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. 2025 Jul 1;31(13):2710-2718.
doi: 10.1158/1078-0432.CCR-24-3335.

Characterization of Plasma Cell-Free DNA Variants as of Tumor or Clonal Hematopoiesis Origin in 16,812 Advanced Cancer Patients

Daniel Magee  1 , Valeriy Domenyuk  1 , Jim Abraham  1 , Nieves Perdigones Borderias  1 , Jeff Swensen  1 , Praveena Solipuram  2 , Adanma Ayanambakkam  3 , Raja Mehdi  4 , Jagathi Challagalla  5 , Elisabeth Heath  6 , Megan Landsverk  7 , Magdalena Jurkiewicz  8 , Brian Shimkus  9 , Ian Pinto  10 , Daniel Patterson  11 , David Hsiehchen  12 , Supriya Koya  3 , Bradley Somer  13 , Michel Velez  14 , Anthony F Shields  6 , Jennifer Cultrera  15 , Jennifer R Ribeiro  1 , Robert Hahn-Lowry  1 , George W Sledge  1 , Matthew Oberley  1 , Milan Radovich  1 , David Spetzler  1
Affiliations

Characterization of Plasma Cell-Free DNA Variants as of Tumor or Clonal Hematopoiesis Origin in 16,812 Advanced Cancer Patients

Daniel Magee et al. Clin Cancer Res. .

Abstract

Purpose: Plasma-based liquid biopsy tests can detect tumor-specific genetic alterations and offer many advantages that complement tissue-based comprehensive genomic profiling. However, age-related clonal hematopoiesis (CH) mutations can confound liquid biopsy results and potentially lead to incorrect therapy choice.

Experimental design: We assessed the landscape of 16,812 liquid profiles across 49 cancer types using the Caris Assure assay, a whole-exome and whole-transcriptome next-generation sequencing workflow that independently sequences both plasma-derived cell-free total nucleic acids and the white blood cell DNA and RNA from the buffy coat. The variant source was identified algorithmically by comparing plasma and buffy coat variant frequency and read quality metrics.

Results: Of 16,812 patients, 42.3% presented at least one CH variant among reportable clinical genes. We found 39% of BRCA2 variants to be of CH origin, as well as 37.9% of CHEK2, 27.4% of BRCA1, 20.1% of ATM, 7.3% of NRAS, 5.8% of BRAF, 2.1% of EGFR, 2.1% of KRAS, and 18.5% of TP53. For patients aged 65 to 69 years, the median proportion of CH variant classification was 20%, whereas it was 33% for patients aged 70 to 74 years, 33% for ages 75 to 79 years, and 50% for ages 80+ years. We found high rates of CH detected in what would be otherwise druggable targets in many cancer types typically treated with PARP inhibitors, including breast, female genital tract, ovarian, pancreatic, prostate, and endometrial cancers.

Conclusions: This large study highlights the need for thorough CH classification during liquid biopsy to appropriately recommend therapies, especially PARP inhibitors. See related commentary by Bernard and Micol, p. 2545.

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Conflict of interest statement

D. Magee reports other support from Caris Life Sciences during the conduct of the study, as well as employment with and stock ownership in Caris Life Sciences. V. Domenyuk reports other support from Caris Life Sciences outside the submitted work. J. Abraham reports other support from Caris Life Sciences during the conduct of the study, as well as other support from Caris Life Sciences outside the submitted work. N. Perdigones Borderias reports other support from Caris Life Sciences outside the submitted work. J. Swensen reports other support from Caris Life Sciences during the conduct of the study. A.F. Shields reports personal fees and other support from Caris Life Sciences outside the submitted work. J.R. Ribeiro reports personal fees from Caris Life Sciences during the conduct of the study, as well as personal fees from Caris Life Sciences outside the submitted work. R. Hahn-Lowry reports other support from Caris Life Sciences during the conduct of the study, as well as being employed with Caris Life Sciences and holding equity in Caris Life Sciences. G.W. Sledge reports other support from Caris Life Sciences outside the submitted work. M. Oberley reports other support from Caris Life Sciences outside the submitted work. M. Radovich reports personal fees from Caris Life Sciences during the conduct of the study, as well as personal fees from Caris Life Sciences outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Variant classification methodology. BC, buffy coat.
Figure 2.
Figure 2.
A, Proportion of CH vs. tumor variants by genes (genes with reportable variants >100). B, Variant classification by gDNA and plasma VF (a close-up image of the 0%–20% region is shown in Supplementary Fig. S2 to allow visualization of low VF data). C, Mean VF by gene of CH variants in buffy coat and plasma.
Figure 3.
Figure 3.
Prevalence of CH, tumor, and germline mutations by gene and cancer type.
Figure 4.
Figure 4.
Percent of patients by cancer type with a CH variant in a gene that would drive therapy selection. TKI, tyrosine kinase inhibitor.
See this image and copyright information in PMC

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