CCDC149
Overview
CCDC149 (Coiled-Coil Domain Containing 149) is a coiled-coil domain protein whose primary oncologic relevance is as a novel 5’ fusion partner for ALK in thyroid cancer. Identified by Landa et al. (2016) via targeted deep sequencing of advanced thyroid tumors, the ALK-CCDC149 rearrangement was not previously described in the literature and represents the third ALK fusion partner found in PDTC alongside the known STRN and EML4 partners.
Alterations observed in the corpus
- ALK-CCDC149 gene fusion: novel rearrangement detected in PDTC by MSK-IMPACT 341-gene targeted deep sequencing (117 advanced thyroid tumors — 84 PDTC + 33 ATC); one of three ALK fusions found among PDTC (together with ALK-STRN and ALK-EML4); all three ALK-fusion PDTCs lacked BRAF/RAS point mutations PMID:26878173.
Cancer types (linked)
- THPD (Poorly Differentiated Thyroid Cancer): CCDC149 identified as ALK fusion partner within the 14% of PDTCs that carry gene fusions; fusion-bearing PDTCs were younger at diagnosis (median 49 vs 58 years, P = 0.04) and were mutually exclusive with point-mutation drivers PMID:26878173.
Co-occurrence and mutual exclusivity
- ALK-CCDC149 fusion is mutually exclusive with BRAF V600E, RAS point mutations, RET fusions, and PAX8-PPARG rearrangements within PDTC PMID:26878173.
Therapeutic relevance
- ALK fusions (including the novel ALK-CCDC149 rearrangement) are potentially targetable with ALK inhibitors (e.g., crizotinib, alectinib); the study does not test ALK-directed therapy but the fusion provides a rationale for ALK inhibitor consideration in ALK fusion-positive PDTC PMID:26878173.
Open questions
- The functional equivalence of the CCDC149 coiled-coil domain to canonical ALK fusion partners (EML4, STRN) in driving constitutive ALK kinase activity has not been experimentally validated.
- Whether ALK-CCDC149 confers sensitivity to ALK inhibitors comparable to EML4-ALK in NSCLC is unknown.
Sources
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