CDK5RAP2
Overview
CDK5RAP2 (CDK5 Regulatory Subunit Associated Protein 2) encodes a centrosomal protein involved in mitotic spindle regulation and cell division. In cancer genomics, CDK5RAP2 is notable as a fusion partner for BRAF, forming the CDK5RAP2-BRAF rearrangement that acts as an oncogenic driver in melanoma. This fusion was identified in the pan-cancer MSK-IMPACT cohort as a novel recurrent event, expanding the landscape of BRAF fusion partners beyond previously characterized genes.
Alterations observed in the corpus
- A novel recurrent CDK5RAP2-BRAF fusion was identified in two melanoma cases from the msk_impact_2017 cohort (10,945 tumors across 62 tumor types profiled by MSK-IMPACT); the fusion involves BRAF as the 3’ partner and is predicted to drive RAS-independent BRAF dimerization PMID:28481359.
Cancer types (linked)
- MEL: CDK5RAP2-BRAF fusion detected in 2 melanoma cases in the msk_impact_2017 dataset; one of 33 BRAF fusions across 11 principal tumor types comprising 18 distinct partner genes (10 novel) PMID:28481359.
Co-occurrence and mutual exclusivity
- CDK5RAP2-BRAF fusions occurred in melanomas lacking V600E mutations, consistent with acting as alternative BRAF-activating drivers; the broader class of BRAF intragenic deletions and fusions are predicted to drive RAS-independent dimerization PMID:28481359.
Therapeutic relevance
- CDK5RAP2-BRAF fusions, like other BRAF fusions predicted to drive RAS-independent dimerization, may benefit from RAF-dimer inhibitors; this connection was noted in the context of 71% radiographic clinical-benefit rate for BRAF-directed therapy in non-melanoma BRAF-altered patients PMID:28481359.
Open questions
- The clinical actionability of CDK5RAP2-BRAF specifically (versus the broader class of BRAF fusions) has not been prospectively tested; only 2 cases identified in the discovery cohort PMID:28481359.
Sources
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