A whole-genome sequencing–based, error-corrected method for detecting cancer from blood samples could be more sensitive and accurate in monitoring disease status posttreatment among patients with cancer compared with prior methods, according to a recent study published by Cheng et al in Nature Methods. The findings could represent a critical step toward the goal of routine blood test–based screening for early cancer detection.
Background
Blood test–based liquid biopsy technology designed for early cancer detection and the monitoring of cancer burden in patients could significantly benefit cancer care. However, sensitively and accurately identifying the mutational signatures of cancer from low concentrations of tumor DNA in blood samples has involved major challenges.
Previous research has showed that blood samples could provide opportunities to reliably detect advanced melanoma and lung cancer, even without access to sequence data from tumor samples.
“We’re now entering an era of low-cost DNA sequencing, and in this study, we took advantage of that to apply whole-genome sequencing techniques that in the past would have been considered wildly impractical,” explained senior study author Dan Landau, MD, PhD, the Bibliowicz Family Professor of Medicine and a member of the Englander Institute for Precision Medicine and the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, an oncologist at the NewYork-Presbyterian/Weill Cornell Medical Center, and a member of the New York Genome Center.
Study Methods and Results
In the study, researchers benchmarked the cancer-detection performance of a new commercial sequencing platform. They demonstrated that the low cost of the sequencing platform enabled a depth of whole-genome sequencing coverage that would have been prohibitively expensive with older technology. Using that platform alone—and having the known mutational patterns in patient tumors as a guide—the researchers were able to detect circulating tumor DNA in patient blood samples at concentrations in the part-per-million range. All of the samples included in the study were collected after obtaining informed consent from the patients.
The researchers then enhanced the accuracy of the approach with an error-correction method that utilized the redundant information in natural two-stranded DNA. The combined technique had low error rates, making it feasible in principle to use on blood samples without also requiring access to patient tumors.
Conclusions
The results of the study exhibited the potential of the novel high-sensitivity, low-error approach to detect very low cancer levels in patients with urothelial carcinoma and melanoma from blood samples alone.
“This collaboration allowed us to analyze circulating tumor DNA from patients with [urothelial carcinoma] and identify … distinct mutational signatures,” highlighted co–study author Bishoy M. Faltas, MD, Associate Professor of Medicine and Cell and Developmental Biology at Weill Cornell Medicine, Chief Research Officer of the Englander Institute for Precision Medicine, and a urologic oncologist at the NewYork-Presbyterian/Weill Cornell Medicine Center. “Incorporating these signatures into the analysis significantly increased the sensitivity of circulating tumor DNA detection,” he added.
“We were able, for example, to see increases in circulating tumor DNA levels after treatment in patients with cancers that progressed or recurred and declines in those levels in patients whose cancers had full or partial responses,” added lead study author Alexandre Cheng, PhD, of the École de Technologie Supérieure and the Centre de Recherche du Centre Hospitalier de l’Université de Montréal.
“These results allow us to think about a future in which we can detect and track cancer from blood tests alone,” concluded Dr. Landau.
Disclosure: The research in this study was supported in part by the National Cancer Institute of the National Institutes of Health, the Mark Foundation Aspire Award, the Burroughs Wellcome Fund Career Award for Medical Scientists, and the Melanoma Research Alliance Established Investigator Award. For full disclosures of the study authors, visit nature.com.
