| Title: | Prediction of risk for myeloid malignancy in clonal hematopoiesis. |
| Journal: | NEJM Evidence |
| Published: | 25 Apr 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37483562/ |
| DOI: | https://doi.org/10.1056/evidoa2200310 |
| URL: | https://evidence.nejm.org/doi/pdf/10.1056/EVIDoa2200310 |
Publication 11380
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Background: Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) ≥ 0.02, in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults and defining predictors of MN risk would aid clinical management and research.</p>
Methods: We analyzed sequenced exomes of healthy UK Biobank (UKB) participants (n = 438,890) in separate derivation and validation cohorts. Genetic mutations, laboratory values, and MN outcomes were used in conditional probability-based recursive partitioning and Cox regression to determine predictors of incident MN. Combined statistical weights defined a clonal hematopoiesis risk score (CHRS). Independent CHIP/CCUS patient cohorts were used to test prognostic capability of the CHRS in the clinical setting.</p>
Results: Recursive partitioning distinguished CHIP/CCUS cases with 10-year probabilities of MN ranging from 0.0078 - 0.85. Multivariable analysis validated partitioning variables as predictors of MN. Key features, including single DNMT3A mutations, high risk mutations, ≥ 2 mutations, VAF ≥ 0.2, age ≥ 65 years, CCUS vs CHIP and red blood cell indices, influenced MN risk in variable direction. The CHRS defined low risk (n = 10018, 88.4%), intermediate risk (n = 1196, 10.5%), and high risk (n = 123, 1.1%) groups. In clinical cohorts, most MN events occurred in high risk CHIP/CCUS patients.</p>
Conclusions: The CHRS provides simple prognostic framework for CHIP/CCUS, distinguishing a high risk minority from the majority of CHIP/CCUS which has minimal risk for progression to MN.</p>
19 Authors
- Lachelle D Weeks
- Abhishek Niroula
- Donna Neuberg
- Waihay Wong
- R Coleman Lindsley
- Marlise Luskin
- Nancy Berliner
- Richard M Stone
- Daniel J DeAngelo
- Robert Soiffer
- Md Mesbah Uddin
- Gabriel Griffin
- Caitlyn Vlasschaert
- Christopher J Gibson
- Siddhartha Jaiswal
- Alexander G Bick
- Luca Malcovati
- Pradeep Natarajan
- Benjamin L Ebert
1 Application
| Application ID | Title |
|---|---|
| 50834 | Identifying the regulators of clonal hematopoiesis of indeterminate potential (CHIP) |
Enabling scientific discoveries that improve human health