PHOTO BY BRUCE POWELL
Kenan Onel, MD, PhD, center, and his laboratory team: (back row) Timothy Best, left, Mark Sasaki, Eric Hungate, Sapana Vora, (front row) Imge Hular, left, and Kate Wolak.
others, are working closely together to follow up the t-AML study, Onel said. The mapping of the human genome in 2003 raised hopes of a “genomic revolution” in which sequencing would illuminate the genetic profiles of different diseases, lighting the way to new, targeted therapies. Genome wide association studies (GWAS), whereby a person’s DNA is scoured to identify genetic variations associated with particular conditions, were viewed as a key way to realize this vision. But while they have identified numerous genetic mutations linked to diseases, these associations have mostly been so weak as to be “meaningless,” said Onel. The genomic revolution has been delayed. “The failure of most GWAS stem from their inability to adequately characterize environmental exposures,” said Best, a graduate student in the University’s Committee on Cancer Biology and a member of Onel’s lab. By focusing on t-AML and postHodgkin second cancer, Onel and his team introduced a more nuanced approach. They could account not only for genetic factors, but also for environmental variables (something GWAS have hitherto been largely blind to) and the interplay between them — so-called “exposure-driven genetic susceptibility.” Using GWAS, Onel set out to capture the nature and nurture of cancer. uchospitals.edu/midway
In the Nature Medicine study, his team analyzed a pool of patients exposed to a single, known toxin, but in which only a subset developed cancer as a result. They could ask the question, what was genetically different in the cohort that developed cancer versus the one that stayed healthy? “When you take strong potentiating events like chemo- or radiotherapy, you can pick out the genetic variants that play a strong role as a consequence,” said Le Beau. “It’s a unique approach that maximizes the power of GWAS at a time when people have become a little disenchanted with them.” It also advances an emerging view of cancer that is moving away from segmenting it by organ of origin toward identifying cellular mechanisms that may be common across ostensibly disparate cancers. Onel and his team note in Nature Medicine that the variants linked to susceptibility to postHodgkin second cancer affect PRDM1, a gene “frequently lost in many cancer types,” for example. “Although cancer is complex, we’re seeing it converge on the same cellular pathways,” said Le Beau. “Drugs you identify for one disease may be effective in others.” Onel, who received his MD and PhD at Cornell University, had long aspired to attempt this sort of inquiry, but it was only when he arrived at the University
of Chicago in 2004 that he found the resources to put his ideas into action. The University had painstakingly collected records of patients with t-AML, providing the raw material and impetus for his work. “It enabled us to do an experiment no one else could do,” he said. For his part, Onel brought an irrepressible spirit, and a flair for collaboration and connecting the dots, say colleagues and students. “Ken thinks big and is extremely upbeat and positive in his approach to science,” said Le Beau. “All our projects have multiple collaborators and the need to get samples from different labs,” said Mark Sasaki, PhD’07, whom Onel helped advise toward his doctorate in cancer biology and who recently joined Onel’s lab as a postdoctoral fellow in genomics, having completed a postdoctoral fellowship in neuroscience at the University of Oregon. “A lot of our ability to do them is Ken going to meetings, Ken talking to people. He really pushes the interdisciplinary aspect.” In his latest venture, Onel has joined forces with Professor of Ecology and Evolution Chung-I Wu, PhD, in an intriguing and potentially groundbreaking study that is applying principles from evolutionary biology to cancer. By conceiving of cancer cells as analogous to any other population of organisms in facing selective pressures (competition between cells and the depredations of the body’s natural defense mechanisms, for example) that shape their evolution, they hope to identify the genes that drive cancer development with greater precision. “It’s an evolutionist meets a cancer biologist,” said Wu. “I’ve learned so much from him and I hope he finds my perspective useful.” To Onel, it’s another piece of a complex puzzle. “Again, it is big picture,” he said. “It is about how we get cancer; why some people get it and others don’t. The t-AML studies gave us information about genetic predisposition in the context of environmental exposure; the evolution stuff will enable us to study the transition from normal to cancer. And ultimately they’re going to connect.”
MEDICINE ON THE MIDWAY
SUMMER 2012
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