Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis

Abstract

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7–22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6–33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.

Clonal hematopoiesis and its emerging effects on cellular therapies

“…In addition to genetic changes, malignant transformation is fueled by epigenetic modifications, such as altered expression patterns of genes involved in tumorigenesis like oncogenes and tumor-suppressor genes [10,11]. Signs of aging are further the increased frequency of other mutational events including larger chromosome breaks, that accumulate throughout the life span of a tissue, like hematopoiesis [12][13][14][15][16][17].…”

“…CH patients are described to be enriched in illnesses like hemophagocytic lymphohistiocytosis [58], severe COVID-19 [59], anti-neutrophil antibody-associated vasculitis [60], to name a few examples of the expanding list. Third, cytostatic therapy, but not immune checkpoint blockade, is a major risk factor for development of CH and shapes the mutational spectrum [15,[61][62][63]. Conversely, the presence of CH negatively impacts the prognosis of patients with solid cancers [62] and aggressive lymphomas [64] undergoing cytostatic therapy.…”

Germline risk of clonal haematopoiesis

“…An individual can have both mCAs and CHIP simultaneously, which occurs frequently with point mutations in JAK2 (a tyrosine kinase involved in multiple cytokine signalling pathways 28 ) and mCA events at the same locus 17 , 29 . However, aside from the JAK2 locus, the co-occurrence of CHIP and mCAs as identified by bulk sequencing/genotyping from the same individual appears to be a rare event 18 , 27 , although the prevalence is higher among patients treated for solid tumours 30 .…”

“…With respect to larger chromosomal abnormalities, epidemiological studies have demonstrated associations between the mLOY and a broad range of health outcomes in men, including all-cause mortality 15 , 21 , numerous types of cancer 11 , 14 , 21 , 33 , 38 – 40 , cardiovascular events 41 , Alzheimer disease 42 , schizophrenia 43 , autoimmune disease 44 , 45 , diabetes 15 and age-related macular degeneration 46 . Autosomal mCA events have been associated with an increased risk of haematological malignancies 17 , 18 , 26 , 30 as well as with all-cause mortality only partially explained by excess cancer deaths 9 . Additionally, even as mCAs are independently associated with a heightened risk of myeloid malignancies, a retrospective analysis of patients with solid tumours found relatively increased rates of haematological malignancies in patients with both mCAs and CHIP compared to those with either alone 30 .…”

“…Autosomal mCA events have been associated with an increased risk of haematological malignancies 17 , 18 , 26 , 30 as well as with all-cause mortality only partially explained by excess cancer deaths 9 . Additionally, even as mCAs are independently associated with a heightened risk of myeloid malignancies, a retrospective analysis of patients with solid tumours found relatively increased rates of haematological malignancies in patients with both mCAs and CHIP compared to those with either alone 30 . Whether the presence of dual mCAs/CHIP is an indicator of individuals with particularly unstable genomes or whether the combination of these lesions cooperatively leads to malignancy risk remains to be determined.…”