The assessment of clonal hematopoiesis (CH) of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs), when combined with complete blood count parameters, may accurately predict the risk of developing myeloid malignancies as well as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is according to research findings published in Nature Medicine.
A priority in CH involves the detection of people who are at increased risk of developing specific hematologic malignancies.
“To that end, the genetic abnormalities identified in this study, which can easily be incorporated into next-generation sequencing assays, together with readily available peripheral blood count data, may enable screening and monitoring of individuals at high risk of developing malignancies,” wrote the study authors, led by Abhishek Niroula, MD.
Dr. Niroula, of the Broad Institute of the Massachusetts Institute of Technology and Harvard, and colleagues examined CHIP in 55,383 people and autosomal mCAs in 420,969 individuals who had no history of hematologic malignancies and were included in the U.K. Biobank (UKB) and Mass General Brigham Biobank.
Somatic variants were examined in myeloid and lymphoid driver genes with whole-exome sequence (WES) data comprising 46,706 unrelated people between ages 40 and 70 (median age = 58) who had no prior hematologic malignancy. A total of 236 genes that recurrently mutated in lymphoid malignancies were collated by the researchers.
The investigators identified 597 people in the WES data from the UKB who carried 617 variants (lymphoid CHIP). In an assessment of 56 genes known to drive myeloid malignancies and CHIP, the researchers found 2,708 individuals who carried 2,975 variants (myeloid CHIP).
While the prevalence of lymphoid CHIP was lower than that of myeloid CHIP, the prevalence of both increased with advancing age. The top three genes in myeloid CHIP that were mutated in 87% of individuals included DNMT3A, TET2, and ASXL1. In contrast, lymphoid CHIP variants were distributed evenly across several genes.
The investigators examined the associations between myeloid and lymphoid CHIP with incident myeloid and lymphoid malignancies that were diagnosed between six months and 12 years following biobank recruitment. During the median 10-year follow-up period, a total of 159 individuals were diagnosed with a myeloid malignancy, with a median time to diagnosis of 5.8 years. Additionally, 416 people were diagnosed with a lymphoid malignancy with a median time to diagnosis of 6.3 years. Myeloid CHIP was significantly associated with a higher incidence of myeloid malignancies (hazard ratio [HR] = 7.0; 95% CI 5.0-9.8; p<0.001), while lymphoid CHIP was significantly associated with a higher incidence of lymphoid malignancies (HR=4.2; 95% CI 2.7-6.7; p<0.001).
The researchers also assessed the risk of myeloid and lymphoid malignancies associated with autosomal mCAs using data for 400,452 UKB individuals. The association between mCAs and risk of incident hematologic malignancies over a median follow-up of 11.1 years was also assessed. During the follow-up period, 1,408 people were diagnosed with a myeloid malignancy (median time to diagnosis = 6.6 years), and 3,872 people were diagnosed with a lymphoid malignancy (median time to diagnosis = 6.3 years).
Myeloid mCA significantly increased the risk of myeloid malignancies (HR=28.9; 95% CI 24.2-34.4; p<0.001), while lymphoid mCA significantly increased the risk of lymphoid malignancies (HR=11.1; 95% CI 9.9-12.3; p<0.001). Additionally, ambiguous mCA increased the risk of both myeloid malignancies (HR=5.9; 95% CI 4.0-8.8; p<0.001) and lymphoid malignancies (HR=5.8; 95% CI 4.6-7.3; p<0.001).
Aberrant myeloid cell parameters, independent of CH, were also associated with a risk of myeloid malignancies, while increased lymphocyte count correlated with a risk of CLL/SLL. The investigators stratified the UKB cohort based on complete blood count (CBC) parameters, as well as type and number of genetic alterations and clone size to integrate CHIP and mCA with CBC parameters. The researchers found that in both lineages, abnormal CBC was associated with an increased risk of malignancies even without detected genetic alterations.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Niroula A, Sekar A, Murakami MA, et al. Distinction of lymphoid and myeloid clonal hematopoiesis [published online ahead of print, 2021 Oct 18]. Nat Med. doi:10.1038/s41591-021-01521-4.
