GENE INTERACTION AND SINGLE-GENE EFFECTS IN COLON-TUMOR SUSCEPTIBILITY IN MICE

To dissect the multigenic control of colon tumour susceptibility in th e mouse(1) we used the set of 20 CcS/Dem (CcS) recombinant congenic (R C) strains(2). Each CcS strain carries a unique, random subset of appr oximately 12.5% of the genome of strain STS/A (STS) on the genetic bac kground of BALB/cHeA (BALB/c)(3). Previously, applying a protocol of 2 6 injections of 1,2-dimethylhydrazine (DMH), we detected two susceptib ility loci, Scc1 and Scc2, on chromosome 2 (refs 4, 5). Using a shorte r tumour-induction procedure, combining DMH and N-ethyl-N-nitrosourea (ENU) treatment, we demonstrate that BALB/c, STS and most CcS strains are relatively resistant. The strain CcS-19, however, is susceptible, probably due to a combination of BALB/c and STS alleles at several loc i. Analysis of 192 (BALB/c x CcS-19) F2 mice revealed, in addition to the Scc1/Scc2 region, three new susceptibility loci: Scc3 on chromosom e 1, Scc4 on chromosome 17 and Scc5 on chromosome 18. Scc4 and Scc5 ha ve no apparent individual effect, but show a strong reciprocal interac tion. Their BALB/c and STS alleles are not a priori susceptible or res istant but the genotype at one locus determines the effect of the alle le at the second locus and vice versa. These findings and the accompan ying paper on lung tumour susceptibility(6) show that interlocus inter actions are likely to be an important component of tumour susceptibili ty.