RT Journal Article
SR Electronic
T1 Clonal hematopoiesis in individuals with <em>ANKRD26</em> or <em>ETV6</em> germline mutations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.17.468983
DO 10.1101/2021.11.17.468983
A1 Michael W. Drazer
A1 Claire C. Homan
A1 Kai Yu
A1 Marcela Cavalcante de Andrade Silva
A1 Kelsey E. McNeely
A1 Matthew J. Pozsgai
A1 Maria G. Acevedo
A1 Jeremy P. Segal
A1 Peng Wang
A1 Jinghua Feng
A1 Sarah L. King-Smith
A1 Erika Kim
A1 Sophia C. Korotev
A1 David M. Lawrence
A1 Andreas W. Schreiber
A1 Christopher N. Hahn
A1 Hamish S. Scott
A1 Raman Sood
A1 NISC Comparative Sequencing Program
A1 Elvira D R P Velloso
A1 Anna L. Brown
A1 Paul P. Liu
A1 Lucy A. Godley
YR 2021
UL http://biorxiv.org/content/early/2021/11/22/2021.11.17.468983.abstract
AB 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.Competing Interest StatementMWD has received consulting fees from Cardinal Health. HSS has received honoraria from Celgene. LAG receives royalties from a coauthored article on inherited hematopoietic malignancies in UpToDate, Inc.