International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)

Table of Contents * Complex Genetics * Developmental Genetics * Gene Annotation * Gene Discovery * Genome Sequencing * Functional Genomics * Mutagenesis * Presentations * Verne Chapman Memorial Lecture

IDENTIFICATION OF MOUSE AND HUMAN CANCER MODIFIER GENES USING MOUSE MODELS

Alain Balmain
UCSF Comprehensive Cancer Center
234D Sutter Street
Box 0875, Room S227
San Francisco CA 94143 USA

The risk of developing cancer is due to a combination of environmental factors and inheritance of high or low penetrance cancer modifier genes. Mouse models using interspecific crosses between Mus spretus, which is relatively cancer resistant, and inbred strains of Mus musculus, which are relatively cancer susceptible have been used to map cancer modifier genes. We have mapped 13 mouse skin cancer modifier loci using this approach. One locus, Skts13, on distal chromosome 2, shows strong linkage for skin tumor susceptibility with a p-value of 5.5 x 10-7 (Wilcoxon rank sum test). In addition, in another mouse cancer model, approximately 63% of lymphomas from F1 mice show tumor modifier gene maps to this locus in mouse. To narrow down the locus, we used a combination of linkage analysis together with haplotype analysis in a backcross between outbred Mus Spretus and NIH/Ola. Linkage analysis localized the QTL to an interval of approximately 20cM, but a common haplotype spanning approximately 1.5cM was present only in the haplotypes associated with papilloma resistance. The orthologous region of the human genome, 20q13.2, is amplified in a variety of tumor types including breast cancer, colon cancer and ovarian cancer. A series of candidate SNP's in four genes in this interval are being tested in association studies of human breast cancer cases and controls. The results suggest that this combination of linkage and haplotype analysis can circumvent many of the problems associated with the fine mapping of tumour modifier loci.