Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study

Gillis, Nancy; Ball, Markus; Zhang, Qing; Ma, Zhenjun; Zhao, Yi‐Fang; Yoder, Sean; Balasis, Maria E.; Mesa, Tania; Sallman, David A.; Lancet, Jeffrey E.; Komrokji, Rami; List, Alan F.; McLeod, Howard L.; Alsina, Melissa; Baz, Rachid; Shain, Kenneth H.; Rollison, Dana E.; Padron, Eric

doi:10.1016/s1470-2045(16)30627-1

Cited by 253 publications

(220 citation statements)

References 27 publications

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“…One murine model of TET2-deficient clonal hematopoiesis implicates macrophage TET2 deficiency in accelerated atherogenesis and CVD, 16,44 whereas another recent case control analysis revealed higher rates of atherosclerotic heart disease associated with mutations in DNMT3A, TET2, ASXL1, and JAK2 among CHIP patients. 15 Although clonal hematopoiesis does not always result in a clinical presentation of MDS, 8,11,12 our data showing a steadily increasing incidence of cardiovascular and cerebrovascular events from the time of MDS diagnosis may suggest a common underlying pathophysiology. Although the SEER database does not contain comprehensive molecular data, we noted that among patients with RARS, which is enriched for SF3B1 mutations and characterized by slower rates of progression, the proportion of deaths attributed to MDS was relatively steady with time, whereas the proportion of deaths attributed to CVD increased as patients lived longer from their time of diagnosis.…”

Section: Cumulative Incidence (%)mentioning

confidence: 77%

“…This association has been characterized as clonal hematopoiesis of indeterminate potential (CHIP). [8][9][10] Patients with CHIP have an increased risk of developing a hematologic malignancy (rate of progression 0.5-1%/year), [11][12][13][14] but they also have an increased risk of fatal cardiovascular events and all-cause mortality for unclear reasons. 13 CHIP patients appear to specifically have an increased risk of atherosclerotic heart disease.…”

Section: Introductionmentioning

confidence: 99%

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Risk and timing of cardiovascular death among patients with myelodysplastic syndromes

Brunner

Blonquist²,

Hobbs

et al. 2017

Blood Advances

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Section: Cumulative Incidence (%)mentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Risk and timing of cardiovascular death among patients with myelodysplastic syndromes

Brunner

Blonquist²,

Hobbs

et al. 2017

Blood Advances

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“…Indeed, CHIP mutations are primarily found in elderly (otherwise) healthy individuals. Therefore, CHIP has also been termed age-related clonal hematopoiesis [15-19, 42-44]. …”

Section: Clonal Hematopoiesis Of Indeterminate (Clinical) Potentialmentioning

confidence: 99%

ICUS, IDUS, CHIP and CCUS: Diagnostic Criteria, Separation from MDS and Clinical Implications

Valent

2018

Pathobiology

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Various myeloid neoplasms, including the myelodysplastic syndromes (MDS), bear a certain risk of progression to secondary acute myeloid leukemia (sAML). The evolution from low-risk to high-risk MDS and finally to sAML suggests that leukemogenesis is a multistep process. However, even before an overt neoplasm, such as an MDS, develops, “prediagnostic” clonal conditions may be identified. With the advent of large-scale genomic screens, such conditions may be detected quite frequently and early in apparently healthy individuals. Recent data suggest that these conditions increase with age and are indeed associated with an increased risk of the occurrence of MDS or another myeloid neoplasm. In other patients, unexplained cytopenia may be detected and may precede MDS. More recently, diagnostic criteria for potential pre-MDS conditions, including idiopathic cytopenia of uncertain significance and clonal hematopoiesis with indeterminate potential, have been proposed. The current article provides an overview of pre-MDS states and related criteria through which these conditions can be discriminated from each other and from MDS. In addition, the clinical implications and management of pre-MDS states are discussed.

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“…13 However, recent evidence from our studies and others has revealed that t-MN driver mutations preexist as CHIP before patients are exposed to chemotherapy/radiation therapy. [4][5][6] The current data provide additional evidence that t-MN-associated CNAs can also preexist as CHIP. In 1 patient (UID984) who did not have a detectable point mutations in known leukemia driver genes in the t-MN sample, CNAs were the only abnormalities detected as CHIP.…”

Section: Discussionmentioning

confidence: 52%

“…[4][5][6] We showed that CHIP can be detected in 70% of patients with cancer who subsequently developed t-MNs and that CHIP is an independent risk factor for t-MNs. 4 Chromosome-arm level structural variations (SVs) or copy number alterations (CNAs) have also been reported as clonal mosaicism in the blood of healthy adults, and detection of these abnormalities has been linked to an increased risk of hematologic malignancy.…”

Section: Introductionmentioning

confidence: 90%

Copy number alterations detected as clonal hematopoiesis of indeterminate potential

Takahashi

Wang

Kantarjian³

et al. 2017

Blood Advances

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Key Points• CNAs can be detected as part of CHIP.Recent studies have revealed that clonal hematopoiesis of indeterminate potential (CHIP) is an important risk factor for therapy-related myeloid neoplasms (t-MNs). CHIP is currently defined as a clonal hematopoietic population carrying somatic point mutations in 1 of the leukemia-associated genes. Patients with t-MNs often present with chromosomal abnormalities in addition to somatic point mutations. It remains unclear whether chromosomal abnormalities can cooccur with point mutations as part of CHIP. Here we report that 3 of 14 patients with t-MNs had low amplitude but detectable chromosome arm-level copy number alterations (CNAs) in the peripheral blood samples that were taken at the time of their primary cancer diagnosis and before exposure to therapy. These CNAs were the same CNAs seen in t-MN bone marrow samples and affected the same allele, suggesting the same clonal origin. These data suggest that not only somatic point mutations but also chromosome armlevel CNAs are detectable as CHIP and preexist before patients' exposure to chemotherapy and/or radiation therapy. These data suggest that screening of both somatic point mutations and CNAs might allow more complete ascertainment of CHIP.

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Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study

Abstract: Moffitt Cancer Center.

Cited by 253 publications

References 27 publications

Risk and timing of cardiovascular death among patients with myelodysplastic syndromes

Risk and timing of cardiovascular death among patients with myelodysplastic syndromes

ICUS, IDUS, CHIP and CCUS: Diagnostic Criteria, Separation from MDS and Clinical Implications

Copy number alterations detected as clonal hematopoiesis of indeterminate potential

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