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Abstract
Human colorectal cancer (CRC) is one of the better-understood systems for studying the genetics of cancer initiation and progression. To develop a cross-species comparison strategy for identifying CRC causative gene alterations, we performed array comparative genomic hybridization (aCGH) to investigate CNAs in 10 sporadic canine CRCs. The results revealed for the first time a strong degree of genetic homology between canine and human CRCs. First, when mapping the identified CNAs onto syntenic regions of the human genome, we noted that the canine orthologs of genes participating in known human CRC pathways were recurrently disrupted, indicating that these pathways might be altered in the canine CRCs as well. Second, we observed a significant overlapping of CNAs between human and canine tumors, and tumors from the two species were clustered according to the tumor subtypes but not the species. Significantly, we found that species-specific CNAs localize to evolutionarily unstable regions. These findings indicate that CNAs recurrent between human and dog CRCs may have a higher probability of being cancer-causative, compared with CNAs found in one species only. As an expansion, we used this novel human-dog comparison strategy to address a central aim of cancer research: cancer driverpassenger distinction. We compared the CNAs of our 10 canine CRCs to 29 human CRCs. This led to the identification of 73 driver candidate genes (DCGs) altered in both species, and 38 passenger candidate genes (PCGs) altered in humans only. We noted that DCGs significantly differ from PCGs in every analysis conducted. Importantly, while PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality in establishing and maintaining epithelial cell polarity. Meanwhile, many DCGs also participate in processes that regulate cell proliferation and death. These observations indicate that, in sporadic CRCs, cell polarity genes not only play a critical role 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, expansion of which would make more driver-passenger distinctions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control