Experiment
From a recombinant congenic (RC) panel generated from crossing the donor strain STS/A onto the background strain BALB/cHeA two highly susceptible RC strains (CcS19/Dem and CcS11/Dem) and the two most resistant RC (CcS10/Dem And CcS20/Dem) strains to colon tumors were tested for their susceptibility to lung tumors. It was observed that, concordant with colon tumor susceptibility or resistance, CcS19 was highly susceptibly to ENU-induced lung tumors compared to Ccs20; and CcS11 was highly susceptible to ENU-induced lung tumors compared to CcS10.
To elucidate the concorndant extreme susceptibility of CcS19 and resistance of CcS10 mice to both colon and lung tumors Sluc loci were mapped in an ENU-treated intercross of 226 (CcS10 x CcS19) F2 mice. The progeny were PCR-genotyped using 23 mircosatellite markers with a maximal distance less than 10 cM between any two markers. The chromosomal regions affecting tumor load, size and number were determined by analysis of variance (ANOVA) using the indiviual microsatellite markers used in the genotyping.
Fifteen Sluc loci were detected that affect tumor size, load and number. Eight of the loci had individual effects and seven were detected only in pair wise interactions in which the effect of one Sluc locus depended on the genotype of a second interacting Sluc locus.
Five of the 15 loci were reported as novel:
Sluc31 was detected as a significant, main effects QTL mapping to Chromosome 2 linked with marker D2Mit99 (50.3 cM) in the STS/A donor region, between D2Mit37 (44.1 cM) and D2Nds3 (73.0 cM), inherited from CcS19; p=00001, effecting tumor size in male mice. [Table 3A, Table S2].
An interaction was also detected between Sluc31a (D2Mit99) and Sluc43i (D4Mit15), p=0.007, also effecting tumor size in male mice. [Table 3B, Table S2].
Sluc32 mapped to Chromosome 17 linked with marker D17Mit72 (47.4 cM) in the STS/A donor region, between D17Mit38 (45.3 cM) and D17Mit123 (56.7 cM), inherited from CcS19. Sluc32 was detected in a significant interaction with Sluc44d (D10Mit28), p=0.008, effecting the number of tumors in female mice. [Table 3B, Table S2].
Sluc33 was detected as a significant, main effects QTL mapping to Chromosome 5 linked with marker D5Mit68 (65.0 cM) in the STS/A donor region, between D5Mit10 (54.0 cM) and D5Mit159 (67.0 cM), inherited from CcS10; p=0.001, effecting tumor load in male mice.
A signifcant interaction was detected between Sluc33a (D5Mit68) and Sluc44e (D10Mit28), p=0.001, effecting tumor load in male mice.
Another interaction was detected between Sluc33b (D5Mit68) and Sluc34b (D15Mit16), p=0.00001, effecting tumor numbers in female mice. [Table 3A, 3B and Table S2].
Curator Note: We assigned official nomenclature to the QTL representing significant interactions between QTL where a different trait was measured and or the same trait achieved a different p valve.
Sluc34 mapped to Chromosome 15 linked with marker D15Mit16 (61.7 cM) in the STS/A donor region, between D15Mit41 (54.5 cM) and D15Mit40 (65.0 cM), inherited from CcS10.
Sluc34 (D15Mit16) was detected in a significant interaction with Sluc44f (D10Mit28), p=0.004, effecting tumor numbers in both sexes.
Sluc34a (D15Mit16) was detected in an interaction with Sluc44g (D10Mit28), p=0.006, effecting the number of tumors in male mice.
Sluc34b (D15Mit16) was detected in an interaction with Sluc33a (D5Mit68), p=0.00001, effecting the number of tumors in female mice. [Table 3B, Table S2].
Sluc35 mapped to Chromosome 19 linked with marker D19Mit6 (55.0 cM) in the STS/A donor region, between D19Mit35 (53.0 cM) and D19Mit137 (55.70 cM), inherited from CcS10.
Sluc35 was detected in a significant interaction with Sluc39c (D9Mit254), p=0.007, effecting the number of tumors in male mice. [Table 3B, Table S2].
Analysis of these loci strongly indicates that most susceptibility genes for lung and colon cancer are not genetically independent but are pairwise linked.
Analysis Tools