Coiled-coil domain containing 68 (CCDC68) demonstrates a tumor-suppressive role in pancreatic ductal adenocarcinoma.
Using integrative genomics and functional screening, we identified coiled-coil domain containing 68 (CCDC68) as a novel putative tumor suppressor gene (TSG) in pancreatic ductal adenocarcinoma (PDAC). CCDC68 allelic losses were documented in 48% of primary PDAC patient tumors, 50% of PDAC cell lines and 30% of primary patient derived xenografts. We also discovered a single nucleotide polymorphism (SNP) variant (SNP rs1344011) that leads to exon skipping and generation of an unstable protein isoform CCDC68Δ(69-114) in 31% of PDAC patients. Overexpression of full length CCDC68 (CCDC68(wt)) in PANC-1 and Hs.766T PDAC cell lines lacking CDCC68 expression decreased proliferation and tumorigenicity in scid mice. In contrast, the downregulation of endogenous CCDC68 in MIAPaca-2 cells increased tumor growth rate. These effects were not observed with the deletion-containing isoform, CCDC68Δ(69-114).
1] Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology Department, University of Toronto, Toronto, ON, Canada.
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Radulovich
1] Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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Leung
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
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Ibrahimov
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
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Navab
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
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Sakashita
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
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Zhu
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
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Kaufman
British Columbia Cancer Research Centre and Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
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Lockwood
British Columbia Cancer Research Centre and Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
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Thu
Department of Molecular Genetics, Banting & Best Department of Medical Research, University of Toronto, Toronto, ON, Canada.
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Fedyshyn
Department of Molecular Genetics, Banting & Best Department of Medical Research, University of Toronto, Toronto, ON, Canada.
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Moffat
British Columbia Cancer Research Centre and Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
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Lam
1] Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada [2] Department of Laboratory Medicine and Pathobiology Department, University of Toronto, Toronto, ON, Canada [3] Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016513:Mice, SCID; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
C000602811:CCDC68 protein, human; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins