A study published today in Nature Genetics has revealed that tumor metastases accumulate copy number alterations (CNAs) such as genome doubling rather than genetic mutations. The CNAs can help metastases evade the immune system and resist immunotherapy. These findings could assist clinicians in making better decisions around the choice of precision medicine treatments, especially immunotherapy drugs such as checkpoint inhibitors.
“Our study found that during metastasis, cancer cells tend to evolve by maximizing CNAs, while not generating too many mutations that could potentially stimulate an immune response,” said Chaitanya Bandlamudi, PhD, cancer genomics researcher at Memorial Sloan Kettering Cancer Center (MSK).
While both mutations and CNA changes are known to accumulate in tumors as they evolve, there is still limited knowledge about which type of alterations are more likely to occur in metastases as compared to primary tumors. A key limitation of previous studies is that they compared primary tumors and metastasis from different patients, making it difficult to account for the heterogeneity seen across individual cases.
The current study looked at samples from primary tumor and metastasis sites within the same patients. In total, researchers at Weill Cornell Medicine and MSK analyzed 8,171 tumor samples from 3,732 cancer patients, making it the largest study of its kind to date.
“We found that whole-genome duplication—which is the doubling of the entire set of chromosomes in a cancer cell—was the most common genetic event during metastasis, occurring in nearly one-third of patients,” said Karena Zhao, medical student at MSK and Weill Cornell Medical College and first author of the study.
Whole genome duplication was found in 47% of metastatic tumor samples, compared to 38% of primary tumors, when analyzing sample pairs from the same patients. Of all patients without whole genome duplication in their primary tumor, 28.5% saw it emerge de novo in their metastasis sites.
Typically, a higher mutation number can make tumors more easily recognizable by the immune system and offer weaknesses that can be exploited by cancer drugs. In contrast, some types of CNAs, including whole genome duplication, can offer a ‘buffer’ for the negative effects that accumulating mutations can have on a tumor.
“Genome doubling allows cancer cells to hedge their bets, creating additional copies of genes, so that one copy can be mutated or deleted, while the other copy survives intact,” said Xi Kathy Zhou, PhD, professor of research in population health sciences at Weill Cornell Medicine. “This enhances the tumor cell’s ability to adapt, survive, and resist treatments.”
Tumors with higher numbers of CNAs are linked to significantly poorer survival rates and lower tumor response to checkpoint inhibitors and other immunotherapies, indicating that different strategies may be more suitable when it comes to treating patients with metastatic cancer. In the paper, the authors suggest that treatments such as cytotoxic system therapy or targeted therapies to modify the tumor microenvironment may be more successful at achieving long-term tumor responses in these cases.
“Understanding these key genomic differences between primary and metastatic tumors is vital for clinical care, as biomarkers like CNAs and tumor mutational burden are increasingly used by clinicians to inform decision-making, especially around the use of immunotherapy drugs,” said Luc Morris, MD, surgeon and director of the cancer genetics research lab at MSK.
