Extrachromosomal DNA is common in human cancer and drives poor patients outcomes

August 17, 2020

The multiplication of genes located in extrachromosomal DNA that have the potential to cause cancer drives poor patient outcomes across many cancer types, according to a Nature Genetics study published Aug. 17, 2020 by a team of researchers including Professors Vineet Bafna and Dr.Paul Mischel of the University of California San Diego and Professor Roel Verhaak of Jackson Laboratories.

This is the first time that a study has shown that the multiplication of these extrachromosomalDNA (ecDNA) genes--a phenomenon called ecDNA oncogene amplification-- is present in a broad range of cancer tumor types. The researchers found that ecDNA is a common event in human cancer, occuring at minimum in 14% of human tumors, with far, far higher frequencies in the most malignant forms of cancer, including glioblastoma, sarcoma, esophageal, ovarian, lung, bladder, head and neck, gastric, and many others. The findings demonstrate that ecDNA plays a critical role in cancer.

"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 Dr. Mischel, one of the study's authors and a distinguished professor at the UC San Diego School of Medicine and a member of the Ludwig Institute for Cancer Research.

The shorter overall survival raises the possibility that cancer patients whose tumors are driven by ecDNA may not be as responsive to current therapies and may be in need of new forms of treatment. The researchers' hope is that these findings will be applied to the development of powerful anti-cancer therapies for individuals with ecDNA-driven cancers.

"This study provides a new window into the molecular epidemiology of ecDNA in cancer, providing a unique opportunity to study patients longitudinally to better understand how and why they respond poorly to treatment," Dr. Mischel said.

The researchers observed that ecDNA amplification occurs in many types of cancers, but not in normal tissue or in whole blood, and that the most common recurrent oncogene amplifications frequently arise on ecDNA. Notably, ecDNA-based circular markers of amplification were found in 25 of 29 cancer types analyzed, and at high frequency in many cancers that are considered to be among the most aggressive histological types, such as glioblastoma, sarcoma, 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," Dr. Mischel said.

To get to this finding, the research team used intensive computational analysis of 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 observe the impact of ecDNA amplification on patient outcomes.

"We developed a powerful computational approach called Amplicon Architect, which identifies ecDNA based on three key features- circularity, high copy number, and "reuse of breakpoints," said paper coauthor Bafna,a professor in the UC San Diego Department of Computer Science and Engineering.

Dr. Mischel and Bafna are cofounders of Boundless Bio, a company developing innovative new therapies directed to extrachromosomal DNA (ecDNA) in aggressive cancers.

"These results point to the urgent need for therapies that can target ecDNA and interfere with their ability to drive aggressive cancer growth, resistance, and recurrence," said Jason Christiansen, chief technology officer of Boundless Bio.

What is ecDNA?

Extrachromosomal DNA, or ecDNA, are distinct circular units of DNA containing functional genes that are located outside cells' chromosomes and can make many copies of themselves. ecDNA rapidly replicate within cancer cells, causing high numbers of oncogene copies, a trait that can be passed to daughter cells in asymmetric ways during cell division. Cancer cells have the ability to upregulate or downregulate oncogenes located on ecDNA to ensure survival under selective pressures, including chemotherapy, targeted therapy, immunotherapy, or radiation, making ecDNA one of cancer cells' primary mechanisms of recurrence and treatment resistance. ecDNA are rarely seen in healthy cells but are found in many solid tumor cancers. They are a key driver of the most aggressive and difficult-to-treat cancers, specifically those characterized by high copy number amplification of oncogenes.
-end-
Frequent extrachromosomal oncogene amplification drives aggressive tumors

Nam-phuong Nguyen and Kristen Turner, Boundless Bio scientists

Paul Mischel, M.D., Distinguished Professor at the University of California San Diego (UC San Diego) School of Medicine and a member of the Ludwig Institute for Cancer Research

Vineet Bafna, Ph.D., Professor of Computer Science & Engineering, UC San Diego

Howard Chang, M.D., Ph.D., Virginia and D.K. Ludwig Professor of Cancer Genomics and Genetics, Stanford University

Roel Verhaak, Ph.D., Professor and Associate Director of Computational Biology, The Jackson Laboratory

University of California - San Diego

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.