Year: 2025
Type: article
Study design: Observational Study
Abstract: NRAS and KRAS mutations, commonly identified alongside ancestral co-mutations, are generally regarded as pathogenic in adults presenting with monocytosis and/or cytopenia(s). However, their significance in isolation is not well defined. We studied a multi-institutional cohort of 52 patients with isolated RAS mutations and found that 26 (50%) did not meet diagnostic criteria for a myeloid neoplasm. Compared to patients with typical chronic myelomonocytic leukemia/myelodysplastic syndrome, these patients exhibited distinctive clinical features, including a younger age (65 years; range, 29-92 years), female predominance (60%), frequent immune-related disorders (39%), and splenomegaly (65%). Mutations predominantly involved KRAS (92%), with 87% affecting codons G12 or G13, and typically occurred at high variant allele frequency (39.0%; range, 2.6-53.0%). In three flow-sorted samples, KRAS/NRAS mutations were detected not only in granulocytes and monocytes but also in lymphocytes, reminiscent of pediatric RASopathies. A subset of patients (7/26, 27%) progressed to develop a myeloid malignancy, with acquisition of additional genetic alterations or the development of dysplasia. These findings challenge the assumption that isolated RAS mutations are sufficient to diagnose myeloid neoplasms. Instead, some cases may reflect adult-onset RASopathies or early clonal proliferations with distinct biological behavior. Recognition of such cases warrants refinement of diagnostic criteria and may influence therapeutic decision-making.
Source: Haematologica
Authors: Sa A. Wang, Chi Young Ok, Harrison K. Tsai, Naima Loayza, Parnaz Daneshpajouhnejad, Neha Seth, Miguel D. Cantu, Adam Bagg, Wayne Tam, Olga Weinberg, Paul D. Barone, Julia T. Geyer, Coleman R. Lindsley, Guillermo Montalban-Bravo, Cody R. Simon, Daniel A. Arber, Carlos E. Bueso-Ramos, Eric D. Hsi, Kathryn Foucar, Attilio Orazi, Mrinal M. Patnaik, Robert P. Hasserjian, Kaaren K. Reichard
Institutions: The University of Texas MD Anderson Cancer Center, Brigham and Women's Hospital, Hofstra University, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, University of Pennsylvania, The University of Texas Southwestern Medical Center, Weill Cornell Medicine, Weill Cornell Medical Center, Dana-Farber Cancer Institute, University of Chicago, Mayo Clinic, University of New Mexico, Texas Tech University, Massachusetts General Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,157
OpenAlex ID: W7117109332