Evolution of Cancer Genomes During Metastasis

When cancer spreads from a primary tumor to other parts of the body, it undergoes changes that increase its genetic complexity.

A new study by researchers at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSK) provides insights into how cancers evolve during metastasis. These findings may inform the development of future treatment strategies.

The research team analyzed genomic data from more than 3,700 patients diagnosed with 24 different types of cancer. Each patient had biopsies taken from multiple tumor sites over time. The study was led by Dr. Luc Morris, a surgeon and director of MSK’s cancer genetics research laboratory; Dr. Xi Kathy Zhou, a professor of population health sciences at Weill Cornell Medicine; and Dr. Chaitanya Bandlamudi, a cancer genomics researcher at MSK.

The tumor samples were examined using MSK’s proprietary sequencing method. This allowed the researchers to compare the genetic makeup of primary tumors and their corresponding metastatic sites within the same patients.

Metastatic Tumors Harbor More Copy-Number Alterations

The team’s findings showed that tumors evolve over time and that metastatic tumors tend to accumulate more copy-number alterations (CNAs) than point mutations. This led the researchers to explore why CNAs, rather than mutations, are more frequently observed during metastasis.

Mutations are small changes in the genetic code that can alter gene function, potentially leading to abnormal protein production or changes in gene expression. CNAs, on the other hand, involve larger-scale gains or losses of genetic material.

One notable type of CNA, known as genome doubling, was found to play an important role during the metastatic process.

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.

Dr. Karena Zhao, Study First Author, Weill Cornell Medical

Mutations arise as cancer cells divide and replicate their DNA, sometimes introducing errors. Some of these mutations can promote cell growth, while others may interfere with essential genes and lead to cell death.

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. This enhances the tumor cell’s ability to adapt, survive, and resist treatments.

Dr. Xi Kathy Zhou, Professor, Weill Cornell Medicine

Understanding Genomic Differences Between Primary and Metastatic Tumors Is Critical

Unlike CNAs, additional mutations can make tumors more detectable by the immune system. This is because changes in genetic sequences may result in abnormal proteins that the immune system recognizes as foreign. The researchers found that tumors with more CNAs were less responsive to immunotherapy, while those with higher mutation rates were more likely to respond.

In the end, 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.

Dr. Chaitanya Bandlamudi, Cancer Genomics Researcher, Memorial Sloan Kettering Cancer Center

According to the researchers, these findings suggest that new approaches, such as therapies that target genetic instability in highly altered cells or that modify the tumor microenvironment, may be important for achieving more durable responses in metastatic cancer.

“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,” concluded Dr. Luc Morris, Surgeon and Director, Cancer Genetics Research Lab, Memorial Sloan Kettering Cancer Center