Oncologic therapy shapes the fitness landscape of clonal hematopoiesis

Bolton, Kelly L.; Ptashkin, Ryan; Gao, Teng; Braunstein, Lior Z.; Devlin, Sean M.; Kelly, Daniel; Patel, Minal; Berthon, Antonin; Syed, Aijazuddin; Yabe, Mariko; Coombs, Catherine C.; Caltabellotta, Nicole M.; Walsh, Meghara; Offit, Kenneth; Stadler, Zsofia K.; Mandelker, Diana; Schulman, Jessica; Patel, Akshar; Philip, John; Bernard, Elsa; Gundem, Gunes; Arango, Juan E.; Levine, Max F.; Medina, Juan; Farnoud, Noushin; Glodzik, Dominik; Li, Sonya; Robson, M.; Lee, Choonsik; Pharoah, Paul D.P.; Stopsack, Konrad H.; Spitzer, Barbara; Mantha, Simon; Fagin, James A.; Boucai, Laura; Gibson, Christopher J.; Ebert, Benjamin L.; Young, Andrew L.; Druley, Todd E.; Takahasi, Koichi; Gillis, Nancy; Ball, Markus; Padron, Eric; Hyman, David M.; Baselga, J.; Norton, Larry; Gardos, Stuart; Klimek, Virginia M.; Scher, Howard I.; Bajorin, Dean F.; Paraiso, Eder; Benayed, Ryma; Arcila, Maria E.; Ladanyi, Marc; Solit, David B.; Berger, Michael F.; Tallman, Martin S.; García‐Closas, Montserrat; Chatterjee, Nilanjan; Díaz, Luis A.; Levine, Ross L.; Morton, Lindsay M.; Zehir, Ahmet; Papaemmanuil, Elli

doi:10.1101/848739

Cited by 18 publications

(61 citation statements)

References 47 publications

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“…3a,b). As previously reported 17 , across patients in the metastasis cohort, we found that the emergence of CH is positively influenced by age and by the exposure to cytotoxic (but not non-cytotoxic) treatments (Fig. 3a).…”

Section: Resultssupporting

confidence: 83%

“…Only CBL, NRAS, and KRAS appear below the statistical power of the IntOGen pipeline in these two cohorts. Nevertheless, all known CH drivers are identified when signals of positive selection are probed across 24,146 targeted-sequenced paired blood/tumor samples 17,49 (targeted cohort) in which a mutation calling filtering variants in common with the tumor sample has been carried out (Fig. 2c; Supp.…”

Section: Resultsmentioning

confidence: 99%

“…Note). Other genes with signals of positive selection, like ATM and CHEK2 are known to drive myeloid malignancies 17 . A third group of genes, such as CUX1 (mentioned in several studies as possibly related to CH) 13,21 , ABL2, FOXP1 or TP63 while known cancer drivers 50 , have not been previously proved to be involved in CH.…”

Section: Resultsmentioning

confidence: 99%

“…One stepping stone in this path is the identification of all genes with mutations capable of driving CH. Moreover, the identification of all CH-related genes is a requisite to understand the mechanisms behind this process and its relationship with disease conditions, as has been done for mutations affecting chromatin remodelling and DNA damage response genes classically associated with the condition 2,16,17,51 . In this regard, the discovery of CH-related genes across populations of various ethnicities and with different lifestyles, will allow us to understand the different constraints faced by hematopoietic cells in their evolution and the outcome of each of them.…”

Section: Discussionmentioning

confidence: 99%

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Discovering the drivers of clonal hematopoiesis

Pich

Reyes-Salazar

González-Pérez

et al. 2020

Preprint

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Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify cancer genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch. This approach recovers all known CH genes, and discovers novel candidates. Generating this compendium is an essential step to understand the molecular mechanisms of CH and to accurately detect individuals with CH to ascertain their risk to develop related diseases.

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Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Discovering the drivers of clonal hematopoiesis

Pich

Reyes-Salazar

González-Pérez

et al. 2020

Preprint

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“…Since the combination of clonal hematopoiesis and cytotoxic therapy is a probable major factor in the pathogenesis of t-AML, the incentives should be strong to screen for high-risk mutations in cancer patients about to start chemotherapy [97,111], or to screen cancer patients post treatment as surveillance [192,193]. Including inherited risk-alleles in these gene panels could also be of value to detect unnoticed syndromes at high risk for inherited AML [20].…”

Section: Screening For Preleukemic Mutations?mentioning

confidence: 99%

Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting

Nilsson

Hulegårdh

Garelius

et al. 2019

Biology of Blood and Marrow Transplantation

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Secondary acute myeloid leukemia (s-AML) refers to patients with either therapy-related AML (t-AML), that is, AML after treatment with chemo-and/or radiation for a prior disease, or AML progressing from an antecedent hematologic disorder (AHD-AML), typically a myelodysplastic syndrome (MDS) or a myeloproliferative neoplasm. Patients with s-AML present with higher rates of adverse cytogenetic aberrations and higher frequencies of adverse mutations and, subsequently, respond worse to therapy, and have poorer outcome compared to de novo AML. To identify clinical and molecular factors that may improve prognostication is therefore of importance to guide clinical decision-making. The general aim of this thesis was to broaden the real-world knowledge of s-AML, regarding disease properties and outcome, using population-based registries, and additionally to investigate the importance of mutations in the transformation from MDS to AML. The research papers presented herein cover mutational screening in MDS and s-AML (study I), general characteristics and outcome of s-AML (study II), the role of allogeneic hematopoietic cell transplantation (HCT) in patients with s-AML (study III), and the epidemiology and treatment outcome specifically for t-AML (study IV). långtidsöverlevare utan transplantation. Att genomgå transplantation i s.k. första remission var överlägset behandling med enbart cytostatika. Studie IV fokuserade på patienter med terapirelaterad AML. Data från svenska AMLregistret på 686 patienter kombinerades med data från Socialstyrelsens cancerregister och Svensk Reumatologis Kvalitetsregister. Huvudsakliga fynd var att incidensen av t-AML tydligt ökar över tid och att andelen terapirelaterad AML av AML-fallen totalt blev allt större. Överlevnaden vid terapirelaterad AML var generellt mycket dyster, men i vissa genetiska undergrupper var den bättre och jämförbar med patienter med motsvarande genetisk riskprofil som nyinsjuknat i AML. Sammanfattningsvis är sekundär-AML en ovanlig sjukdom som är mycket svårbehandlad. Nya läkemedel kommer att krävas för att förbättra överlevnaden, men förhoppningsvis kommer sådana att utvecklas hand i hand med den ökade förståelsen av sjukdomsbiologin. Behandlingen av AML har i stort sett varit oförändrad i årtionden, men nyligen har läkemedel som bl.a. utnyttjar specifika genetiska avvikelser introducerats. Inom andra cancerformer har immun-och cellterapi fått stort genomslag och dessa är potentiellt användbara även mot AML. För gruppen med sekundär-AML är det därför av stor betydelse att sjukdomshistorik, hög ålder och samsjuklighet inte utgör hinder för deltagande i kommande läkemedelsstudier. LIST OF SCIENTIFIC PAPERS I. High-throughput mutational screening adds clinically important information in myelodysplastic syndromes and secondary or therapy-related acute myeloid leukemia.

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A novel method for rapid estimation of active bone marrow dose for radiotherapy patients in epidemiological studies

Yeom,

Braunstein,

Morton

et al. 2024

Medical Physics

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BackgroundIn a dedicated effort to improve the assessment of clonal hematopoiesis (CH) and study leukemia risk following radiotherapy, we are developing a large‐scale cohort study among cancer patients who received radiation. To that end, it will be critical to analyze dosimetric parameters of red bone marrow (ABM) exposure in relation to CH and its progression to myeloid neoplasms, requiring reconstruction method for ABM doses of a large‐scale patients rapidly and accurately.PurposeTo support a large‐scale cohort study on the assessment of clonal hematopoiesis and leukemia risk following radiotherapy, we present a new method for the rapid reconstruction of ABM doses of radiotherapy among cancer patients.MethodsThe key idea of the presented method is to segment patient bones rapidly and automatically by matching a whole‐body computational human phantom, in which the skeletal system is divided into 34 bone sites, to patient CT images via 3D skeletal registration. The automatic approach was used to segment site‐specific bones for 40 radiotherapy patients. Also, we segmented the bones manually. The bones segmented both manually and automatically were then combined with the patient dose matrix calculated by the treatment planning system (TPS) to derive patient ABM dose. We evaluated the performance of the automatic method in geometric and dosimetric accuracy by comparison with the manual approach.ResultsThe pelvis showed the best geometric performance [volume overlap fraction (VOF): 52% (mean) with 23% (σ) and average distance (AD): 0.8 cm (mean) with 0.5 cm (σ)]. The pelvis also showed the best dosimetry performance [absorbed dose difference (ADD): 0.7 Gy (mean) with 1.0 Gy (σ)]. Some bones showed unsatisfactory performances such as the cervical vertebrae [ADD: 5.2 Gy (mean) with 10.8 Gy (σ)]. This impact on the total ABM dose, however, was not significant. An excellent agreement for the total ABM dose was indeed observed [ADD: 0.4 Gy (mean) with 0.4 Gy (σ)]. The computation time required for dose calculation using our method was robust (about one minute per patient).ConclusionsWe confirmed that our method estimates ABM doses across treatment sites accurately, while providing high computational efficiency. The method will be used to reconstruct patient‐specific ABM doses for dose‐response assessment in a large cohort study. The method can also be applied to prospective dose calculation within a clinical TPS to support clinical decision making at the point of care.

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Oncologic therapy shapes the fitness landscape of clonal hematopoiesis

Cited by 18 publications

References 47 publications

Discovering the drivers of clonal hematopoiesis

Discovering the drivers of clonal hematopoiesis

Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting

A novel method for rapid estimation of active bone marrow dose for radiotherapy patients in epidemiological studies

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