Lineage-Specific Clonal Hematopoiesis Predicts Hematologic Malignancy

Clonal expansion of blood cells, known as clonal hematopoiesis, results from somatic mutations in blood cells and can occur in healthy individuals, with prevalence increasing with age. Clonal hematopoiesis with indeterminate potential (CHIP) refers to when alterations arise in genes recurrently mutated in hematologic malignancies. Previous CHIP studies have focused on variants in genes mutated in myeloid malignancies, reporting an association between CHIP and risk of these diseases. To explore whether clonal hematopoiesis can also contribute to risk of lymphoid malignancies, Niroula and colleagues analyzed somatic variants in myeloid and lymphoid driver genes in whole-exome sequencing data of individuals in the UK Biobank (UKB) ages 40 to 70 years with no previous hematologic malignancy (n = 46,706), defining a list of genes recurrently mutated in lymphoid malignancies (L-CHIP) and a list of genes known to drive CHIP and myeloid malignancies (M-CHIP). L-CHIP was associated with higher incidence of lymphoid malignancies diagnosed between 6 months and 12 years following initial recruitment into the UKB, whereas M-CHIP was associated with higher incidence of myeloid malignancies, revealing a distinct lineage specificity. Given that mosaic chromosomal alterations (mCA) have been associated with risk of lymphoid malignancies, mCAs identified from the SNP-array intensity data from the UKB (n = 400,452) were analyzed to determine whether myeloid- and lymphoid-specific mCAs were similarly associated with risk of lineage-specific malignancies. Indeed, myeloid mCAs increased risk of myeloid malignancies, whereas lymphoid mCAs increased risk of lymphoid malignancies. Moreover, specific types of clonal hematopoiesis were associated with subtypes of myeloid and lymphoid malignancies, with L-CHIP and lymphoid mCAs strongly connected with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). Notably, incorporating the presence of abnormal peripheral blood counts with the presence of lineage-specific CHIP and mCAs increased power to predict risk of developing myeloid malignancies and CLL/SLL. In summary, this work highlights the potential clinical utility of integrating analysis of genetic alterations and peripheral blood counts to identify individuals at risk of developing specific hematologic malignancies.

Niroula A, Sekar A, Murakami MA, Trinder M, Agrawal M, Wong WJ, et al. Distinction of lymphoid and myeloid clonal hematopoiesis. Nat Med 2021;27:1921–7.

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