A landmark study published by researchers at Johns Hopkins University indicates that the genetic underpinnings of cancer may be more complex than previously thought, a finding that represents a potential boon for personalized medicine, but one with a number of obstacles.
In the study, published in the Sept. 7 online issue of Science
, a team led by Victor Velculescu, Ken Kinzler, and Bert Vogelstein at Hopkins’ Kimmel Cancer Center sequenced the protein-coding regions of around 13,000 well-characterized genes in 11 breast tumors and 11 colon tumors to identify 189 genes that were not previously known to play a role in cancer.
This finding surprised even the researchers who conducted the study. “We expected to find a handful of genes, not 200,” said Tobias Sjöblom, lead author on the paper and a postdoctoral fellow at the Kimmel Cancer Center, in a statement.
“The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion,” the authors wrote.
They noted that the genes represent a wealth of new targets for diagnostic and therapeutic development — albeit against a genetic backdrop that is much more complicated than previously thought.
Significantly, the study identified “substantial” differences among the panel of 189 so-called “cancer candidate,” or CAN, genes mutated in the two tumor types, and found “considerable heterogeneity” among CAN genes mutated in different tumor specimens from the same tissue type.
“It has been documented that virtually all biochemical, biological, and clinical attributes are heterogeneous within human cancers of the same histologic subtype,” the authors wrote. They noted that data from the study suggest that “differences in the CAN-genes mutated in various tumors could account for a major part of this heterogeneity.”
These differences “might explain why it has been so difficult to correlate the behavior, prognosis, or response to therapy of common solid tumors with the presence or absence of a single gene alteration,” they wrote. “Such alterations reflect only a small component of each tumor's mutational composition.”
But sorting through these new genes and determining their specific roles in tumor formation and growth presents a daunting challenge. “It will take a long time to unravel this, but this is what cancer is,” Vogelstein told Science. “It’s a much more complex picture than we had anticipated.”
Despite this new level of complexity, the findings represent a veritable goldmine for targeted cancer therapies and personalized medicine, according to some observers.
Mutation differences between tumors derived from the same tissue type “might explain why it has been so difficult to correlate the behavior, prognosis, or response to therapy of common solid tumors with the presence or absence of a single gene alteration.”
“Maximizing the numbers of targets available for drug development in a specific cancer means that patients will ultimately receive more personalized, less toxic therapies,” said Anna Barker, deputy director of the National Cancer Institute, in a statement. She cited cancer drugs Herceptin and Gleevec as examples of cases in which “the discovery of specific genetic changes has led to the development of effective, targeted treatments for cancer.”
Edward Abrahams, executive director of the Personalized Medicine Coalition, described the effort as “an invitation to pursue personalized medicine approaches.”
The fact that cancer is complex “is not news,” Abrahams said. “I think scientists and physicians, if not the public, are generally aware that complex diseases like cancer require a more sophisticated understanding than we presently have.”
The Hopkins study essentially “confirms what a lot of people intuited — including the scientists who made the discovery — that cancer is complex and that genetics plays a big, big role,” Abrahams said.
What it proves, he noted, is that “we are gaining a greater understanding of the genetic basis of [cancer] and suggests that we’re on the right path to combating it — maybe for the first time.”