Impact of radiotherapy site, modality, and dose on subsequent clonal hematopoiesis
Year: 2025
Type: article
Study design: Observational Study
Abstract: Clonal hematopoiesis (CH) is the clonal expansion of hematopoietic stem and progenitor cells harboring somatic mutations, and carries an increased risk of myeloid neoplasia and all-cause mortality.1 Exposure to cancer therapies, including radiotherapy (RT), can select and promote the expansion of CH clones, particularly those carrying mutations in DNA damage response (DDR) genes, including TP53. 2 Notably, TP53-mutant CH is the most common precursor to therapy-related myeloid neoplasms (tMNs) and understanding how RT affects CH can provide important insights into the relationship of RT with tMN risk.3 However, RT is not a uniform treatment modality and can be delivered with variable doses and techniques to distinct anatomic compartments.It remains unknown how these parameters affect CH and subsequent risk of tMN.Here, CH mutations were identified among patients who underwent targeted, deep-coverage sequencing from paired peripheral blood and solid tumor samples (MSK-IMPACT, ie, Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets) after receiving RT. 2 CH was defined as a somatic blood putative-driver mutation with a minimum variant allele frequency (VAF) of 2%, as previously described.2 Patients with active hematologic malignancy or a hematologic malignancy diagnosed within 3 years of sequencing were excluded from analysis.CH mutations in the DDR genes PPM1D, TP53, ATM, and CHEK2 were defined as DDR-CH.To confirm that mutation calls from blood samples did not reflect circulating tumor DNA, we examined the VAF of mutations in the blood relative to mutations from matched tumor sequencing.We defined somatic CH mutations as those identified in the blood with a VAF of ≥2 times that of the tumor or ≥1.5 if tumor biopsy was collected from a lymph node. 2 Clinical and RT characteristics were abstracted from medical records (Table 1).All patients received photon-based RT.To account for differences in RT dose and fractionation, equivalent radiation dose in 2 Gy fractions (EQD 2 ) was calculated with an α/β of 3 because we considered CH a late effect.We then used logistic regression adjusted for age, race, time from diagnosis to blood draw, smoking status, and chemotherapy class (cytotoxic, immune, or targeted therapies) to test for an association between RT parameters and CH.All analyses were conducted using R version 4.3.3.All patients had a tumor and blood sample (as a matched control) sequenced using MSK-IMPACT on an institutional prospective tumor-sequencing protocol (ClinicalTrials.govidentifier: NCT01775072) before 1 July 2019.This study was approved by the MSKCC institutional review board.A subset of patients underwent tumor genomic profiling as the standard of care and did not directly consent, in which case an institutional review board waiver was obtained to allow for inclusion into this study.
Source: Blood Advances
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W4413112167