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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.

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Human 5q22.2 and 18q21.1-21.2 are evolutionarily unstable. A: Human 5q22.2 (112-113 Mb) is shown as the bar with its gene-coding regions (APC, MCC, etc.) shaded. When compared to species above (horse, rhesus, orangutan and chimp; with the orthologous chromosome of the human chromosome 5 represented by the number inside the bar), no rearrangements were found. However, when compared to species below (rat, mouse, pig, dog, cow, opossum, and platypus) or nearby (chicken and lizard), rearrangements were identified within the region. Rearrangement breakpoints are indicated by gaps between the bars, with numbers inside each bar representing the Mb region of a chromosome (e.g., "18, 25.2-26.8" represents 25.2-26.8 Mb of chromosome 18) or a supercontig/ultra-contig/scaffold (e.g., S1,0-3.4). "Un" stands for chromosome "Unknown" in the released genome assembly. The arrow of each bar designates the sequence direction, and a dished arrow indicates that the homology to the human extends beyond 5q22.2 shown here. B: Human 18q21.1-q21.2 (43-50 Mb) encodes three SMAD genes, two MBD genes, DCC, and a number of other genes (not shown). The same as above, no rearrangements were found when compared to species shown above the human. However, when compared to the species shown below, rearrangements were found within the region and/or nearby. In addition, many sequences are missing in the orthologous chicken and lizard sites (demonstrated by large gaps in the alignment). The question mark "?" inside or below the cow bars indicates that the human-cow alignment at this region has not been completely resolved.
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Figure 2: Human 5q22.2 and 18q21.1-21.2 are evolutionarily unstable. A: Human 5q22.2 (112-113 Mb) is shown as the bar with its gene-coding regions (APC, MCC, etc.) shaded. When compared to species above (horse, rhesus, orangutan and chimp; with the orthologous chromosome of the human chromosome 5 represented by the number inside the bar), no rearrangements were found. However, when compared to species below (rat, mouse, pig, dog, cow, opossum, and platypus) or nearby (chicken and lizard), rearrangements were identified within the region. Rearrangement breakpoints are indicated by gaps between the bars, with numbers inside each bar representing the Mb region of a chromosome (e.g., "18, 25.2-26.8" represents 25.2-26.8 Mb of chromosome 18) or a supercontig/ultra-contig/scaffold (e.g., S1,0-3.4). "Un" stands for chromosome "Unknown" in the released genome assembly. The arrow of each bar designates the sequence direction, and a dished arrow indicates that the homology to the human extends beyond 5q22.2 shown here. B: Human 18q21.1-q21.2 (43-50 Mb) encodes three SMAD genes, two MBD genes, DCC, and a number of other genes (not shown). The same as above, no rearrangements were found when compared to species shown above the human. However, when compared to the species shown below, rearrangements were found within the region and/or nearby. In addition, many sequences are missing in the orthologous chicken and lizard sites (demonstrated by large gaps in the alignment). The question mark "?" inside or below the cow bars indicates that the human-cow alignment at this region has not been completely resolved.

Mentions: Through comparison of the genomic sequences of the human and other species (i.e., chimp, orangutan, rhesus macaque, marmoset, mouse, rat, guinea pig, dog, cow, opossum, platypus, chicken, lizard, xenopus, fly, worm, mosquito, honey bee, yeast, zebrafish, puffer fish, tetraodon, and ciona), we found that regions 5q22.2 and 18q21.1-q21.2 are both evolutionarily unstable (compared with an average human genomic site). Genomic rearrangements were identified in many nonhuman species (i.e., 10 out of 14 species shown in Figure 2 and all other species except xenopus listed above but not shown in Figure 2), within these sites and/or nearby regions. Hence, while genes of each region are clustered in the human genome, they are scattered on two or more distinct loci in the genome of many other species.


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)

Human 5q22.2 and 18q21.1-21.2 are evolutionarily unstable. A: Human 5q22.2 (112-113 Mb) is shown as the bar with its gene-coding regions (APC, MCC, etc.) shaded. When compared to species above (horse, rhesus, orangutan and chimp; with the orthologous chromosome of the human chromosome 5 represented by the number inside the bar), no rearrangements were found. However, when compared to species below (rat, mouse, pig, dog, cow, opossum, and platypus) or nearby (chicken and lizard), rearrangements were identified within the region. Rearrangement breakpoints are indicated by gaps between the bars, with numbers inside each bar representing the Mb region of a chromosome (e.g., "18, 25.2-26.8" represents 25.2-26.8 Mb of chromosome 18) or a supercontig/ultra-contig/scaffold (e.g., S1,0-3.4). "Un" stands for chromosome "Unknown" in the released genome assembly. The arrow of each bar designates the sequence direction, and a dished arrow indicates that the homology to the human extends beyond 5q22.2 shown here. B: Human 18q21.1-q21.2 (43-50 Mb) encodes three SMAD genes, two MBD genes, DCC, and a number of other genes (not shown). The same as above, no rearrangements were found when compared to species shown above the human. However, when compared to the species shown below, rearrangements were found within the region and/or nearby. In addition, many sequences are missing in the orthologous chicken and lizard sites (demonstrated by large gaps in the alignment). The question mark "?" inside or below the cow bars indicates that the human-cow alignment at this region has not been completely resolved.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Human 5q22.2 and 18q21.1-21.2 are evolutionarily unstable. A: Human 5q22.2 (112-113 Mb) is shown as the bar with its gene-coding regions (APC, MCC, etc.) shaded. When compared to species above (horse, rhesus, orangutan and chimp; with the orthologous chromosome of the human chromosome 5 represented by the number inside the bar), no rearrangements were found. However, when compared to species below (rat, mouse, pig, dog, cow, opossum, and platypus) or nearby (chicken and lizard), rearrangements were identified within the region. Rearrangement breakpoints are indicated by gaps between the bars, with numbers inside each bar representing the Mb region of a chromosome (e.g., "18, 25.2-26.8" represents 25.2-26.8 Mb of chromosome 18) or a supercontig/ultra-contig/scaffold (e.g., S1,0-3.4). "Un" stands for chromosome "Unknown" in the released genome assembly. The arrow of each bar designates the sequence direction, and a dished arrow indicates that the homology to the human extends beyond 5q22.2 shown here. B: Human 18q21.1-q21.2 (43-50 Mb) encodes three SMAD genes, two MBD genes, DCC, and a number of other genes (not shown). The same as above, no rearrangements were found when compared to species shown above the human. However, when compared to the species shown below, rearrangements were found within the region and/or nearby. In addition, many sequences are missing in the orthologous chicken and lizard sites (demonstrated by large gaps in the alignment). The question mark "?" inside or below the cow bars indicates that the human-cow alignment at this region has not been completely resolved.
Mentions: Through comparison of the genomic sequences of the human and other species (i.e., chimp, orangutan, rhesus macaque, marmoset, mouse, rat, guinea pig, dog, cow, opossum, platypus, chicken, lizard, xenopus, fly, worm, mosquito, honey bee, yeast, zebrafish, puffer fish, tetraodon, and ciona), we found that regions 5q22.2 and 18q21.1-q21.2 are both evolutionarily unstable (compared with an average human genomic site). Genomic rearrangements were identified in many nonhuman species (i.e., 10 out of 14 species shown in Figure 2 and all other species except xenopus listed above but not shown in Figure 2), within these sites and/or nearby regions. Hence, while genes of each region are clustered in the human genome, they are scattered on two or more distinct loci in the genome of many other species.

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