Tiny circles called ecDNA are critical in cancer development and drug resistance. An international Stanford Medicine-led team publishes landmark studies detailing new findings and potential therapies.
A trio of research papers from Stanford Medicine researchers and their international collaborators transforms scientists’ understanding of how small DNA circles – until recently dismissed as inconsequential – are major drivers of many types of human cancers.
The papers, published simultaneously in Nature on Nov. 6, detail the prevalence and prognostic impact of the circles, called ecDNA for extrachromosomal DNA, in nearly 15,000 human cancers; highlight a novel mode of inheritance that overthrows a fundamental law of genetics; and describe an anti-cancer therapy targeting the circles that is already in clinical trials.
The team, jointly known as eDyNAmiC, is a group of international experts led by pathology Professor Paul Mischel, MD. In 2022, Mischel and the eDyNAmiC team were awarded a $25 million grant from the Cancer Grand Challenges initiative to learn more about the circles. Cancer Grand Challenges, a research initiative co-founded by Cancer Research U.K. and the National Cancer Institute in the United States, supports a global community of interdisciplinary, world-class research teams to take on cancer’s toughest challenges.
“We’re in the midst of a completely new understanding of a common and aggressive mechanism that drives cancer,” said Mischel, who holds the Fortinet Founders Professorship. “Each paper alone is noteworthy, and taken together they represent a major inflection point in how we view cancer initiation and evolution.” Mischel is also an institute scholar at Stanford Medicine’s Sarafan ChEM-H.
Mischel is co-senior author of each of the three papers; Howard Chang, MD, PhD, professor of dermatology and of genetics, the Virginia and D.K. Ludwig Professor in Cancer Research and a Howard Hughes Medical Institute investigator, is the co-senior author of two of the three papers and a co-author on the third paper.
Those featured circles, ecDNAs, are small and often contain a few genes on their circular DNA. Frequently, these genes are cancer-associated genes called oncogenes. When a cancer cell contains multiple oncogene-encoding ecDNAs, they can supercharge the cell’s growth and allow it to evade internal checkpoints meant to regulate cell division. The ecDNAs also sometimes encode genes for proteins that can tamp down the immune system’s response to a developing cancer – further advantaging tumor growth.
Greater prevalence than previously thought
Until recently, it was believed that only about 2% of tumors contained meaningful amounts of ecDNA. But in 2017, research in Mischel’s lab showed that the small circles were widespread and likely to play a critical role in human cancers. In 2023, Mischel and Chang further showed that their presence jumpstarts a cancerous transformation in precancerous cells.
In the first of the three papers, of which Chang is a co-author and Mischel is a co-senior author, researchers in the United Kingdom built on Mischel’s 2017 finding by analyzing the prevalence of ecDNA in nearly 15,000 cancer patients and 39 tumor types. They found that 17.1% of tumors contained ecDNA, that ecDNA was more prevalent after targeted therapy or cytotoxic treatments like chemotherapy, and that the presence of ecDNA was associated with metastasis and poorer overall survival.
The researchers also showed that the circles can contain not just cancer-driving oncogenes and genes that modulate the immune response, but also that others can contain only DNA sequences called enhancers that drive the expression of genes on other circles by linking two or more ecDNAs together.