Genetics of Cancer: Loss of Heterozygosity is Driven by Genetic Similarity

Peter J. Stambrook, Ph.D.
University of Cincinnati
P01ES05652

Background: Tumor suppressor genes, which code for proteins that inhibit uncontrolled cell proliferation, are frequently mutated in human cancer. Heterozygous cells, cells with a single copy of a particular tumor suppressor gene, will not undergo aberrant cell proliferation leading to tumor formation. However, if the normal copy of the gene is lost, the cell becomes predisposed to abnormal growth and if enough mutations accumulate, a tumor may form. Losing the gene is known as loss of heterozygosity (LOH) the mechanisms of which are not fully understood.

Advance: LOH can occur during cell division when chromosomes exchange DNA also known as mitotic recombination . The mechanism of mitotic recombination is not well understood; however, this team of researchers has demonstrated that the level of mitotic recombination in mice is affected by the degree of similarity between the two sets of chromosomes, one of which is inherited from each parent. When two unrelated strains of mice were crossed, the mitotic recombination and the subsequent loss of heterozygooisty were diminished. However, when back crosses of the progeny were performed causing a higher degree of chromosomal similarity, the mitotic recombination and subsequent chromosomal exchange were restored making these animals more susceptible to developing genetic diseases.

Implication: This finding may have implications in the development of human cancer. Genetic differences between individuals is probably sufficient to reduce the risk of mitotic recombination and therefore, reduce the risk of cancer. These data suggest, however, that if a high degree of genetic similarity exists between parents, their offspring may be more susceptible to diseases, like cancer, that are associated with mitotic recombination and loss of heterozygosity.

Publication: Shao C, Stambrook PJ, Tischfield JA. Mitotic recombination is suppressed by chromosomal divergence in hybrids of distantly related mouse strains. Nat Genet. 2001 Jun;28(2):169-72.