CCDC6, the Coiled Coil Domain Containing 6 gene, was initially identified as part of a chimeric gene formed by fusion with RET in some thyroid tumors [1,2]. It functions as a tumor suppressor in the DNA repair system and is a pro-apoptotic phosphoprotein responsive to genotoxic stress [2]. CCDC6 also plays a role in sustaining DNA damage checkpoints [1].

CCDC6-RET fusion protein activates the Ras/MAPK signaling cascade through a unique signal niche [3]. FGFR2-CCDC6 fusion gene promotes cell proliferation by activating the AKT and ERK signaling pathways downstream of FGFR2 [4]. In hepatobiliary carcinoma, high CCDC6 expression is associated with advanced tumor grades, poor prognosis in HCC patients, and is involved in cell cycle, gene transcription, and immune cell-related pathways [5]. In high-grade urothelial bladder cancer, CCDC6 deficiency determines PARP-inhibitor sensitivity, and its levels are modulated by USP7 [6]. In thyroid cancer, CCDC6-RET fusions have distinct clinicopathological features compared to NCOA4-RET fusions [7]. Ccdc6 knock-in mice with a deletion of exon 2 develop thyroid hyperplasia associated with enhanced CREB1 activity, suggesting a role of CCDC6 functional impairment in thyroid papillary carcinoma development [8].

In conclusion, CCDC6 is a significant gene involved in DNA repair, apoptosis, and multiple signaling pathways. Its alterations, such as gene fusions and mutations, play roles in various cancers including thyroid, hepatobiliary, and urothelial bladder cancers. The study of CCDC6 in mouse models has provided valuable insights into its function in disease development, especially in thyroid carcinoma.