‘Bursts’ of chromosome changes fuel breast cancer tumor growth

Study provides insight into tumor evolution; may point to improved diagnosis and treatment

As with most cancers, triple-negative breast cancer (TNBC) cells have abnormal amounts of chromosomes or DNA copy number aberrations (CNAs) in their genomes. A new study used single cell sequencing technology to provide previously unknown details about how and when CNAs impact tumor formation and growth, information that may have significant implications for diagnosis and treatment.

The research results, published in the Aug. 15 online issue of Nature Genetics, challenge the prevailing belief CNAs take place slowly and gradually over time. Instead, study findings revealed chromosomal changes occur in short, punctuated “bursts” at the earliest stages of tumor growth.

“The current model asserts CNAs are acquired gradually and sequentially over extended periods of time, leading to successively more malignant stages of cancer,” said Nicholas Navin, Ph.D., professor of Genetics at The University of Texas MD Anderson Cancer Center, and lead author of the paper. “Another model is punctuated evolution in which CNAs are acquired in short bursts of crisis, followed by stable clonal expansion that form the tumor mass. Our study suggests punctuated copy number evolution is common in TNBC patients.”

Navin’s study supports the “bursts” model and demonstrates the majority of CNAs are acquired at the earliest stages of tumor evolution. The discovery is important since most genomic studies have focused on a single point in time, after a tumor has been surgically removed, making it difficult to study the natural history of chromosome evolution during tumor growth.

The finding also indicated other cancers may demonstrate similar CNA behavior.

“Our preliminary data in cancers such as prostate, colon, liver and lung suggest a punctuated model of copy number evolution is also likely to be operative in other solid cancers,” said Navin. “This model has important implications for our evolutionary understanding of cancer growth dynamics and for the clinical diagnosis and treatment of TNBC patients.”

The research team developed a new method called highly multiplexed single-nucleus sequencing (HM-SNS) to investigate CNA’s clonal substructure and evolution in a cohort of 12 TNBC patients, whose tumors had been surgically removed prior to further therapy. HM-SNS allows researchers to sequence the genomes of single tumor cells and study multiple cells simultaneously, both lowering the cost and boosting data analysis for such studies.

MD Anderson study team participants included Ruli Gao, Ph.D., Alexander Davis, Emi Sei, Ph.D., Yong Wang, Ph.D., Pei-Ching Tsai, Anna Casasent, and Jill Waters, all of Genetics; Hong Zhang, M.D., Ph.D., Pathology; and Funda Meric-Bernstam, M.D., Surgical Oncology. Other participating institutions included Peking Union Medical College, Beijing; Dana-Farber Cancer Institute, Boston; and Chan School of Public Health, Boston.

The study was funded by the Lefkofsky Family Foundation, the Andrew Sabin Family Fellowship Program, the National Institutes of Health (CA169244-01, UL1 TR000371, CA016672 and CA193461-01), the American Cancer Society (RSG-16-092-01-TBG), the Nellie B. Connally Breast Chair in Breast Cancer Research, the Susan G. Komen (SAC10006), the Cancer Prevention and Research Institute (RP110584), and Nadia’s Gift Foundation (DRR-25-13).