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Ludwig study shows free-floating circles of DNA are common across cancers and drive poor patient outcomes

AUGUST 20, 2020, New York— The multiplication of cancer genes located on DNA that is not associated with chromosomes drives poor patient outcomes across many cancer types, according to a study led by Ludwig San Diego’s Paul Mischel, his colleague at the University of California San Diego Vineet Bafna, and Roel Verhaak of the Jackson Laboratory for Genomic Medicine in Farmington, Connecticut.

Such circles of extrachromosomal DNA (ecDNA) are associated with accelerated tumor evolution and high heterogeneity of cells within tumors. But it wasn’t entirely clear how common ecDNA is across cancer types and what its clinical impact might be.

Mischel and his colleagues report in the current issue of Nature Genetics that ecDNA is a common feature of human cancer, occurring at minimum in 14% of human tumors, with far higher frequencies in the most malignant forms of cancer, such as the brain cancer glioblastoma, sarcoma, and esophageal, ovarian, lung, bladder, head and neck and gastric cancers.

“We also find that patients whose cancers have ecDNA have significantly shorter survival than all other cancer patients whose tumors are driven by other molecular lesions, even when grouped by tumor type,” said Mischel, who is also a distinguished professor at the UC San Diego School of Medicine.

The researchers report that ecDNA-based circular markers of amplification were found in 25 of 29 cancer types analyzed. They occurred with high frequency in many cancers that are considered among the most aggressive, such as glioblastoma and esophageal carcinoma.

“It seems that cancers have pulled an ancient evolutionary trick. Oncogenes and surrounding regulatory regions untether themselves from their chromosomal constraints, driving high oncogene copy number, accelerating tumor evolution, contributing to therapeutic resistance, and endowing tumors with the ability to rapidly change their genomes in response to rapidly changing environments, thereby accelerating tumor evolution and contributing to therapeutic resistance,” said Mischel.

The research team computationally analyzed whole-genome sequencing data from more than 3,200 tumor samples in The Cancer Genome Atlas (TCGA) and the Pan-Cancer Analysis of Whole Genomes (PCAWG), totaling over 400 terabytes of raw sequencing data, to capture the impact of ecDNA amplification on patient outcomes.

Mischel and Bafna, who is a professor of computer science and engineering at the Jacobs School of Engineering at UC San Diego, are cofounders of Boundless Bio, a company developing innovative new therapies directed to ecDNA in aggressive cancers.

The UC San Diego news release from which this summary is derived can be found here.


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