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Cancer driver–passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer

Oncogene volume 33, pages 814–822 (2014)Cite this article

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Abstract

Herein we report a proof-of-principle study illustrating a novel dog–human comparison strategy that addresses a central aim of cancer research, namely cancer driver–passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species, and with 27 from the whole genome and 46 from dog–human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, although PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A and AVL9). Expansion of this study would make more driver–passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals.

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Acknowledgements

We thank Ms Huan Xiong for her work; Dr Bert Vogelstein for providing various CRC lines and Dr Timothy A Chan of Memorial Sloan-Kettering Cancer Center for providing the IHA cells; and Drs Dong M Shin, J David Puett, Claiborne Glover, Georgia Chen,and Lisa J Stubb for their help and advice on this study. This work was funded by the American Cancer Society and the Georgia Cancer Coalition (principal investigator (PI): S Zhao), as well as NCI P50 CA128613 (PI: Dr Dong M Shin) and GM085354 (PI: Dr Stephen Dalton).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, GA, USA

    J Tang, Y Li, K Lyon, S Dalton & S Zhao

  2. Genetics Branch, Center for Cancer Research, National Cancer Institute/NIH, MD, Bethesda, USA

    J Camps & T Ried

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Correspondence to S Zhao.

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Tang, J., Li, Y., Lyon, K. et al. Cancer driver–passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer. Oncogene 33, 814–822 (2014). https://doi.org/10.1038/onc.2013.17

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