Although several familial cancer genes with
high-penetrance mutations have been identified, the major
genetic component of susceptibility to
sporadic cancers is attributable to low-penetrance
alleles. These 'weak'
tumor susceptibility genes do not segregate as single
Mendelian traits and are therefore difficult to find in studies of human populations. Previously, we have proposed that a combination of germline mapping and analysis of allele-specific imbalance in
tumors may be used to refine the locations of susceptibility genes using
mouse models of cancer. Here, we have used
linkage analysis and
congenic mouse strains to map the major
skin tumor susceptibility locus Skts1 within a
genetic interval of 0.9 cM on
proximal chromosome 7. This interval lies in an apparent recombination
cold spot, and corresponds to a physical distance of about 15 Mb. We therefore, used patterns of allele-specific imbalances in
tumors from
backcross and
congenic mice to refine the location of Skts1. We demonstrate that this single
tumor modifier locus has a dramatic effect on the
allelic preference for imbalance on
chromosome 7, with at least 90% of
tumors from the
congenics showing preferential
gain of markers on the
chromosome carrying the susceptibility variant. Importantly, these alterations enabled us to refine the location of Skts1 at higher resolution than that attained using the
congenic mice. We conclude that low-penetrance susceptibility genes can have strong effects on patterns of allele-specific
somatic genetic changes in
tumors, and that analysis of the directionality of these
somatic events provides an important and rapid route to identification of germline
genetic variants that confer increased cancer risk.
