When the Signal Isn’t Tumor: Understanding Clonal Hematopoiesis in Liquid Biopsy
Clonal hematopoiesis (CH) is an increasingly important consideration in liquid biopsy interpretation as blood-based genomic profiling is being more widely used to guide therapy selection in solid tumors.
In our recent webinar, “When the Signal Isn’t Tumor: Understanding Clonal Hematopoiesis in Liquid Biopsy,” the Northstar Medical Affairs team explored what CH is, why it occurs, and why confidence in distinguishing tumor-derived variants from non-tumor signal is critical for confident treatment decisions.
Here’s a quick summary of the key takeaways.
What Is Clonal Hematopoiesis?
Clonal hematopoiesis refers to the expansion of blood cell clones that acquire somatic mutations over time. These alterations are not related to a patient’s tumor, but they can still appear in a blood sample and confound liquid biopsy interpretation.
CH becomes more common with age and may also be influenced by factors such as smoking, or exposure to therapy. In fact, studies have shown that in approximately 25% of patients, at least one clinically actionable or reportable mutation detected by liquid biopsy originates from white blood cells rather than from the tumor.1 As a result, some patients—especially in older adults—may harbor blood-cell-derived variants that are detectable in plasma even when they are not present in the tumor.
Why CH Matters in Liquid Biopsy
Liquid biopsy is designed to detect cell-free DNA in blood, but blood samples also contain DNA shed from normal cells, including white blood cells. When CH-related alterations are present, they can appear alongside tumor-derived variants and create uncertainty around variant attribution.
Accurately distinguishing tumor-derived alterations from clonal hematopoiesis is particularly critical for clinically actionable DNA repair genes, where somatic alterations may impact therapy selection (e.g. PARPi). Without a reliable way to distinguish tumor signal from non-tumor signal, there is a risk of mis-classifying a variant as actionable when it is not actually coming from the tumor. By removing false signals driven by clonal hematopoiesis, you can optimize a patient’s treatment and avoid exposing them to unnecessary toxicity and potentially ineffective treatments.
The Role of Buffy-Coat Sequencing
One of the main challenges discussed in the webinar is that liquid biopsies that utilize plasma-only sequencing may potentially overlook a CH-derived variant and mis-classify it as tumor derived. To improve confidence in variant attribution, the webinar reviewed the role of buffy-coat sequencing, which analyzes DNA from white blood cells to confidently determine whether a variant is likely hematopoietic in origin rather than tumor-derived. Some guidelines even advise and recommend buffy-coat sequencing of white blood cells (WBC) for clinically actionable tumor suppressor genes such as DNA repair genes.2
When used in conjunction with bioinformatic filtering (which is appropriate for some genes), buffy-coat sequencing can help resolve ambiguous findings and support more accurate classification of variants across the panel. This kind of approach is especially important when a result could directly influence therapy selection.
Why Accurate Attribution Supports Better Treatment Decisions
Ultimately, the goal of CH-aware liquid biopsy interpretation is not just cleaner reporting—it is better clinical decision-making.
By helping distinguish true tumor-derived alterations from CH false positives, clinicians can make treatment decisions with greater confidence and reduce the risk of acting on non-tumor signals. As liquid biopsy continues to play a larger role in oncology care, approaches that account for CH will be increasingly important to ensure results are both actionable and accurate.
Watch the Webinar Recap
Want the full overview?
Watch the recap to hear the discussion and learn why CH resolution is becoming an important part of accurate liquid biopsy interpretation and informed therapy selection.
References:
- Coombs CC , Zehir A , Devlin SM , Kishtagari A , Syed A , Jonsson P , et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell 2017;21:374–82.e4.
- Pascual, J., Attard, G., Bidard, FC., Curigliano, G., De Mattos-Arruda., … .& Turner, NC. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022 Aug;33(8):750-768. doi: 10.1016/j.annonc.2022.05.520. Epub 2022 Jul 6.
