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. 2025 Jul:9:e2500200.
doi: 10.1200/PO-25-00200. Epub 2025 Jul 9.

Risk Assessment With Ultra-Low-Pass Whole-Genome Sequencing of Cell-Free DNA for Large B-Cell Lymphoma

Davidson Zhao  1   2 , Noémie Lang  1   3 , Ting Liu  1 , Victoria Shelton  1 , Juan Rangel-Patiño  1 , Inna Y Gong  1 , Michael Hong  1 , Anthea Travas  1 , Vanessa Murad  1 , Ibrahim Alrekhais  1 , Ur Metser  1 , Anca Prica  1 , Vishal Kukreti  1 , Sita Bhella  1 , Abi Vijenthira  1 , Michael Crump  1 , John Kuruvilla  1 , Andrea Arruda  1 , Mark D Minden  1   2 , Bernard Lam  4 , Robert Kridel  1   2
Affiliations

Risk Assessment With Ultra-Low-Pass Whole-Genome Sequencing of Cell-Free DNA for Large B-Cell Lymphoma

Davidson Zhao et al. JCO Precis Oncol. 2025 Jul.

Abstract

Purpose: Although deep targeted DNA sequencing of liquid biopsies has shown prognostic utility in large B-cell lymphoma (LBCL), the routine clinical adoption of these assays remains limited because of their high costs.

Materials and methods: Here, leveraging a well-annotated cohort encompassing both frontline and relapsed/refractory (R/R) LBCL, we profiled patient plasma samples with two complementary modalities-ultra-low-pass whole-genome sequencing (ULP-WGS) and deep targeted DNA sequencing, the former being a cost-effective method to profile large scale chromosomal abnormalities and estimate tumor burden.

Results: Our findings revealed a strong association of high cell-free tumor burden by both genomic profiling modalities with established measures of tumor burden and patient survival. Notably, the associations with survival remained statistically significant after accounting for international prognostic index scoring. Furthermore, we showed that del(17p) in circulating tumor DNA as detected by ULP-WGS was strongly associated with TP53 mutation status and predicted for significantly inferior outcome in frontline LBCL patients but not in patients with R/R LBCL.

Conclusion: Our study demonstrates that ULP-WGS can provide robust prognostic biomarkers for both frontline and R/R LBCL, highlighting its broad applicability for risk stratification.

Trial registration: ClinicalTrials.gov NCT03702309.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Robert Kridel

Stock and Other Ownership Interests: Telix Pharmaceuticals, ITM Isotope Technologies Munich

Research Funding: Roche (Inst), AbbVie (Inst), Bristol Myers Squibb/Celgene (Inst), AstraZeneca (Inst)

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Association of tumor fraction with orthogonal measures of tumor burden in LBCL. (A) Study overview (Created with BioRender.com). (B and C) Scatterplots for ctDNA concentration (hGE/mL) from ULP-WGS and capseq for the (B) frontline and (C) second-line LBCL cohorts. (D) Serum LDH levels across the two cohorts. (E) The maximum tumor diameter across the two cohorts. (F and G) Scatterplots for ctDNA concentration from ULP-WGS and MTV for the (F) frontline and (G) second-line LBCL cohorts. ctDNA, circulating tumor DNA; hGE/mL, haploid genome equivalents per milliliter; LBCL, large B-cell lymphoma; LDH, lactate dehydrogenase; MTV, metabolic tumor volume; ND, not detected; PET-CT, positron emission tomography-computed tomography; R/R, relapsed/refractory; ULP-WGS, ultra-low-pass whole-genome sequencing.
FIG 2.
FIG 2.
Association of cell-free tumor burden with newly diagnosed LBCL patient outcomes. (A and B) Kaplan-Meier plots for (A) OS and (B) PFS of the frontline LBCL cohort treated with curative-intent chemoimmunotherapy, as stratified by the upper quartile value of ctDNA concentration from ULP-WGS. (C and D) Kaplan-Meier plots for (C) OS and (D) PFS of the frontline LBCL cohort treated with curative-intent chemoimmunotherapy, as stratified by the upper quartile value of ctDNA concentration from capseq. (E and F) Multivariable survival analysis for (E) OS and (F) PFS for the curative-intent frontline LBCL cohort. ctDNA, circulating tumor DNA; hGE/mL, haploid genome equivalents per milliliter; HR, hazard ratio; IPI, international prognostic index; LBCL, large B-cell lymphoma; OS, overall survival; PFS, progression-free survival; ULP-WGS, ultra-low-pass whole-genome sequencing.
FIG 3.
FIG 3.
Association of cell-free tumor burden with R/R LBCL patient outcomes. (A and B) Kaplan-Meier plots for (A) OS and (B) TTF of the R/R LBCL cohort intended for ASCT, as stratified by the lower quartile value of ctDNA concentration from ULP-WGS, (C and D) Kaplan-Meier plots for (C) OS and (D) TTF of the R/R LBCL cohort intended for ASCT, as stratified by the lower quartile value of ctDNA concentration from capseq. (E and F) Multivariable survival analysis for (E) OS and (F) TTF for the R/R LBCL cohort intended for ASCT. ASCT, autologous stem cell transplantation; ctDNA, circulating tumor DNA; hGE/mL, haploid genome equivalents per milliliter; HR, hazard ratio; IPI, international prognostic index; LBCL, large B-cell lymphoma; OS, overall survival; R/R, relapsed/refractory; TTF, time to treatment failure; ULP-WGS, ultra-low-pass whole-genome sequencing.
FIG 4.
FIG 4.
Prognostic impact of del(17p) status in ctDNA with patients with newly diagnosed LBCL. (A and B) Kaplan-Meier plots for (A) OS and (B) PFS of the frontline LBCL cohort treated with curative-intent chemoimmunotherapy, as stratified by del(17p) status from ULP-WGS. (C and D) Kaplan-Meier plots for (C) OS and (D) PFS of the frontline LBCL cohort treated with curative-intent chemoimmunotherapy, as stratified by TP53 alteration status (del(17p) and/or TP53 mutation). (E and F) Multivariable survival analysis for (E) OS and (F) PFS for the curative-intent frontline LBCL cohort. (G) The total number of CNAs from ichorCNA for the frontline and R/R LBCL cohorts, as stratified by del(17p) status. CNAs, copy number alterations; ctDNA, circulating tumor DNA; HR, hazard ratio; IPI, international prognostic index; LBCL, large B-cell lymphoma; OS, overall survival; PFS, progression-free survival; R/R, relapsed/refractory; ULP-WGS, ultra-low-pass whole-genome sequencing.
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