The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA) and multiple cfDNA targeted sequencing panels are now commercially available for FDA-approved biomarker indications to guide treatment.
More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner.
We used machine-learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer vs. non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, N=198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, N=320). Each cohort was split 70/30% into training and validation sets.
In the UW cohort, training cross validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer vs. non-cancer AUC was 0.99.
To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.
Annals of oncology : official journal of the European Society for Medical Oncology. 2023 Jun 15 [Epub ahead of print]
K T Helzer, M Sharifi, J M Sperger, Y Shi, M Annala, M L Bootsma, S R Reese, A Taylor, K R Kaufmann, H Krause, J Schehr, N Sethakorn, D Kosoff, C Kyriakopoulos, M Burkard, N R Rydzewski, M Yu, P M Harari, M Bassetti, G Blitzer, J Floberg, M Sjöström, D A Quigley, S Dehm, A J Armstrong, H Beltran, R R McKay, F Y Feng, R O'Regan, K Wisinski, H Emamekhoo, A W Wyatt, J M Lang, S G Zhao
Department of Human Oncology, University of Wisconsin, Madison, WI, USA., Carbone Cancer Center, University of Wisconsin, Madison, WI, USA; Department of Medicine, University of Wisconsin, Madison, WI, USA., Department of Medicine, University of Wisconsin, Madison, WI, USA., Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada; Prostate Cancer Research Center, Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere, Finland., Department of Human Oncology, University of Wisconsin, Madison, WI, USA; Department of Medicine, University of Wisconsin, Madison, WI, USA., Carbone Cancer Center, University of Wisconsin, Madison, WI, USA., Carbone Cancer Center, University of Wisconsin, Madison, WI, USA; Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA., Department of Human Oncology, University of Wisconsin, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin, Madison, WI, USA., Department of Radiation Oncology, University of California San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA; Department of Urology, University of California San Francisco, San Francisco, CA., Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Duke Cancer Institute Center for Prostate and Urologic Cancers, Department of Medicine, Duke University, Durham, NC, USA., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Moores Cancer Center, University of California San Diego, La Jolla, CA, USA., Department of Radiation Oncology, University of California San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA., Carbone Cancer Center, University of Wisconsin, Madison, WI, USA; Department of Medicine, University of Wisconsin, Madison, WI, USA; Department of Medicine, University of Rochester, Rochester, NY, USA., Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada; Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada., Department of Human Oncology, University of Wisconsin, Madison, WI, USA; Carbone Cancer Center, University of Wisconsin, Madison, WI, USA; William S. Middleton Memorial Veterans' Hospital, Madison, WI. Electronic address: .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/37330052
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