Chindris, Ana-Maria2; Thompson, E. Aubrey3; Bernet, Victor2; Smallridge, Robert C.2
1 Internal Medicine, Mayo Clinic Jacksonville, Jacksonville, FL, USA
2 Department of Endocrinology, Mayo Clinic Jacksonville, Jacksonville, FL, USA
3 Department of Cancer Biology, Mayo Clinic Jacksonville, Jacksonville, FL, USA
Background/Purpose: The BRAF(V600E) mutation has been associated with increased aggressiveness in PTC and identified as a potential marker of prognosis, however its mechanism is not fully defined. Our previous study of twenty patients with PTC found significant down regulation of immune function genes in the BRAF(V600E) mutant. This study seeks to confirm these findings in the 496 patients of The Cancer Genome Atlas (TCGA) Papillary Thyroid Cancer database.
Methods: Genes identified as differentially expressed between BRAF(V600E) mutants and BRAF wild-type in the previous study were cross referenced to markers used in the TCGA database. Those genes referenced in both studies with concordant variation and p<0.01 in both datasets were then cross referenced to their respective gene ontology process pathways and the most expressed pathways determined.
Results: 563 genes were found to be differentially expressed in the original 20 samples, 533 of which were also annotated in TCGA. 469 of these showed concordant variation-374 with significance of p<0.01. The five most commonly repressed pathways in BRAF(V600E) were all immune related, including dendrite assembly, establishment of T-cell and lymphocyte polarities, immunological synapse formation, and T-cell activation. None of the top 5 induced pathways were immune-related. Additionally HLA-G was upregulated, which is associated with downregulation of cytotoxic CD8+ T cell and natural killer cell function.
Discussion & Conclusions: Analysis of the TCGA database confirms a significant correlation between the BRAF(V600E) mutation and reduced immune pathway expression, suggesting reduced immune surveillance as a possible mechanism by which BRAF(V600E) conveys a more aggressive phenotype in PTC.
- Smallridge, RC et al; RNA Sequencing Identifies Multiple Fusion Transcripts, Differentially Expressed Genes, and Reduced Expression of Immune Function Genes in BRAF (V600E) Mutant vs BRAF Wild-Type Papillary Thyroid Carcinoma. J Clin Endocrinol Metab 2014; 99 (2): E338-E347. doi: 10.1210/jc.2013-2792
- Basolo, F. et al; Correlation between the BRAF V600E Mutation and Tumor Invasiveness in Papillary Thyroid Carcinomas Smaller than 20 Millimeters: Analysis of 1060 Cases. J Clin Endocrinol Metab 2010; 95 (9): 4197-4205. doi: 10.1210/jc.2010-0337
- The Cancer Genome Atlas Research Network; Integrated Genomic Characterization of Papillary Thyroid Carcinoma, Cell, Volume 159, Issue 3, 23 October 2014, Pages 676-690, ISSN 0092-8674, https://dx.doi.org/10.1016/j.cell.2014.09.050.