Prevalence of clonal hematopoiesis of indeterminate potential (CHIP) measured by an ultra-sensitive sequencing assay: Exploratory analysis of the Circulating Cancer Genome Atlas (CCGA) study.
Abstract
12003 Background: CHIP is defined by the presence of age-dependent acquired mutations in hematopoietic progenitor cells and has been reported to occur in up to 30% of individuals 60-70 years of age. CHIP is a risk factor for hematologic malignancies and cardiovascular disease; its biological mechanisms and clinical significance are just now being studied. Using an assay ~100X more sensitive than exome sequencing, we determined the prevalence and features of CHIP in the CCGA cohort, and the impact on interpretation of cell-free DNA (cfDNA) somatic variants. Methods: Blood was prospectively collected (N = 1627) from 749 controls (no cancer, C) and 878 participants (pts) with newly-diagnosed untreated cancer (20 tumor types, all stages) for WBC and cfDNA isolation. Paired white blood cell (WBC) and cfDNA targeted sequencing (507 genes, 60,000X median coverage) identified somatic single nucleotide variants/indels. Unique molecular barcodes and a machine learning-based noise model achieved a specificity of 1 false positive variant call per Mb of genome targeted at a limit of detection of ~0.1% variant allele frequency (VAF). Results: 1412 samples were eligible and evaluable (576 C, 836 pts; 18 solid tumor types, all stages). Of somatic cfDNA variants matched in WBC (CHIP), 7% of individuals had CHIP with VAF > 10%, 39% had CHIP with VAF > 1%, and nearly all pts (92%) had a somatic mutation with VAF > 0.1%. The rate was similar between C and pts (median age 62, 60), increasing in prevalence by 160% per decade, such that we observed 2.5 variants/Mb at age 60. Of CHIP variants identified, 92% were unique to individual patients, most of which were present at low VAF. Genes impacted by CHIP included DNMT3A (40%), TET2 (27%), and TP53 (10%), consistent with previous reports in patients with solid tumors. Conclusions: An ultra-sensitive sequencing assay demonstrated that CHIP signal in WBC and cfDNA is much more common than previously appreciated. The clinical significance of CHIP warrants further study and must be accounted for when interpreting cfDNA variants for both early cancer detection and tumor genotyping (liquid biopsy). Clinical trial information: NCT02889978.
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This data is consistent with the CCGA report that up to 54% of somatic mutations detected in blood from lung cancer patients came from hematopoietic cells, not tumors.
“This data is consistent with the recent report from Circulating Cell-Free Genome Atlas (CCGA) study showing that up to 54% of the somatic mutations detected in the blood samples from lung cancer patients were from hematopoietic cells’ somatic mutations, but not from tumors[28].”
From Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in <i>EGFR</i> -Mutant NSCLC (2018) · cites this paper as [28]
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“To mitigate this issue, paired sequencing of patient-derived leukocytes is increasingly used; however, removing the contribution of other sources of background genetic alterations may be challenging (20).”
- Authors
- Swanton, C., Venn, O., Aravanis, A., Hubbell, E., Maddala, T., Beausang, J. F., Filippova, D., Gross, S., Jamshidi, A., Shen, L., Valouev, A., Zhang, N., Bolton, K. L., Yeatman, T. J., Seiden, M., Oxnard, G. R., Liu, M. C., Williams, R. T., Hartman, A.-R., & Baselga, J.
- Affiliations
- The Francis Crick Institute (GB)
- Grail (United States) (US)
- GRAIL, Inc., Menlo Park, CA;
- Memorial Sloan Kettering Cancer Center (US)
- Gibbs Cancer Center and Research Institute, Spartanburg, SC;
- McKesson (United States) (US)
- Dana-Farber Cancer Institute (US)
- Mayo Clinic, Rochester, MN;
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2018-05-20
- Volume
- 36
- Issue
- 15_suppl
- Pages
- 12003-12003
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2889848575
- Cited by
- 57
- References
- 0
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 15 · 2020: 6 · 2019: 8 · 2018: 2
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- clonal hematopoiesis of indeterminate potential, cell-free DNA, liquid biopsy, variant allele frequency, DNMT3A, TET2, TP53, somatic mutations, solid tumors, hematologic malignancy risk
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