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×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.
Highlights
Cancer is one of the leading causes of morbidity and mortality worldwide
Concordant with the colon tumor susceptibility or resistance, CcS-19 is highly susceptible to ENU-induced lung tumors compared to CcS-20 (p,0.0001, Wilcoxon test), and CcS-11 is highly susceptible to ENU-induced lung tumors compared to CcS-10 (p = 0.0012, Wilcoxon test) (Figure 2B lower)
These data suggest that the small subsets of 12.5% STS genes received by these recombinant congenic (RC) strains contain either predominantly susceptible (CcS-11, CcS-19), or predominantly resistant (CcS10, CcS-20) alleles at most colon (Scc) and lung cancer (Sluc) genes, suggesting their pair-wise linkage or identity (Figure 2A upper)
Summary
Cancer is one of the leading causes of morbidity and mortality worldwide. Genome-wide association (GWA) studies have revealed common variants associated with risk of cancers of colon [2,3,4,5,6,7,8,9,10], lung [11,12,13,14,15,16], breast [17,18,19,20,21,22,23] and prostate [24,25,26,27,28,29,30], but these variants explain only a fraction of population risk [31] and their organ specificity is unknown. We report systematic tests involving three species that reveal genetic linkage and possible identity of most susceptibility genes for the two cancers.
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