André Uchimura Bastos
MOLECULAR ANALYSIS OF PAPILLARY THYROID CARCINOMAS REVEALS DIVERSE TRANSCRIPTOMA SIGNATURE OF TUMORS WITH BRAF V600E OR RET/PTC AND THE IDENTIFICATION OF TUMORS WITH DUAL MUTATIONS
AU Bastos, G Oler, J Hemerly, JM Cerutti
UNIFESP, São Paulo, Brazil
Background: BRAF V600E activating mutation is the most common genetic event found in papillary thyroid carcinoma, followed by RET/PTC rearrangements. In most series described so far, BRAF and RET/PTC are mutually exclusive.
Objectives: To investigate the prevalence of RET/PTC rearrangements in a Brazilian cohort of 118 PTC, whose BRAF V600E mutational status was known. Our molecular findings were correlated with clinicopathological features. We next investigated whether the expression of iodide-metabolizing genes (NIS, TSHR, TPO and TG), hypoxia (HIF1) or glucose transporter genes (GLUT1 and GLUT3) were modulated by RET/PTC or BRAF V600E. Lastly, we investigated genetic alterations along PI3K/AKT pathway.
Methods: Nested RT-PCR was used to identify the RET/PTC isoforms. Quantitative PCR was used to investigate gene expression. Gene mutation was investigated by direct sequencing.
Results BRAF V600E and RET/PTC alterations were found in a high prevalence. A high percentage of tumors have dual mutations. Although BRAF V600E and RET/PTC convey signals along same pathway, expression signatures in our analysis showed differences between these two effectors. Alterations along PI3K/AKT were rarely found.
Conclusions: The signatures in our analysis may explain the clinical behavior. Different than expected PI3K/AKT pathway may not play a role in the pathogenesis and progression of PTC. The recognition of dual mutation has important implications for drug treatment and the development of resistance.