CCDC6

Overview

CCDC6 (Coiled-Coil Domain Containing 6) encodes a ubiquitously expressed protein involved in cell survival signaling and apoptotic regulation. In thyroid cancer, CCDC6 is best known as the 5’ fusion partner in the RET/PTC1 rearrangement (CCDC6-RET), one of the most frequent gene fusions driving papillary thyroid carcinoma and, at lower prevalence, poorly differentiated thyroid carcinoma (PDTC). The fusion juxtaposes the CCDC6 dimerization domain to the RET kinase domain, generating a constitutively active oncoprotein that activates RAS-MAPK and PI3K signaling.

Alterations observed in the corpus

  • CCDC6-RET gene fusion (RET/PTC1 rearrangement) detected in PDTC: among 14% of PDTCs (84 tumors) that harbored gene fusions, 5 were RET fusions involving either CCDC6 or NCOA4 as the 5’ partner; gene fusions in PDTC were mutually exclusive with BRAF/RAS point mutations PMID:26878173.
  • Identified as the 5’ partner in the recurrent CCDC6-RET fusion in THCA (4.2% of cases); 33 THCA samples were flagged as druggable on RET; the fusion is an inframe protein kinase fusion with overexpression of the 3’ RET oncogene, also seen in LUAD PMID:29617662.

Cancer types (linked)

  • THPD (Poorly Differentiated Thyroid Cancer): CCDC6-RET fusions present among the 14% of PDTCs carrying gene fusions; PDTCs with fusions were younger at diagnosis (median 49 vs 58 years, P = 0.04) PMID:26878173.

Co-occurrence and mutual exclusivity

  • CCDC6-RET fusion is mutually exclusive with BRAF V600E, RAS (NRAS/HRAS/KRAS) point mutations, and other gene fusions (PAX8-PPARG, ALK fusions) in PDTC PMID:26878173.

Therapeutic relevance

  • RET fusions (including CCDC6-RET) are targetable with RET kinase inhibitors; the study does not directly test specific agents but the fusion status provides a rationale for RET-directed therapy in fusion-positive PDTC PMID:26878173.

Open questions

  • The precise breakdown of CCDC6-RET vs NCOA4-RET cases among the 5 fusion-positive PDTCs is not specified in the corpus.

Sources

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