Cancer 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; Ossa, Juan Arango; Levine, Max F.; Martínez, Juan; Farnoud, Noushin; Glodzik, Dominik; Li, Sonya; Robson, Mark E.; 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.; Takahashi, 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:10.1038/s41588-020-00710-0

Cited by 484 publications

(507 citation statements)

References 53 publications

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“…Clinical annotations including age, gender, race, primary cancer diagnosis, length of follow-up, serial blood counts, and smoking history were available for most patients in the study. For 10,375 patients complete treatment data was previously collected 26 . The patients in this study had no record of hematologic malignancies within 3 months following sequencing (Methods).…”

Section: Resultsmentioning

confidence: 99%

“…10). For a subset of 10,375 patients whose complete clinical treatment history had been previously collected 26 , we explored the association of mCA with receipt of oncologic therapy. We found that mCA was positively associated with external beam radiation therapy (OR = 1.7, P = 0.022) but not cytotoxic chemotherapy (OR = 0.9, P = 0.56) ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It is likely that differences in exposures to oncologic therapies may partially account for the distinct mCA representation in different tumor types. However, the association between therapies and mCAs is likely to be heterogeneous 26 . Larger datasets with more complete treatment annotation are needed to fully assess the association between specific subclasses of therapy and specific types of mCAs.…”

Section: Resultsmentioning

confidence: 99%

“…To evaluate the relationship between mCAs and acquired gene mutations, we characterized gene mutations in our patient cohort using an established variant calling procedure from our previous studies 25,26 . A total of 14,789 mutations were detected in 9854 (30%) individuals across 457 genes captured in our clinical sequencing assay 28 ( Supplementary Fig.…”

Section: Global Characteristics Of Mcas In Relation To Gene Mutationsmentioning

confidence: 99%

“…Recent studies showed that solid tumor cancer patients have high rates of CH and are at an increased risk of secondary leukemias [25][26][27] . Here we seek to understand the relationship between mCAs, acquired gene mutations, and the incidence of hematological neoplasms in patients with cancer.…”

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

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Global Characteristics Of Mcas In Relation To Gene Mutationsmentioning

confidence: 99%

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confidence: 99%

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

et al. 2021

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Association of Diet Quality With Prevalence of Clonal Hematopoiesis and Adverse Cardiovascular Events

et al. 2021

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IMPORTANCE Clonal hematopoiesis of indeterminate potential (CHIP), the expansion of somatic leukemogenic variations in hematopoietic stem cells, has been associated with atherosclerotic cardiovascular disease. Because the inherited risk of developing CHIP is low, lifestyle elements such as dietary factors may be associated with the development and outcomes of CHIP. OBJECTIVE To examine whether there is an association between diet quality and the prevalence of CHIP. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study used data from participants in the UK Biobank, an ongoing population-based study in the United Kingdom that examines whole-exome sequencing data and survey-based information on health-associated behaviors. Individuals from the UK Biobank were recruited between 2006 and 2010 and followed up prospectively with linkage to health data records through May 2020. The present study included 44 111 participants in the UK Biobank who were age 40 to 70 years, had data available from whole-exome sequencing of blood DNA, and were free of coronary artery disease (CAD) or hematologic cancer at baseline. EXPOSURES Diet quality was categorized as unhealthy if the intake of healthy elements (fruits and vegetables) was lower than the median of all survey responses, and the intake of unhealthy elements (red meat, processed food, and added salt) was higher than the median. Diets were classified as healthy if the intake of healthy elements was higher than the median, and the intake of unhealthy elements was lower than the median. The presence of CHIP was detected by data from whole-exome sequencing of blood DNA. MAIN OUTCOMES AND MEASURESThe primary outcome was CHIP prevalence. Multivariable logistic regression analysis was used to examine the association between diet quality and the presence of CHIP. Multivariable Cox proportional hazards models were used to assess the association of incident events (acute coronary syndromes, coronary revascularization, or death) in each diet quality category stratified by the presence of CHIP. RESULTS Among 44 111 participants (mean [SD] age at time of blood sample collection, 56.3 [8.0] years; 24 507 women [55.6%]), 2271 individuals (5.1%) had an unhealthy diet, 38 552 individuals (87.4%) had an intermediate diet, and 3288 individuals (7.5%) had a healthy diet. A total of 2507 individuals (5.7%) had CHIP, and the prevalence of CHIP decreased as diet quality improved from unhealthy (162 of 2271 participants [7.1%]) to intermediate (2177 of 38 552 participants [5.7%]) to healthy (168 of 3288 participants [5.1%]; P = .003 for trend). Compared with individuals without CHIP who had an intermediate diet, the rates of incident cardiovascular events progressively decreased among those with CHIP who had an unhealthy diet (hazard ratio [HR], 1.52; 95% CI, 1.04-2.22) and those with CHIP who had a healthy diet (HR, 0.99; 95% CI, 0.62-1.58) over a median of 10.0 years (interquartile range, 9.6-10.4 years) of follow-up.CONCLUSIONS AND RELEVANCE This cohort study suggests that an unhealth...

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Clinical Importance of Clonal Hematopoiesis in Metastatic Gastrointestinal Tract Cancers

et al. 2023

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ImportanceClonal hematopoiesis (CH) has been associated with development of atherosclerosis and leukemia and worse survival among patients with cancer; however, the association with cancer therapy efficacy, in particular immune checkpoint blockade (ICB), and toxicity has not yet been established. Given the widespread use of ICB and the critical role hematopoietic stem cell–derived lymphocytes play in mediating antitumor responses, CH may be associated with therapeutic efficacy and hematologic toxicity.ObjectiveTo determine the association between CH and outcomes, hematologic toxicity, and therapeutic efficacy in patients with metastatic gastrointestinal tract cancers being treated with systemic therapy, both in the first-line metastatic treatment setting and in ICB.Design, Setting, and ParticipantsThis retrospective cohort study included 633 patients with stage IV colorectal (CRC) and esophagogastric (EGC) cancer who were treated with first-line chemotherapy and/or ICB at Memorial Sloan Kettering Cancer Center. Patients underwent matched tumor and peripheral blood DNA sequencing using the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing assay between January 1, 2006, and December 31, 2020.ExposuresClonal hematopoiesis–related genetic alterations were identified by next-generation sequencing of patients’ tumor and normal blood buffy coat samples, with a subset of these CH alterations annotated as likely putative drivers (CH-PD) based upon previously established criteria.Main Outcomes and MeasuresPatients with CH and CH-PD in peripheral blood samples were identified, and these findings were correlated with survival outcomes (progression-free survival [PFS] and overall survival [OS]) during first-line chemotherapy and ICB, as well as baseline white blood cell levels and the need for granulocyte colony-stimulating factor (G-CSF) support.ResultsAmong the 633 patients included in the study (390 men [61.6%]; median age, 58 [IQR, 48-66] years), the median age was 52 (IQR, 45-63) years in the CRC group and 61 (IQR, 53-69) years in the EGC group. In the CRC group, 161 of 301 patients (53.5%) were men, compared with 229 of 332 patients (69.0%) in the EGC group. Overall, 62 patients (9.8%) were Asian, 45 (7.1%) were Black or African American, 482 (76.1%) were White, and 44 (7.0%) were of unknown race or ethnicity. Presence of CH was identified in 115 patients with EGC (34.6%) and 83 with CRC (27.6%), with approximately half of these patients harboring CH-PD (CRC group, 44 of 83 [53.0%]; EGC group, 55 of 115 [47.8%]). Patients with EGC and CH-PD exhibited a significantly worse median OS of 16.0 (95% CI, 11.6-22.3) months compared with 21.6 (95% CI, 19.6-24.3) months for those without CH-PD (P = .01). For patients with CRC and EGC, CH and CH-PD were not associated with PFS differences in patients undergoing ICB or first-line chemotherapy. Neither CH nor CH-PD were correlated with baseline leukocyte levels or increased need for G-CSF support.Conclusions and RelevanceThese findings suggest CH and CH-PD are not directly associated with the treatment course of patients with metastatic gastrointestinal tract cancer receiving cancer-directed therapy.

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Cancer therapy shapes the fitness landscape of clonal hematopoiesis

Cited by 484 publications

References 53 publications

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

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

Association of Diet Quality With Prevalence of Clonal Hematopoiesis and Adverse Cardiovascular Events

Clinical Importance of Clonal Hematopoiesis in Metastatic Gastrointestinal Tract Cancers

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