New and painstaking research by a group that includes Robert Wood Johnson Foundation (RWJF) Harold Amos Medical Faculty Development program Scholar Levi Garraway, M.D., Ph.D., plumbs new depths of understanding about the genetic blueprint of several different types of prostate tumors. Using a groundbreaking technology called “whole genome sequencing,” Garraway and his fellow researchers have identified a new category of genetic alterations that they believe plays an important role in the development of some forms of prostate cancer.
Whole genome sequencing involves a deeper analysis of the human genome than standard research. Rather than focusing solely on specific sections of the genome, identifying flaws in particular bits of DNA, whole genome sequencing captures the complete picture by looking at the entire genome. Thus, researchers can discover nearly all mutations that occurred in a cancer and observe new complexities, including the ways whole sections of DNA detach from the genome, and then reattach elsewhere. Such mutations and “rearrangements” can set off a chain of events that lead to the development of a tumor.
"This first whole genome view showed us tantalizing evidence for several new prostate cancer genes that likely would have remained undiscovered had we not been taking a genome-wide approach," says Garraway. “We're realizing that by sequencing whole genomes in prostate cancer, there's a lot more to see. These discoveries are teaching us a great deal about prostate cancer biology that we simply hadn't appreciated previously."
New Technology a Key
The researchers’ deeper look at the genome is possible because of advances in technology in the decade since the human genome was first mapped. “The initial mapping of the genome took years and years,” Garraway said. But with newer, more powerful computers, and with new machines designed specifically for the purpose, he explains, “we can sequence the genome of a tumor in two to six weeks.”
The whole genome sequencing approach had been applied to tumors resulting from leukemia, melanoma, breast cancer and lung cancer, but Garraway’s study was the first whole genome sequencing study of prostate cancer. He says that prostate cancers lend themselves to examination by the whole genome sequencing method because rearrangements of large sections of the genome may play a more prominent role in prostate cancer than in certain other malignancies.
Garraway and his colleagues foresee a number of future applications of the knowledge gained from such research. He says this type of genetic data could help doctors identify which prostate cancers in patients are likely to be indolent, and which might be lethal. That is a particularly difficult problem for physicians now, making it challenging to determine if a cancer will advance quickly, and therefore be a candidate for aggressive treatment, or if it will grow slowly, suggesting a more cautious approach.
In addition, better identification of the genetic errors that contribute to the cancer could help researchers as they work to develop targeted therapies for particular cancers.
Prostate cancer claims the lives of 30,000 American men a year, making it the second most lethal cancer among men. About 200,000 new cases are diagnosed each year.
Garraway credits the Harold Amos program for giving his career an early boost. “Having the Harold Amos award was crucial for me early on,” he says. “When you’re an early-career investigator, it’s hard to free up discretionary money to try new things. So the program allowed me to spend time trying new directions. And, of course, it was also a real point of leverage in getting other grants to help move our research forward.”
Garraway is an assistant professor of medicine at the Dana-Farber Cancer Institute in Boston and a senior associate member of the Broad Institute. His colleagues on the study, published in the February 10, 2011, issue of Nature, include co-senior author Mark Rubin, M.D., of Weill Cornell Medical College; lead authors Michael F. Berger, Ph.D., of Sloan-Kettering Cancer Center; Francesca Demichelis, Ph.D., of Weill Cornell Medical College; Michael Lawrence, Ph.D., of the Broad Institute; and Yotam Drier of the Weizmann Institute of Science.