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Human Genome News, September 1990; 2(3)
Raymond L. White and Webster V. Cavenee are the 1990 winners of the Charles S. Mott prize for outstanding contributions to the understanding or prevention of cancer. White is cochairman of the Department of Human Genetics at the University of Utah School of Medicine and an investigator at the Howard Hughes Medical Institute (HHMI); Cavenee is director of the Montreal Branch of the Ludwig Institute for Cancer Research at McGill University.
Using restriction fragment length polymorphism (RFLP) analysis, White and Cavenee demonstrated the first proof that loss of a protective suppressor gene, one that prevents cells from becoming malignant, can trigger cancer [Nature 305: 779-784 (1983)]. Their discovery is "one of the most important in human cancer genetics," says Margaret Kripke of the University of Texas, M. D. Anderson Cancer Center.
Reading the Genes
RFLP analysis takes advantage of subtle DNA variations among individuals and between the genes that individuals inherit from each parent. These variations, called polymorphisms, can be detected by exposing DNA, obtained from an individual's white blood cells, to restriction enzymes that cut the DNA into many fragments.
Variations in the lengths of corresponding fragments (RFLPs) from different individuals are used as markers along the DNA. If a disease gene is near the marker, both were probably inherited together. This approach is used to locate genetic alleles that cause various diseases or make one susceptible to them. White and Cavenee used it to study the genes of families with retinoblastoma, a rare hereditary eye cancer. To streamline the search, they also used RFLPs to compare the genes of both normal and cancerous cells within the same individual. A combination of the two approaches allows scientists to specify which genetic elements associated with the disease are inherited and which occur later, during the disease process.
A Defective Gene Revealed
When White and Cavenee began their award-winning work, funded by HHMI, there were two theories explaining how loss of a gene might trigger cancer. First, the loss could mean that once-separated genes were now neighbors, a circumstance that could trigger changes in gene expression. The other possibility-proved correct by White and Cavenee-was that loss of one copy of a gene would leave only one version of the gene to be expressed. If the unmasked gene were defective, cancer would develop.
"We knew members of this family were missing a chunk of DNA from chromosome 13, but only some [members] got retinoblastoma," White explained. In those who escaped it, the missing DNA was found to be "stuck in the middle of another chromosome," said White. This discovery argued against the first explanation in the case of retinoblastoma and suggested that loss of a normal gene function was allowing a defective version of the gene to take over, an occurrence not seen before in studies of human cancer.
The researchers then applied the RFLP technique to show that retinoblastoma is caused by loss of a particular gene on chromosome 13-a gene that can prevent malignant transformation. This landmark study provided the first proof of the theory put forward by Alfred Knudson, winner of the Mott Prize in 1988, that development of retinoblastoma and other hereditary cancers requires two genetic events, each affecting one of the two copies of a particular gene. White and Cavenee extended Knudson's theory to show how the gene loss can be one of those events. They began their work just as other geneticists were discovering oncogenes, normal genes that can trigger cancer when damaged or inappropriately activated. White and Cavenee proved that there are also genes that protect against malignancy.
The award, sponsored by the General Motors Cancer Research Foundation, is supported by grants totaling $14.2 million. It originated in 1979 and is named for Charles S. Mott, philanthropist and long-time General Motors Corporation officer.
HGMIS Staff
The electronic form of the newsletter may be cited in the following style:
Human Genome Program, U.S. Department of Energy, Human Genome News (v2n3).
The Human Genome Project (HGP) was an international 13-year effort, 1990 to 2003. Primary goals were to discover the complete set of human genes and make them accessible for further biological study, and determine the complete sequence of DNA bases in the human genome. See Timeline for more HGP history.
Published from 1989 until 2002, this newsletter facilitated HGP communication, helped prevent duplication of research effort, and informed persons interested in genome research.
