Gene sequencing of solid tumors sheds light on cancer metastasis

Cancers that have spread are far more genetically diverse than primary tumors, scientists have discovered.

Scientists at the University of Michigan wanted to understand what makes solid tumors spread—and, by extension, how the growing selection of personalized drugs could best be employed in patients whose cancers have metastasized. But to accomplish that they needed far more detailed genetic analyses of tumors than commercially available tests could provide.

So they created their own gene-sequencing technique and tested it on 500 patients with cancers that had metastasized. But they didn’t just sequence the primary tumors. Instead, they ran their test on the tumors that had spread beyond the cancer’s point of origin. In so doing they discovered that patients whose tumors have spread harbor significantly more mutations—and more diverse mutations—than what’s generally found in the primary tumor. They published their findings in the journal Nature.

To complete their analysis, the Michigan scientists sequenced both the DNA and RNA from biopsies of metastatic tumors, which were taken from patients enrolled in the Michigan Oncology Sequencing Program. Why RNA? Because it’s part of the tumor microenvironment and a key player in processes that turn on cancer-causing genes or that inhibit the genes that have the power to fight cancer. All told, they scrutinized more than 30 cancer types and 22 organs.

Virtually every patient had an increased number of mutations in their metastatic tumors, according to a press release. The scientists hypothesized that the cancers developed more mutations over time and in response to drugs used to treat the tumors.

"Tumors are evolving as part of metastasis and under therapy,” said Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology, in the release. “We need to biopsy the metastatic tumors and then suggest therapies, rather than using archival tissue from the primary tumor."

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Examining RNA allowed the team to zero in on immune cells surrounding the tumors, which could eventually lead to clues about who is most likely to respond to immunotherapy, Chinnaiyan said.

The Michigan team also compared tumor DNA to normal DNA, which led them to a surprising discovery: 12% of the patients with metastatic tumors had an inherited mutation. About 75% of those mutations were linked to DNA repair—a mechanism that’s targeted by several existing cancer therapies. That finding led Chinnaiyan to suggest that when inherited mutations are found in people with metastatic solid tumors, family members should consider whether to seek out genetic testing and counseling to assess their cancer risks.

The next step for the researchers is to analyze treatment outcomes for the patients whose tumors were sequenced. Preliminary findings suggest that 75% have “actionable mutations,” meaning there are already treatments on the market that target the abnormalities in their metastatic tumors.