Copy number abnormalities in sporadic canine colorectal cancers.
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 or genomic alterations, we performed array comparative genomic hybridization (aCGH) to investigate copy number abnormalities (CNAs), one of the most prominent lesion types reported for human CRCs, in 10 spontaneously occurring canine CRCs. The results revealed for the first time a strong degree of genetic homology between sporadic canine and human CRCs. First, we saw that between 5% and 22% of the canine genome was amplified/deleted in these tumors, and that, reminiscent of human CRCs, the total altered sequences directly correlated to the tumor's progression stage, origin, and likely microsatellite instability status. Second, 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. Last, 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, compared with the shared CNAs, we found that species-specific (especially human-specific) CNAs localize to evolutionarily unstable regions that harbor more segmental duplications and interspecies genomic rearrangement breakpoints. 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.
Tang
Jie
J
Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens, Georgia 30602, USA.
Le
Shoshona
S
Sun
Liang
L
Yan
Xiuzhen
X
Zhang
Mucheng
M
Macleod
Jennifer
J
Leroy
Bruce
B
Northrup
Nicole
N
Ellis
Angela
A
Yeatman
Timothy J
TJ
Liang
Yanchun
Y
Zwick
Michael E
ME
Zhao
Shaying
S
D000818:Animals; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization / Q000379:methods; D004285:Dogs; D016678:Genome; D015894:Genome, Human; D006801:Humans; D053842:Microsatellite Instability; D056916:Segmental Duplications, Genomic; D017384:Sequence Deletion