Measuring the effects of radiotherapy on cancer may open up new avenues of treatment
International team identifies biomarker that suggests a better way to monitor radiation therapy
PHOENIX, Ariz. — May 27, 2021 — Radiation therapy, or radiotherapy (RT), is such an integral part of modern cancer treatment that it is used in the clinical management of more than half of all patients with cancer. By damaging the cancer DNA, RT reduces the ability of cancer cells to reproduce.
The results of an international study, however, suggest that RT also causes mutations, deletions and other changes in cancer DNA that can significantly undermine its effectiveness in subsequent treatments when the cancer recurs.
Led by researchers at The Jackson Laboratory for Genomic Medicine (JAX), and including a new investigator for the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, their findings appear today in Nature Genetics.
“We found that a higher load of RT-associated DNA deletions was linked to worse patient outcomes,” said Floris Barthel, M.D., a researcher specializing in brain tumors at JAX, and a newly-recruited assistant professor at TGen. Dr. Barthel is one of the study’s senior authors. “Additional rounds of RT in patients with recurrent tumors, or tumors that have spread to other parts of the body, contain a significant increase in DNA deletions and are unlikely to further extend cancer progression-free survival.”
Importantly, researchers identified a genetic biomarker, a CDKN2A homozygous deletion, as a potential indicator of RT resistance, possibly indicating that the patient has received enough radiation.
“A biomarker able to readily detect an increased deletion burden may help reduce treatment costs and avoid RT-associated patient comorbidities and side effects,” according to Roel Verhaak, Ph.D., professor at JAX and co-senior author of the study.
Researchers used genomic sequencing to analyze the DNA of 190 glioma brain tumors, both before and after RT. When cancer DNA is damaged by RT, the cancer attempts to repair itself, leaving tell-tale genetic changes that may be identified through sequencing.
“A high radiation-associated deletion burden was associated with worse clinical outcomes, suggesting that effective repair of radiation-induced DNA damage is detrimental to patient survival,” according to Emre Kocakavuk, M.D., first author of the study.
Researchers hypothesized that RT may have similar effects in other tumor types. They evaluated whole genome sequences of mutational profiles from 3,693 metastatic tumors — those that spread to other parts of the body — including bone, soft-tissue, lung and breast cancers, resulting in findings similar to their analyses of brain tumors.
The authors conclude their report by suggesting that, “Combined, these results suggest that a higher deletion burden may reflect a scenario that is favorable to the tumor, characterized by proficient DNA repair, resulting in less tumor cell killing and decreased treatment efficacy.”
Dr. Barthel added: “Identifying the DNA repair processes involved in irradiated tumors is very exciting because it suggests that slowing this repair process during radiotherapy could potentially increase the effectiveness of treatment.”
Contributing to this research were: Glioma Longitudinal Analysis Consortium, Hartwig Medical Foundation, Center for Personalized Cancer Treatment, University Hospital Essen, Germany; New York University Langone Health; Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Brain Tumor Center Amsterdam, the Netherlands.
This study — Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer — was supported by: the National Institutes of Health, National Cancer Institute, Department of Defense, the Musella Foundation, B*CURED Foundation, Brain Tumor Charity, JAX Scholar Program, Jane Coffin Childs Memorial Fund for Medical Research, an American Cancer Society Fellowship, Boehringer Ingelheim Fonds, and the German National Academic Foundation.
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About TGen, an affiliate of City of Hope
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is affiliated with City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases: CityofHope.org. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: tgen.org. Follow TGen on Facebook, LinkedIn and Twitter @TGen.
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