Genetic Risk and Disease
Two of the most important contemporary issues in human genetics are: (1) What is the burden of inherited disease contributed by unstable repetitive elements (UREs) in the human genome? And (2) what genetic loci, including UREs, interact to increase the genetic risk of common human diseases? We study a particular type of URE, designated the hypervariable minisatellite, as a causal factor in the common disease cancer.
Minisatellites occur throughout the human genome, often next to genes and gene clusters. We showed several years ago that rare alleles of the highly unstable minisatellite region immediately adjacent to the HRAS1 proto-oncogene were associated with a two-fold increased risk of several common cancers. Because more than 20 percent of cancer patients bear these alleles, one in 11 cancers of the colon, breast, lung, prostate and urinary bladder may be attributed to the influence of the HRAS1 minisatellite. Now there is evidence that the HRAS1 minisatellite interacts with other genetic loci to modify their effects on cancer type and age of onset. For example, carriers of disease alleles at the familial breast cancer locus BRCA1 have a higher risk of getting ovarian cancer at an earlier age if they also bear high-risk alleles at HRAS1.
We are currently investigating the interaction of the HRAS1 minisatellite with other cancer-related loci in the human genome by conducting a study of sib pairs affected with breast, colon, prostate and lung cancer. We also are conducting laboratory studies directed toward understanding the molecular basis of HRAS1 minisatellite effects. Transgenic mouse strains bearing distinct forms of the human HRAS1 minisatellite are being constructed and will be employed in an analysis of the mutational process, as well as possible epistatic and developmental effects of minisatellite mutations. The contributions to disease phenotypes of other minisatellites, such as those located in the proximity of the IGH, INS and RB1 loci, also are under investigation.