Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study.
BACKGROUND
We are developing a cross-species comparison strategy to distinguish between cancer driver- and passenger gene alteration candidates, by utilizing the difference in genomic location of orthologous genes between the human and other mammals. As an initial test of this strategy, we conducted a pilot study with human colorectal cancer (CRC) and its mouse model C57BL/6J ApcMin/+, focusing on human 5q22.2 and 18q21.1-q21.2.


METHODS
We first performed bioinformatics analysis on the evolution of 5q22.2 and 18q21.1-q21.2 regions. Then, we performed exon-targeted sequencing, real time quantitative polymerase chain reaction (qPCR), and real time quantitative reverse transcriptase PCR (qRT-PCR) analyses on a number of genes of both regions with both human and mouse colon tumors.


RESULTS
These two regions (5q22.2 and 18q21.1-q21.2) are frequently deleted in human CRCs and encode genuine colorectal tumor suppressors APC and SMAD4. They also encode genes such as MCC (mutated in colorectal cancer) with their role in CRC etiology unknown. We have discovered that both regions are evolutionarily unstable, resulting in genes that are clustered in each human region being found scattered at several distinct loci in the genome of many other species. For instance, APC and MCC are within 200 kb apart in human 5q22.2 but are 10 Mb apart in the mouse genome. Importantly, our analyses revealed that, while known CRC driver genes APC and SMAD4 were disrupted in both human colorectal tumors and tumors from ApcMin/+ mice, the questionable MCC gene was disrupted in human tumors but appeared to be intact in mouse tumors.


CONCLUSIONS
These results indicate that MCC may not actually play any causative role in early colorectal tumorigenesis. We also hypothesize that its disruption in human CRCs is likely a mere result of its close proximity to APC in the human genome. Expanding this pilot study to the entire genome may identify more questionable genes like MCC, facilitating the discovery of new CRC driver gene candidates.
Ji
Xinglai
X
Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens 30602, GA, USA.
Tang
Jie
J
Halberg
Richard
R
Busam
Dana
D
Ferriera
Steve
S
Peña
Maria Marjorette O
MM
Venkataramu
Chinnambally
C
Yeatman
Timothy J
TJ
Zhao
Shaying
S
D000818:Animals; D001483:Base Sequence; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D019295:Computational Biology; D019143:Evolution, Molecular; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC / Q000502:physiology*; D016163:Genes, DCC / Q000502:physiology; D017431:Genes, MCC / Q000502:physiology*; D015894:Genome, Human; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010865:Pilot Projects; D051901:Smad4 Protein / Q000235:genetics; D013045:Species Specificity
D051901:Smad4 Protein