CHIP Crucial for ctDNA Analysis, Frequently Involves Specific Genes
Researchers posit that clonal hematopoiesis of indeterminate potential (CHIP) is an important factor in circulating tumor DNA (ctDNA) analysis, and that the most common genes CHIP involves are DNMT3A, TET2, and TP53, according to data being presented at the virtual 2020 ASCO Annual Meeting.
“CHIP is an age-related phenomenon where somatic mutations accumulate in cells of the blood or bone marrow. It is a source of biological noise that causes false-positives in ctDNA analysis and is present in up to 20% of individuals over the age of 70,” wrote Hsin-Ta Wu, PhD, Natera, San Carlos, California, and colleagues.
CHIP’s presence has also been associated with an increased risk for hematologic cancers and cardiovascular disease, they added.
According to Dr Wu et al, certain tests, such as the Signatera assay, reduce false-positive results by filtering CHIP mutations through tumor tissue and germline sequencing. This allows for monitoring of certain tumor-specific mutations in each patient every time a test is ordered.
Thus, an analysis was conducted in which characterization of CHIP mutations was done using whole exome sequencing data (average depth ~250x) analyzed from the buffy coat of 159 patients. A variant caller with an allele frequency threshold between 1% and 10% was used for variant calling.
“[V]ariant annotation and selection was performed based on the top 54 genes that are most implicated in myeloid disorders,” Dr Wu and colleagues wrote, adding that the variants were screened further using reported variants in the literature and/or the Catalog of Somatic Mutations in Cancer.
According to the analysis, patients had an average of 0.14 CHIP mutations each, with an average variant allele frequency of 3.49%. DNMT3A, TET2, and TP53 genes were the most common CHIP mutations, observed in 17, 7, and 7 patients, respectively; 4.2%, 1.94%, and 1.38% of patients had at least 1 mutation in each of the respective genes.
CEBPA, ETV6, HRAS, PDGFRA, NRAS, KMT2A, EZH2, GATA2, GNAS genes were also found to contain CHIP mutations, but at a frequency <1%.
Of note, the researchers did not report any CHIP mutations in patients aged <40 years, although CHIP mutations did increase in frequency every decade thereafter. Between the ages of 40 to 50 years and >60 years, the incidence of CHIP increased from 0.04 to 0.18.
“CHIP, a common finding in the elderly population is an important factor to consider in ctDNA analysis and most frequently involves DNMT3A, TET2, and TP53 genes. The frequency of CHIP can be impacted by a number of other factors such as cytotoxic chemo- or radiotherapy,” Dr Wu and co-investigators wrote.—Hina M. Porcelli
Wu HT, Kalashnikova E, Mehta S, et al. Characterization of clonal hematopoiesis of indeterminate potential mutations from germline whole exome sequencing data. Presented at: the 2020 ASCO Annual Meeting; May 29-31, 2020. Abstract 1525.