Clonal hematopoiesis in individuals with ANKRD26 or ETV6 germline mutations

Abstract

Currently, there are at least a dozen recognized hereditary hematopoietic malignancies (HHMs), some of which phenocopy others. Among these, three HHMs driven by germline mutations in ANKRD26, ETV6, or RUNX1 share a phenotype of thrombocytopenia, qualitative platelet defects, and an increased lifetime risk of hematopoietic malignancies (HMs). Prior work has demonstrated that RUNX1 germline mutation carriers experience an elevated lifetime risk (66%) for developing clonal hematopoiesis (CH) prior to age 50. Germline mutations in ANKRD26 or ETV6 phenocopy RUNX1 germline mutations, but no studies have focused on the risk of CH in individuals with germline mutations in ANKRD26 or ETV6.To determine the prevalence of CH in individuals with germline mutations in ANKRD26 or ETV6, we performed next generation sequencing on hematopoietic tissue from twelve individuals with either germline ANKRD26 or germline ETV6 mutations. Each patient had thrombocytopenia but had not developed HMs. Among the seven individuals with germline ANKRD26 mutations, one patient had a CH clone driven by a somatic SF3B1 mutation (p.Lys700Glu). This mutation increased from a variant allele frequency (VAF) of 9.4% at age 56 to 17.4% at age 60. None of the germline ETV6 mutation carriers had evidence of CH at the limits of detection of the NGS assay (5% VAF). Unlike individuals with germline mutations in RUNX1, no individuals under the age of 50 with germline mutations in ANKRD26 or ETV6 had detectable CH. This work demonstrates that ANKRD26 germline mutation carriers, but not ETV6 mutation carriers, experience elevated risk for CH.

Stagnation in quality of next-generation sequencing assays for the diagnosis of hereditary hematopoietic malignancies

“…Sequencing non-germline tissue, particularly from patients with active hematopoietic malignancies, increases the risk for false positive HHM test results, as NGS assays may detect both somatic mutations in residual tumor tissue or clonal hematopoiesis-related mutations. 2,[6][7][8][9] It is unclear how the landscape of HHM diagnostic testing has changed since we performed our original analysis of commercial testing practices in 2020. 5 We identified all commercial diagnostic companies that offered NGS panels intended for HHM diagnosis in January 2022 to address this knowledge gap.…”