Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence

Abstract

BACKGROUND Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent. METHODS We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling. RESULTS Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow–biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones. CONCLUSIONS Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.)

Detection of leukemia-associated mutations in peripheral blood DNA of hematologically normal elderly individuals

“…Such variants are typically present in a proportion of peripheral blood cells at a specific time-point but their frequency can increase or decrease over time and even disappear, suggesting a dynamic pattern of clonal change 1 . Consistent with this data, mutations in genes that are often mutated in myeloid malignancy such as TET2, DNMT3A, ASXL1 and JAK2 have also been described in elderly individuals with no evidence of hematological malignancy [5][6][7][8] . Increasing age is accompanied by changes to the hematopoietic stem cell (HSC) compartment, a process known as myeloid shift, with a bias towards the myeloid lineage at the expense of the lymphoid lineage 9 .…”

Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified

“…On the other hand, somatic mutations in genes associated with myeloid neoplasms (such as DNMT3A, TET2, JAK2, ASXL1, TP53, GNAS, PPM1D, BCORL1, and SF3B1) have been frequently found in aging healthy individuals. [10][11][12]29 MDS-associated somatic mutations and clonal hematopoiesis have been recently reported in near half of patients with aplastic anemia, 30 as well as in patients with idiopathic cytopenias of undetermined significance. 29,31 In the latter, variant allele fractions were comparable with MDS.…”

“…However, this approach has been complicated by reports of frequent somatic mutations in healthy populations of older individuals. [10][11][12] The aim of this multicenter study was to molecularly characterize the cases of idiopathic hypereosinophilic syndrome, and compare them with chronic eosinophilic leukemia, not otherwise specified, as defined by the current World Health Organization criteria. Specifically, we sought to determine whether mutation data would provide clinically meaningful information in these two entities.…”

Aspects moléculaires des lymphomes T périphériques (1)

“…Ils suggèrent en effet que des altérations moléculaires importantes pour la transformation surviennent précocement, probablement au niveau d'une cellule souche hématopoïétique. Ce modèle est également proposé dans les hémopathies myéloïdes [85][86][87][88], et d'autres tumeurs lymphoïdes matures, comme la leucémie à tricholeucocytes [89], la leucémie chronique lymphoïde [90,91] et la leucémie/ lymphome T de l'adulte HTLV1 + [92][93][94] qui semblent suivre un schéma similaire. À l'ère des thérapies ciblées (Tableau V), il est indispensable de revoir les stratégies thérapeutiques utilisées avec un LAGC ALK -systémique [76].…”