Zishi Li

A Yale study published on Feb. 8 on the evolutionary pathway of cancer tumors may pave the way to personalized drug therapy and earlier detection of metastasis, the spread of cancer from one organ or body part to another.

Using technology made possible by the Human Genome Project, an international research project with the goal of sequencing human DNA in its entirety, researchers at the Yale School of Public Health were able to pinpoint, on an evolutionary scale, mutations that play a role in the formation of tumors and metastasis. This study was significant in determining which mutations occur early on in the cancer, or even before the cancer develops, and how early mutations leading to metastasis can occur.

“What we did that was novel was we actually applied traditional evolutionary biology approaches to analyzing the data,” said Jeffrey Townsend, study co-author and professor at the School of Public Health. “Essentially, by using these approaches, we’re not saying that cancer is ‘kind of’ an evolutionary process. It is an evolutionary process.”

Samples of primary and metastatic tumors, as well as normal tissue, were taken from 40 deceased patients at autopsy. These samples were then sequenced using only the exomes, the parts of the genome that are expressed. The mutations are then placed on a chronogram — an evolutionary timeline — and compared across patients to see whether common mutations occur earlier or later in cancer development, said Ziming Zhao, co-author of the study and postdoctoral fellow at the School of Public Health.

Townsend explained that there is a long-standing linear model for how cancer develops.

“There is some sort of specific set of mutations that have to arise in order to go from normal tissue, to a neoplasm, to a slow-growing tumor, to a fast-growing tumor and to metastasis,” Townsend said, describing the linear model that proposes that metastases should be more closely related to each other than to the primary model.

The study found that the tumor progression is not a linear pattern, Zhao stated. It is unlikely that a single mutation can trigger metastasis because the metastatic tumors can originate from divergent lineages, she added. Previously, researchers have tried to find genes that induce metastasis, but this study was not able to find significant genes that trigger the spread, she said.

Although a significant origin for metastasis was not pinpointed, the timing of the mutations outlined in the paper is of great importance, according to the researchers.

“We also found that the metastatic lineages can arise early during cancer evolution. Metastases occur even before the diagnosis,” Zhao said.

Yale School of Medicine professor Sidi Chen, a cancer researcher who was not involved with the study, said he finds the discovery of timing for the appearance of mutations to be novel.

He added that current diagnostic methods designed to detect metastasis tend to be late. This information is now common knowledge for many clinical oncologists.

“But to be able to give a date to such a precise degree as this study does is striking,” Chen said.

The discovery of the early mutations offer the greatest implications of the study. Townsend pointed out that the mutations that occur early will be present in the primary tumor as well as the metastases. If drug therapies targeted these early mutations, then the entire cancer, both primary and metastatic, would be targeted.

However, because the origins of metastatic tumors themselves are not clear, Townsend reaffirmed that further research should focus on the mutations of already well-known tumor suppressor genes such as ras and p53. Mutations in these genes occur very early and commonly across the patient samples. He argued that based on what this study has shown, researchers should not spend too much time and money trying to find factors that would lead to metastasis.

Chen disagreed and spoke about the possibility of further research into metastatic origins.

“The authors actually revealed multiple mutations, hitting multiple genes in metastasis,” Chen said. “These genes provide functional candidates to test in animal models. We can knock these genes out and see if they drive metastases.”

He continued by suggesting that the study can be improved by increasing the tumor samples and the number of patients. This would paint a more comprehensive metastasis mutation landscape, he said.

“In the future, we hope we have the funding to do research on more particular tumor types and with larger sample sizes,” Zhao said, echoing the sentiment.

The Human Genome Project, completed in 2003, was a 13-year-long endeavor proposed and funded by the U.S. government.