September 25, 2018

Most tumors in body share important mutations

At a Glance

  • Researchers found that primary and metastatic tumors within an individual all likely rely on the same genetic mutations to grow and spread.
  • While the results need to be confirmed, they suggest that precision metastatic cancer treatments could be chosen based on a single tumor sample.
Lung cancer metastasis Lung cancer cells invading surrounding tissues and starting to spread.Scott Wilkinson, Adam Marcus, National Cancer Institute/Winship Cancer Institute of Emory University

Many cancer drugs now target specific genetic changes, called driver mutations, that allow tumor cells to grow and spread. These targeted therapies counteract the changes caused by the driver mutations. This approach kills cancer cells while minimizing damage to normal cells.

To find out whether a person’s cancer has driver mutations that can be targeted with one of these new drugs, doctors perform genetic testing of tumor tissue samples. However, cancer cells can spread from the place where they first formed to other parts of the body. This process is called metastasis.

It can often be difficult to get tissue samples from metastatic tumors. Therefore, decisions about whether to treat someone with a targeted therapy are usually based on genetic testing of the original (primary) tumor.

Whether the primary and all its secondary tumors, called metastases, usually share the same driver mutations has been unclear. Cancer cells mutate quickly, which helps them adapt and survive. Metastatic tumors might develop different driver mutations as they spread through the body. New mutations may arise or some mutations be selected after toxic treatments such as chemotherapy. If primary and metastatic tumors are driven by different mutations, a targeted drug chosen based on analysis of a primary tumor may not work on metastases.

A team of researchers at Stanford University, Harvard University, Johns Hopkins University, and the Memorial Sloan Kettering Cancer Center wanted to better understand the mutations that drive metastatic tumors. They collected and analyzed tissue samples taken from 20 people with newly diagnosed metastatic cancer. All tissue samples were taken before any treatment was given.

The researchers sampled both the primary tumor and about three metastases from each patient. The tumor types included in the study were pancreatic, endometrial, colorectal, breast, stomach, lung, and prostate cancers, as well as melanoma.

After performing genetic sequencing of all tumors, the researchers compared the mutations they found in the tumors to a list of 299 possible driver genes identified by the Cancer Genome Atlas project. The work was funded in part by NIH’s National Cancer Institute (NCI). Results were published on September 7, 2018, in Science.

The team found that most mutations in driver genes that were shared between primary and metastatic tumors were predicted to have functional consequences. In contrast, mutations in driver genes that were not shared among all analyzed metastases of a patient were unlikely to have a functional impact on these genes. Mathematical modeling of tumor growth and metastases development suggested that the probability that distinct mutations would drive different metastases within a given patient is only about 10%.

“We took samples from multiple untreated metastases of each patient, and we observed a mix of overlapping and differing driver mutations,” says Dr. Johannes Reiter, of Stanford University, one of the lead researchers. “But through computational analyses, we inferred that the driver mutations that were most likely to contribute to cancer development were shared among all metastases in each patient.”

The results suggest that a single tumor tissue sample from an individual could be used to guide precision treatment. “The finding gives us hope that such treatment is possible,” says senior author Dr. Martin Nowak of Harvard University. “Because if metastases share the same driver mutations, then if we target those mutations, it may be possible to control metastatic disease.” The researchers hope to confirm these results in a larger study, using hundreds of samples taken from dozens of cancer types.

—by Sharon Reynolds

Related Links

References: Minimal functional driver gene heterogeneity among untreated metastases. Reiter JG, Makohon-Moore AP, Gerold JM, Heyde A, Attiyeh MA, Kohutek ZA, Tokheim CJ, Brown A, DeBlasio RM, Niyazov J, Zucker A, Karchin R, Kinzler KW, Iacobuzio-Donahue CA, Vogelstein B, Nowak MA. Science. 2018 Sep 7;361(6406):1033-1037. doi: 10.1126/science.aat7171. PMID: 30190408.

Funding: NIH’s National Cancer Institute; Lustgarten Foundation for Pancreatic Cancer Research; Sol Goldman Center for Pancreatic Cancer Research; Virginia and D. K. Ludwig Fund for Cancer Research; Austrian Science Fund; Landry Cancer Biology Consortium; and Office of Naval Research.