Passengers Might Be as Important as Genetic Drivers in Cancer Development

While the Pan-Cancer Analysis of Whole Genomes (PCAWG) project has identified mutations in 179 genes and gene regulators as "drivers"—variations in DNA sequences that lead to the development of cancer—Yale researchers are also interested in the role of “passengers” in cancer development.

Although drivers accounted for a large percentage of the cancer cases analyzed as part of the PCAWG project, they did not explain all. Some scientists, including Yale's Mark Gerstein, now believe that to capture a more panoramic view of cancer progression, they need to pay more attention not only to classical genetic drivers but also to "passengers"—the thousands of non-driver mutations that constitute the overwhelming majority of mutations observed in a typical cancer genome. Historically, scientific consensus has held that these play no role in tumor growth.

"Many of these mutations can have small individual effects but an appreciable cumulative effect, on cancer development," said Gerstein, senior author of a paper published in Cell today. In the paper, Gerstein and colleagues report on experiments intended to show whether passenger mutations could help explain the 10% of cancer cases in which researchers found few or no clear genetic drivers. They found that a subset of passengers has significant impact on genomic regions—often as much impact as drivers—and collectively can have an appreciable effect on tumor growth.

The Yale team also conducted a focused, statistical analysis of eight different cancer types, detecting a cumulative effect of passengers on development of these cancers beyond that which could be explained by drivers alone. Overall, their analysis showed an additional 9% contribution of the passengers in predicting the whether a given sample was indeed cancerous.

Gerstein stressed that some of these passenger variants can actually help hinder cancer development, as opposed to triggering tumor growth. Understanding the full role of passengers could help scientists develop therapies precisely targeted to the individual mutations in a particular person's cancer genome, the authors say.