Multiomics analysis of Papillary thyroid cancers identifies BAIAP2L1-BRAF fusion and requirement of TRIM25, PDE5A and PKCdelta for tumorigenesis

ABSTRACT: Papillary thyroid carcinoma (PTC) is one of the most common forms of thyroid cancer with a cure rate of over 90% after surgery. However, aggressive forms may still occur, and personalized therapeutic strategies are increasingly required. We subjected patient materials from a cohort of patients whose tumors did not harbor BRAF or RAS mutations to genomic and proteomic analysis. In a 23-year-old patient with thyroiditis, we identified by RNA-seq analysis a novel rearrangement leading to a BAIAP2L1-BRAF fusion that kinase-dependently transforms immortalized human thyroid cells. BAIAP2L1-BRAF multimerizes via the dimer interface of the BRAF kinase leading to its activation. Moreover, quantitative proteomic analysis of the same patient samples revealed the upregulation of several proteins including the Ub E3 ligase TRIM25, PDE5A, and PKC-delta. Further, in a cohort of PTC patients, we observed higher expression of TRIM25 and PKC-delta in the tumor and metastatic lesions, when compared to the matched normal tissue. Inhibition of TRIM25, PDE5A and PKC-delta with small molecules or RNA interference affected not only viability and proliferation of BAIAP2L1-BRAF transformed cells, but also the viability, growth and invasion of corresponding 3D spheroid cultures. Apart from unveiling a novel oncogenic BRAF fusion in PTCs, our data may open a novel avenue of therapeutic targeting in human PTCs.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Krishnaraj Rajalingam 

PROVIDER: PXD034229 | JPOST Repository | Wed Feb 22 00:00:00 GMT 2023

REPOSITORIES: jPOST