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Most lung and colon cancer susceptibility genes are pair-wise linked in mice, humans and rats.

Quan L, Stassen AP, Ruivenkamp CA, van Wezel T, Fijneman RJ, Hutson A, Kakarlapudi N, Hart AA, Demant P - PLoS ONE (2011)

Bottom Line: Four CcS/Dem recombinant congenic strains, each differing from strain BALB/cHeA by a different small random subset of ±12.5% of genes received from strain STS/A, suggestively show either extreme susceptibility or extreme resistance for both colon and lung tumors, which is unlikely if the two tumors were controlled by independent susceptibility genes.Analysis of additional Sluc loci that were mapped in OcB/Dem strains and Scc loci in CcS/Dem strains, respectively, shows their widespread pair-wise co-localization (P  =  0.0036).Comparison of molecular mechanisms of susceptibility genes that are organ-specific and those with trans-organ effects can provide a new dimension in understanding individual cancer susceptibility.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.

ABSTRACT
Genetic predisposition controlled by susceptibility quantitative trait loci (QTLs) contributes to a large proportion of common cancers. Studies of genetics of cancer susceptibility, however, did not address systematically the relationship between susceptibility to cancers in different organs. We present five sets of data on genetic architecture of colon and lung cancer susceptibility in mice, humans and rats. They collectively show that the majority of genes for colon and lung cancer susceptibility are linked pair-wise and are likely identical or related. Four CcS/Dem recombinant congenic strains, each differing from strain BALB/cHeA by a different small random subset of ±12.5% of genes received from strain STS/A, suggestively show either extreme susceptibility or extreme resistance for both colon and lung tumors, which is unlikely if the two tumors were controlled by independent susceptibility genes. Indeed, susceptibility to lung cancer (Sluc) loci underlying the extreme susceptibility or resistance of such CcS/Dem strains, mapped in 226 (CcS-10 x CcS-19)F2 mice, co-localize with susceptibility to colon cancer (Scc) loci. Analysis of additional Sluc loci that were mapped in OcB/Dem strains and Scc loci in CcS/Dem strains, respectively, shows their widespread pair-wise co-localization (P  =  0.0036). Finally, the majority of published human and rat colon cancer susceptibility genes map to chromosomal regions homologous to mouse Sluc loci. 12/12 mouse Scc loci, 9/11 human and 5/7 rat colon cancer susceptibility loci are close to a Sluc locus or its homologous site, forming 21 clusters of lung and colon cancer susceptibility genes from one, two or three species. Our data shows that cancer susceptibility QTLs can have much broader biological effects than presently appreciated. It also demonstrates the power of mouse genetics to predict human susceptibility genes. Comparison of molecular mechanisms of susceptibility genes that are organ-specific and those with trans-organ effects can provide a new dimension in understanding individual cancer susceptibility.

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Interspecies correlation between colon and lung cancer susceptibility loci.A. Schematic representation of the part of genome used for the co-localization analyses. The Sluc loci analyzed here included also 2 Sluc loci identified in (CcS10 XCcS19)F2 mice and 1 CcS locus [44] and 1 Par locus [50] identified by other group. B. Interspecies correlation between colon and lung cancer susceptibility loci. This figure summarizes all 21 clusters of colon and lung cancer susceptibility loci mapped in mouse RC strains (orange for lung, blue for colon), human colon (green) and rat colon (purple). Clusters in which the lung and colon cancer loci mapped within 2.5cM of each other are highlighted in squares. Most colon and lung cancer susceptibility loci co-localize, with the exception of human 15q13 and 20p12.3 (colon), and rat rCcr6 and rCcr8 (colon). Orthologous regions of human 18q21, 11q23 (colon) and 5p15, 6p21 and 15q25 (lung), and rat rCcr1, rCcr4 and rCcr9 (colon) are not informative since they were not tested for lung or colon cancer susceptibility in mouse RC strains. †Pas1c has also been detected in our (CcS-10×CcS-19)F2 cross at D6Mit177. Human colon cancer locus 3q21-q24 is mapped to an 18Mb region and orthologous to two mouse chromosomal regions: Chr.6 (Pas1c) and Chr.9 (Sluc11), respectively. †† Two human colon cancer susceptibility loci co-localize with a Sluc locus.
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pone-0014727-g006: Interspecies correlation between colon and lung cancer susceptibility loci.A. Schematic representation of the part of genome used for the co-localization analyses. The Sluc loci analyzed here included also 2 Sluc loci identified in (CcS10 XCcS19)F2 mice and 1 CcS locus [44] and 1 Par locus [50] identified by other group. B. Interspecies correlation between colon and lung cancer susceptibility loci. This figure summarizes all 21 clusters of colon and lung cancer susceptibility loci mapped in mouse RC strains (orange for lung, blue for colon), human colon (green) and rat colon (purple). Clusters in which the lung and colon cancer loci mapped within 2.5cM of each other are highlighted in squares. Most colon and lung cancer susceptibility loci co-localize, with the exception of human 15q13 and 20p12.3 (colon), and rat rCcr6 and rCcr8 (colon). Orthologous regions of human 18q21, 11q23 (colon) and 5p15, 6p21 and 15q25 (lung), and rat rCcr1, rCcr4 and rCcr9 (colon) are not informative since they were not tested for lung or colon cancer susceptibility in mouse RC strains. †Pas1c has also been detected in our (CcS-10×CcS-19)F2 cross at D6Mit177. Human colon cancer locus 3q21-q24 is mapped to an 18Mb region and orthologous to two mouse chromosomal regions: Chr.6 (Pas1c) and Chr.9 (Sluc11), respectively. †† Two human colon cancer susceptibility loci co-localize with a Sluc locus.

Mentions: Co-localization of colon and lung cancer susceptibility genes in mouse suggests that many of them may be related or identical. We therefore investigated possible parallels of this finding in humans and rats (Figure 6A).


Most lung and colon cancer susceptibility genes are pair-wise linked in mice, humans and rats.

Quan L, Stassen AP, Ruivenkamp CA, van Wezel T, Fijneman RJ, Hutson A, Kakarlapudi N, Hart AA, Demant P - PLoS ONE (2011)

Interspecies correlation between colon and lung cancer susceptibility loci.A. Schematic representation of the part of genome used for the co-localization analyses. The Sluc loci analyzed here included also 2 Sluc loci identified in (CcS10 XCcS19)F2 mice and 1 CcS locus [44] and 1 Par locus [50] identified by other group. B. Interspecies correlation between colon and lung cancer susceptibility loci. This figure summarizes all 21 clusters of colon and lung cancer susceptibility loci mapped in mouse RC strains (orange for lung, blue for colon), human colon (green) and rat colon (purple). Clusters in which the lung and colon cancer loci mapped within 2.5cM of each other are highlighted in squares. Most colon and lung cancer susceptibility loci co-localize, with the exception of human 15q13 and 20p12.3 (colon), and rat rCcr6 and rCcr8 (colon). Orthologous regions of human 18q21, 11q23 (colon) and 5p15, 6p21 and 15q25 (lung), and rat rCcr1, rCcr4 and rCcr9 (colon) are not informative since they were not tested for lung or colon cancer susceptibility in mouse RC strains. †Pas1c has also been detected in our (CcS-10×CcS-19)F2 cross at D6Mit177. Human colon cancer locus 3q21-q24 is mapped to an 18Mb region and orthologous to two mouse chromosomal regions: Chr.6 (Pas1c) and Chr.9 (Sluc11), respectively. †† Two human colon cancer susceptibility loci co-localize with a Sluc locus.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3044722&req=5

pone-0014727-g006: Interspecies correlation between colon and lung cancer susceptibility loci.A. Schematic representation of the part of genome used for the co-localization analyses. The Sluc loci analyzed here included also 2 Sluc loci identified in (CcS10 XCcS19)F2 mice and 1 CcS locus [44] and 1 Par locus [50] identified by other group. B. Interspecies correlation between colon and lung cancer susceptibility loci. This figure summarizes all 21 clusters of colon and lung cancer susceptibility loci mapped in mouse RC strains (orange for lung, blue for colon), human colon (green) and rat colon (purple). Clusters in which the lung and colon cancer loci mapped within 2.5cM of each other are highlighted in squares. Most colon and lung cancer susceptibility loci co-localize, with the exception of human 15q13 and 20p12.3 (colon), and rat rCcr6 and rCcr8 (colon). Orthologous regions of human 18q21, 11q23 (colon) and 5p15, 6p21 and 15q25 (lung), and rat rCcr1, rCcr4 and rCcr9 (colon) are not informative since they were not tested for lung or colon cancer susceptibility in mouse RC strains. †Pas1c has also been detected in our (CcS-10×CcS-19)F2 cross at D6Mit177. Human colon cancer locus 3q21-q24 is mapped to an 18Mb region and orthologous to two mouse chromosomal regions: Chr.6 (Pas1c) and Chr.9 (Sluc11), respectively. †† Two human colon cancer susceptibility loci co-localize with a Sluc locus.
Mentions: Co-localization of colon and lung cancer susceptibility genes in mouse suggests that many of them may be related or identical. We therefore investigated possible parallels of this finding in humans and rats (Figure 6A).

Bottom Line: Four CcS/Dem recombinant congenic strains, each differing from strain BALB/cHeA by a different small random subset of ±12.5% of genes received from strain STS/A, suggestively show either extreme susceptibility or extreme resistance for both colon and lung tumors, which is unlikely if the two tumors were controlled by independent susceptibility genes.Analysis of additional Sluc loci that were mapped in OcB/Dem strains and Scc loci in CcS/Dem strains, respectively, shows their widespread pair-wise co-localization (P  =  0.0036).Comparison of molecular mechanisms of susceptibility genes that are organ-specific and those with trans-organ effects can provide a new dimension in understanding individual cancer susceptibility.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.

ABSTRACT
Genetic predisposition controlled by susceptibility quantitative trait loci (QTLs) contributes to a large proportion of common cancers. Studies of genetics of cancer susceptibility, however, did not address systematically the relationship between susceptibility to cancers in different organs. We present five sets of data on genetic architecture of colon and lung cancer susceptibility in mice, humans and rats. They collectively show that the majority of genes for colon and lung cancer susceptibility are linked pair-wise and are likely identical or related. Four CcS/Dem recombinant congenic strains, each differing from strain BALB/cHeA by a different small random subset of ±12.5% of genes received from strain STS/A, suggestively show either extreme susceptibility or extreme resistance for both colon and lung tumors, which is unlikely if the two tumors were controlled by independent susceptibility genes. Indeed, susceptibility to lung cancer (Sluc) loci underlying the extreme susceptibility or resistance of such CcS/Dem strains, mapped in 226 (CcS-10 x CcS-19)F2 mice, co-localize with susceptibility to colon cancer (Scc) loci. Analysis of additional Sluc loci that were mapped in OcB/Dem strains and Scc loci in CcS/Dem strains, respectively, shows their widespread pair-wise co-localization (P  =  0.0036). Finally, the majority of published human and rat colon cancer susceptibility genes map to chromosomal regions homologous to mouse Sluc loci. 12/12 mouse Scc loci, 9/11 human and 5/7 rat colon cancer susceptibility loci are close to a Sluc locus or its homologous site, forming 21 clusters of lung and colon cancer susceptibility genes from one, two or three species. Our data shows that cancer susceptibility QTLs can have much broader biological effects than presently appreciated. It also demonstrates the power of mouse genetics to predict human susceptibility genes. Comparison of molecular mechanisms of susceptibility genes that are organ-specific and those with trans-organ effects can provide a new dimension in understanding individual cancer susceptibility.

Show MeSH
Related in: MedlinePlus