Current sequencing technology has enabled an analysis of cancer evolution that directs research attention away from the search for genes that enable metastasis and toward genes that are mutated early during tumorigenesis.1

This study used tools of evolutionary biology to address questions about how cancers spread. Though cancer has long been thought to be an evolutionary process, questions have remained about the timing and course of tumor progression.

This study, led by Jeffrey Townsend, PhD, associate professor of public health (biostatistics) at Yale University in New Haven, Connecticut, sequenced normal, primary, and metastatic tumor tissue from multiple participants, including persons with a range of cancer types. Then, they used the latest methods from evolutionary biology to map genetic mutations on the tree of cancer evolution that was occurring in each patient. The analysis revealed genetic relationships and tumor chronology.

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Nonlinear patterns of tumor progression and early origins of metastatic lineages were demonstrated. This means that metastases start along different paths within primary tumors and that they spread in a branched, not linear, way. The study also quantified the time when driver mutations occurred.

During the time course of a person’s cancer, metastases genetically diverge from primary tumors early. Further, driver mutations are often mutated before the metastatic lineages diverge.

“The major known cancer driver genes are often mutated in the primary tumor and all metastases, and successfully targeting them in therapy could provide widespread therapeutic benefit,” said Townsend.

This understanding of cancer’s evolution has key implications for treatment, Townsend noted, “In addition to pointing out that we will need to target driver genes that are mutated early in cancer, this evolutionary approach provides a method that accurately characterizes which genes are being mutated early and late. That is extremely useful in terms of prioritizing which mutations should be targeted in order to produce therapies that are going to work.”

The study also provides oncologists with new insights to fight cancer. Townsend stated that the oncologists of the future will need to understand evolutionary biology to fight the disease.

This project was supported by Gilead Sciences, Inc.


1. Zhao ZM, Zhao B, Bai Y, et al. Early and multiple origins of metastatic lineages within primary tumors. [published online ahead of print February 8, 2016] PNAS. doi:10.1073/pnas.1525677113.