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Clinical relevance of clonal hematopoiesis and its interference in cell-free DNA profiling of patients with gastric cancer

  • Kwang Seob Lee ORCID logo , Choong-Kun Lee ORCID logo , Soon Sung Kwon ORCID logo , Woo Sun Kwon ORCID logo , Sejung Park , Seung-Tae Lee ORCID logo , Jong Rak Choi ORCID logo , Sun Young Rha ORCID logo EMAIL logo and Saeam Shin ORCID logo EMAIL logo
Published/Copyright: July 13, 2023
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Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 62 Issue 1

Abstract

Objectives

Clonal hematopoiesis (CH) is a condition in which healthy individuals have somatic mutations in hematopoietic stem cells. It has been reported with increased risk of hematologic malignancy and cardiovascular disease in the general population, but studies of Korean populations with comorbid disease entities are scarce.

Methods

White blood cells (WBCs) from patients with gastric cancer (GC) (n=121) were analyzed using a DNA-based targeted (531 genes) panel with customized pipeline designed to detect single nucleotide variants and small indels with low-allele-frequency of ≥0.2 %. We defined significant CH variants as having variant allele frequency (VAF) ≥2 % among variants found in WBCs. Matched cell-free DNA (cfDNA) samples were also analyzed with the same pipeline to investigate the false-positive results caused by WBC variants in cfDNA profiling.

Results

Significant CH variants were detected in 29.8 % of patients and were associated with age and male sex. The number of CH variants was associated with a history of anti-cancer therapy and age. DNMT3A and TET2 were recurrently mutated. Overall survival rate of treatment-naïve patients with stage IV GC was higher in those with CH, but Cox regression showed no significant association after adjustment for age, sex, anti-cancer therapy, and smoking history. In addition, we analyzed the potential interference of WBC variants in plasma cell-free DNA testing, which has attracted interest as a complementary method for tissue biopsy. Results showed that 37.0 % (47/127) of plasma specimens harbored at least one WBC variant. VAFs of interfering WBC variants in the plasma and WBC were correlated, and WBC variants with VAF ≥4 % in WBC were frequently detected in plasma with the same VAF.

Conclusions

This study revealed the clinical impact of CH in Korean patients and suggests the potential for its interference in cfDNA tests.

Keywords: cell-free DNA; clonal hematopoiesis; gastric cancer; next-generation sequencing
Corresponding authors: Sun Young Rha, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Song-dang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea; and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea, E-mail: ; and Saeam Shin, Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea, E-mail:

  1. Research funding: This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (to SYR, HA15C0005), a grant from the National Research Foundation of Korea (to SS, 2021R1I1A1A01045980) and supported by the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (to KSL, no applicable grant number).

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. KSL, C-KL, SYR, S-TL, and JRC performed research, KSL performed data analysis, WSK and SP managed specimen collection, KSL and SS wrote the manuscript, SSK, SYR reviewed the manuscript, SYR and SS supervised the study.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: This study was approved by the Institutional Review Board of Yonsei University, Severance Hospital (IRB No. 4-2022-0422). All research procedures conformed to the principles of the Helsinki Declaration.

  6. Data availability: The datasets used and/or analyzed during the current study are available from the corresponding author (SS) on reasonable request.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2023-0261).

Received: 2023-03-13
Accepted: 2023-07-02
Published Online: 2023-07-13
Published in Print: 2024-01-26

© 2023 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2023-0261
Keywords for this article
cell-free DNA; clonal hematopoiesis; gastric cancer; next-generation sequencing

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Biological management of diabetes mellitus, the laboratory medicine specialist and the patient
  4. Reviews
  5. Remote HbA1c testing via microsampling: fit for purpose?
  6. The effect of hormonal contraceptive therapy on clinical laboratory parameters: a literature review
  7. Opinion Paper
  8. Continuous glucose monitoring has an increasing role in pre-symptomatic type 1 diabetes: advantages, limitations, and comparisons with laboratory-based testing
  9. IFCC Paper
  10. Comparison and commutability study among four faecal immunochemical tests (FIT) systems
  11. Guidelines and Recommendations
  12. Evidence-based procedures to improve the reliability of circulating miRNA biomarker assays
  13. General Clinical Chemistry and Laboratory Medicine
  14. Commutability assessment of candidate reference materials for plasma renin activity measurement: current challenges
  15. Aggregated data from the same laboratories participating in two glucose external quality assessment schemes show that commutability and transfers of values to control materials are decisive for the biases found
  16. Methodological considerations in determining sex steroids in children: comparison of conventional immunoassays with liquid chromatography-tandem mass spectrometry
  17. From “wet” matrices to “dry” blood spot sampling strategy: a versatile LC-MS/MS assay for simultaneous monitoring caffeine and its three primary metabolites in preterm infants
  18. A sensitive LC-MS/MS methotrexate assay capable of assessing adherence to methotrexate therapy in rheumatoid arthritis
  19. Determination of cortisone and cortisol in human scalp hair using an improved LC-MS/MS-based method
  20. Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases
  21. Combined deficient response to polysaccharide-based and protein-based vaccines predicts a severe clinical phenotype
  22. Reference Values and Biological Variations
  23. A sex-specific association of leukocyte telomere length with thigh muscle mass
  24. Cancer Diagnostics
  25. Optimized procedure for high-throughput transcriptome profiling of small extracellular vesicles isolated from low volume serum samples
  26. Ultra-short cell-free DNA fragments enhance cancer early detection in a multi-analyte blood test combining mutation, protein and fragmentomics
  27. Clinical relevance of clonal hematopoiesis and its interference in cell-free DNA profiling of patients with gastric cancer
  28. Development and analytical validation of a novel nasopharynx swab-based Epstein-Barr virus C promoter methylation quantitative assay for nasopharyngeal carcinoma detection
  29. Infectious Diseases
  30. (Pre)analytical considerations concerning the analysis of synovial calprotectin
  31. Corrigendum
  32. Thermal and chronological stability of monocyte distribution width (MDW), the new biomarker for sepsis
  33. Acknowledgment
  34. Acknowledgment
  35. Letters to the Editor
  36. In-house diagnostic devices under the EU IVDR and unwanted side-effects of intentional transparency
  37. Use of thyroid function tests in urine: a position statement of the Belgian Thyroid Club
  38. State of the art of measurement uncertainty of serum ferritin
  39. Analytical performance evaluation and consumable waste reduction strategies using a tube-based quality control material
  40. Stability of fecal calprotectin extracts using the Diasorin® kit
  41. Reverse cascade testing from newborn screening: the opportunity to improve family healthcare outcomes
  42. An indirect data-mining approach to standardise paediatric serum phosphate reference intervals in Wales
  43. Sodium and risk assessment of osmotic demyelination syndrome: the method matters!
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