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

Abstract

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.