August 2001

From University of Southern California

NIH awards USC team $22 million to seek cancer-causing genes

Los Angeles, CA, August, 2001––Keck School of Medicine researchers have received a five-year, $22 million grant from the National Institutes of Health to continue their search for the genes that cause some of the most prevalent and pernicious forms of cancer.

The grant, entitled "Genetic Susceptibility to Cancer in Multiethnic Cohorts," allows for the continuation of work that has been progressing at USC for the past five years.

"The purpose of the grant is to continue our research into the genetic basis of breast, prostate and colorectal cancer," says Brian E. Henderson, M.D., professor of preventive medicine, Kenneth T. Norris, Jr. Chair in Cancer Prevention and the principal investigator on the study. To achieve that goal, he and his colleagues will rely on the ongoing collection of data from the more than 215,000 participants in the Hawaii/Los Angeles Multiethnic Cohort Study (MEC). The MEC, the only study of its kind and one of the three largest cohorts in the world, is a prospective study of African Americans, Latinos, Japanese and whites. It began in 1993 by looking at the ways in which ethnicity, diet and other environmental factors interact in determining a person’s cancer risk.

Using the MEC to unravel the genetics of the three cancers became a possibility in 1996, when this grant was first funded for some $2.5 million over five years. During that period, the data from the cohort led to a number of significant findings, including:

* a finding reported in the Lancet showing that African-American and Latino men who carry a mutation in a gene for a testosterone-processing enzyme have five times the risk of developing prostate cancer than do men without the mutation;

* a discovery reported in Cancer Research that at least one variant of the gene CYP17, which is involved in the synthesis of estrogen, can increase a woman’s risk of breast cancer as much as 2.5-fold.

This renewal, notes Henderson, is likely to provide even greater insights into cancer risks and susceptibilities, especially with a funding level that is a full order of magnitude higher than the original grant.

The additional money, he says, will allow him to hire some 30 to 40 additional researchers and technicians to collect and analyze blood samples. "We believe that the tremendous potential of the Multiethnic Cohort as a national resource for understanding the causes not only of cancer but of other chronic diseases can only be fully realized by the establishment of a prospectively collected biological specimen bank on the entire cohort," says Henderson. "With this grant, that’s precisely what we’re going to be able to do."

The increased funding will also allow for a collaboration that will pair the top scientists at USC with DNA-deciphering veterans Eric Lander, David Altschuler and Joel Hirshhorn at the Whitehead/MIT Center for Genome Research. This, says Henderson, is "a major link." After all, he explains, "the critical challenge for genetic epidemiology is to merge the genomic resources with large patient collections as typified by the Multiethnic Cohort."

Along with the exponential growth in funding has come a similar expansion in the goals of the research itself. "The scientific thrust has gone way outside the original box," says Henderson.

Up until now, he explains, searching for genes that play a role in any of the three cancers relied on the use of "candidate genes"—genes that scientists had already tagged as likely to play a role in the disease’s pathway. But that tack will only take us so far, Henderson notes. "It will clearly be necessary to screen many genes to find the few that influence each cancer, and to sift through the many polymorphisms that exist in each gene," he explains. (Polymorphisms are different forms of the same normal gene in a population.) "We were originally looking at a single variant in five or six candidate genes; now we’re looking at a much larger number of genes with many, many more variants."

It was the Human Genome Project—in which Lander and his colleagues have played a key role—and its advances in technology that made this sort of research possible, says Henderson. "We used to be able to analyze 50 to 100 segments of DNA a week," he recalls. "Over the five years of this project, we’ll be able to do more than 3 million assays. The scale of this project is just enormous." Enormous, but manageable, thanks to a cohort that is a goldmine of genetic information, and the already-developed technology that will allow the excavation of that mine to begin. "I have the populations and issues, and [Lander’s] got the technology," says Henderson. "It’s the perfect collaboration."












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