Limits...
Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study.

Ji X, Tang J, Halberg R, Busam D, Ferriera S, Peña MM, Venkataramu C, Yeatman TJ, Zhao S - BMC Cancer (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens 30602, GA, USA.

ABSTRACT

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.

Show MeSH

Related in: MedlinePlus

The human colorectal tumorigenesis model proposed by Vogelstein and colleagues [12,13] describes sequential inactivation of tumor suppressors (APC, SMAD4, and P53), activation of oncogene KRAS, and development of genomic instability. However, genes that are near the bona fide tumor suppressors and are disrupted in the human CRC appear not to be cancer-drivers, based on mouse model studies (DCC) or due to lack of evidence for the contribution to cancer (MCC).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2927548&req=5

Figure 1: The human colorectal tumorigenesis model proposed by Vogelstein and colleagues [12,13] describes sequential inactivation of tumor suppressors (APC, SMAD4, and P53), activation of oncogene KRAS, and development of genomic instability. However, genes that are near the bona fide tumor suppressors and are disrupted in the human CRC appear not to be cancer-drivers, based on mouse model studies (DCC) or due to lack of evidence for the contribution to cancer (MCC).

Mentions: Human CRC is one of the better understood systems for studying the genetics of cancer initiation and progression [12-17]. The stepwise model of human CRC development and progression proposed by Vogelstein and colleagues [12,13] (Figure 1) includes: 1) inactivation of the APC, SMAD4, and P53 tumor suppressors; 2) overactivation of the KRAS oncogene; and 3) development of genomic instability in the form of either chromosomal instability (CIN) [12-16] or microsatellite instability (MSI) [16,17].


Distinguishing between cancer driver and passenger gene alteration candidates via cross-species comparison: a pilot study.

Ji X, Tang J, Halberg R, Busam D, Ferriera S, Peña MM, Venkataramu C, Yeatman TJ, Zhao S - BMC Cancer (2010)

The human colorectal tumorigenesis model proposed by Vogelstein and colleagues [12,13] describes sequential inactivation of tumor suppressors (APC, SMAD4, and P53), activation of oncogene KRAS, and development of genomic instability. However, genes that are near the bona fide tumor suppressors and are disrupted in the human CRC appear not to be cancer-drivers, based on mouse model studies (DCC) or due to lack of evidence for the contribution to cancer (MCC).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927548&req=5

Figure 1: The human colorectal tumorigenesis model proposed by Vogelstein and colleagues [12,13] describes sequential inactivation of tumor suppressors (APC, SMAD4, and P53), activation of oncogene KRAS, and development of genomic instability. However, genes that are near the bona fide tumor suppressors and are disrupted in the human CRC appear not to be cancer-drivers, based on mouse model studies (DCC) or due to lack of evidence for the contribution to cancer (MCC).
Mentions: Human CRC is one of the better understood systems for studying the genetics of cancer initiation and progression [12-17]. The stepwise model of human CRC development and progression proposed by Vogelstein and colleagues [12,13] (Figure 1) includes: 1) inactivation of the APC, SMAD4, and P53 tumor suppressors; 2) overactivation of the KRAS oncogene; and 3) development of genomic instability in the form of either chromosomal instability (CIN) [12-16] or microsatellite instability (MSI) [16,17].

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Institute of Bioinformatics, University of Georgia, Athens 30602, GA, USA.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus