Clonal hematopoiesis-related mutations appeared to be misinterpreted as solid tumors mutations when tumor-only sequencing was used for a variety of cancer types, according to results of a gene-sequencing study.
This misinterpretation could ultimately impact patient care and treatment, according to the researchers.
“To our knowledge, this is the largest report on clonal hematopoiesis-solid tumor based on a population of patients with advanced cancer,” Ahmet Zehir, PhD, bioinformatician and director of clinical bioinformatics at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “While a small fraction of patients are affected overall, we show that the prevalence of clonal hematopoiesis-solid tumor is higher in older patients and that tumor-only sequencing results should be evaluated carefully, especially if treatment decisions are based on the variant results.”
Next-generation sequencing of tumor samples is increasingly used to identify genomic alterations and guide treatment for patients. Patient-matched blood control samples are needed to distinguish between somatic and inherited variants, but challenges in implementation of next-generation sequencing have led to use of tumor-only assays.
Clonal hematopoiesis — the somatic acquisition of genomic alterations in hematopoietic stem or progenitor cells — leads to clonal expansion and is common among patients with cancer due to its association with aging, smoking and radiation therapy.
Clonal hematopoiesis also is associated with increased risk for therapy-related hematologic malignant neoplasms. Further, mutated genes in clonal hematopoiesis are commonly altered in hematological malignant neoplasms.
Reports of a common leukemia mutation — JAK2 V617F — found in solid tumors influenced researchers to evaluate whether high prevalence of clonal hematopoiesis in patients with solid tumors would confound tumor-only genomic profiling results due to the latency of leukocytes.
Zehir, Ryan N. Ptashkin, MS, a bioinformatician at Memorial Sloan Kettering Cancer Center, and colleagues analyzed targeted next-generation sequencing data of matched blood and tumor samples from 17,469 patients (mean age, 59.2 years; 53.6% women) with advanced solid malignant neoplasms previously sequenced via Memorial Sloan Kettering Cancer Center’s targeted tumor sequencing test, MSK-IMPACT, between January 2014 and August 2017.
A majority of patients had non-small cell lung (n = 2,621), breast (n = 2,505) or colorectal (n = 1,538) carcinomas.
Mutational analysis of hematopoietic cells identified 7,608 presumptive somatic, nonsilent mutations in 396 genes among 4,628 patients.
Researchers detected 1,075 clonal hematopoiesis mutations — mostly nonrecurrent — in solid tumors of 912 patients, with a median variant allele fraction of 0.04 (range, 0.02-0.21) in the solid tumor samples and 0.16 (range, 0.04-0.53) in the matched blood samples.
Incidence of clonal hematopoiesis solid tumor mutations increased with age (P < .001) and appeared most common among patients with nonmelanoma skin cancer, lung cancer and mesothelioma. DNMT3A, TET2 and PPM1D were the most commonly altered genes.
Among all clonal hematopoiesis mutations, 98.7% were not evident in the population scale databases of germline polymorphisms “and therefore would have been challenging to filter informatically,” the researchers wrote.
Researchers then annotated clonal hematopoiesis alterations in solid tumors with OncoKB — a knowledge base that identifies oncogenic alterations and ranks them as potentially actionable based on evidence supporting it as a predictive biomarker of drug sensitivity to FDA-approved or investigational therapies for a cancer type — and found 49.7% were oncogenic or likely oncogenic.
“As the application of next-generation sequencing technologies continues to expand in clinical settings, it is important to identify sources of potential discrepancies and misleading results,” researchers wrote. “While the use of population scale databases strengthened by cancer databases is a common method of identifying presumptive somatic mutations with tumor-only sequencing, it should be noted that different methodologies can differentially affect reporting and clinical decisions.” – by Melinda Stevens
Disclosures: The authors reports no relevant financial disclosures.