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Article: What Clonal Hematopoiesis Can Teach Us About MDS.

Chan, Irenaeus C C / Wiley, Brian J / Bolton, Kelly L

2022 Volume 12, Page(s) 794021

Abstract: Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs), is a common aging process. CH is a risk factor for the development of hematologic malignancies, most commonly myeloid neoplasms (MNs) ... ...

Abstract	Clonal hematopoiesis (CH), defined as the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs), is a common aging process. CH is a risk factor for the development of hematologic malignancies, most commonly myeloid neoplasms (MNs) including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasm (MPN). Recent work has elucidated how the development and cellular fitness of CH is shaped by aging, environmental exposures, and the germline (inherited) genetic background of an individual. This in turn has provided valuable insights into the pathogenesis of MNs including MDS. Here, in this review, we discuss the genetic origins of CH, the environmental stressors that influence CH, and the implications of CH on health outcomes including MDS. Since MNs have shared risk factors and underlying biology, most of our discussion regarding the implications of CH surrounds MN in general rather than focusing specifically on MDS. We conclude with future directions and areas of investigation including how intervention studies of CH might inform future therapeutic approaches to MN including MDS.
Language	English
Publishing date	2022-02-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.794021
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Article ; Online: Plasma Proteomic Signature Predicts Myeloid Neoplasm Risk.

Tran, Duc / Beeler, J Scott / Liu, Jie / Wiley, Brian / Chan, Irenaeus C C / Xin, Zilan / Kramer, Michael H / Batchi-Bouyou, Armel L / Zong, Xiaoyu / Walter, Matthew J / Petrone, Giulia E M / Chlamydas, Sarantis / Ferraro, Francesca / Oh, Stephen T / Link, Daniel C / Busby, Ben / Cao, Yin / Bolton, Kelly L

Clinical cancer research : an official journal of the American Association for Cancer Research

2024

Abstract: Purpose: Clonal hematopoiesis (CH) is thought to be the origin of myeloid neoplasms (MN). Yet our understanding of the mechanisms driving CH progression to MN and clinical risk prediction of MN remains limited. The human proteome reflects complex ... ...

Abstract	Purpose: Clonal hematopoiesis (CH) is thought to be the origin of myeloid neoplasms (MN). Yet our understanding of the mechanisms driving CH progression to MN and clinical risk prediction of MN remains limited. The human proteome reflects complex interactions between genetic and epigenetic regulation of biological systems. We hypothesized that the plasma proteome might predict MN risk and inform our understanding of the mechanisms promoting MN development. Experimental design: We jointly characterized CH and plasma proteomic profiles of 46,237 individuals in the UK Biobank at baseline study entry. During 500,036 person-years of follow-up, 115 individuals developed MN. Cox proportional hazard regression was used to test for an association between plasma protein levels and MN risk. Results: We identified 115 proteins associated with MN risk of which 30% (N=34) were also associated with CH. These were enriched for known regulators of the innate and adaptive immune system. Plasma proteomics improved the prediction of MN risk (AUC=0.85, p=5×10-9) beyond clinical factors and CH (AUC=0.80). In an independent group (N=381,485), we used inherited polygenic risk scores (PRS) for plasma protein levels to validate the relevance of these proteins to MN development. PRS analyses suggest that most MN-associated proteins we identified are not directly causally linked to MN risk, but rather represent downstream markers of pathways regulating the progression of CH to MN. Conclusions: These data highlight the role of immune cell regulation in the progression of CH to MN and the promise of leveraging multi-omic characterization of CH to improve MN risk stratification.
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-3468
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Article ; Online: Effect of Clonal Hematopoiesis on Cardiovascular Disease in People Living with HIV.

Wiley, Brian / Parsons, Tyler M / Burkart, Samantha / Young, Andrew L / Erlandson, Kristine M / Tassiopoulos, Katherine K / Wu, Kunling / Gurnett, Christina / Presti, Rachel M / Bolton, Kelly L / Challen, Grant A

Experimental hematology

2022 Volume 114, Page(s) 18–21

Abstract: Hematopoietic stem cells (HSCs) with age-associated somatic mutations that disproportionally contribute to hematopoiesis generate the condition known as clonal hematopoiesis (CH). While CH conveys increased risk of hematologic cancer, there is also ... ...

Abstract	Hematopoietic stem cells (HSCs) with age-associated somatic mutations that disproportionally contribute to hematopoiesis generate the condition known as clonal hematopoiesis (CH). While CH conveys increased risk of hematologic cancer, there is also strong association between CH and cardiovascular disease (CVD). Accumulating evidence suggests that inflammation mechanistically links CH to CVD, and we hypothesized that CH may be a predictive biomarker of CVD in conditions of chronic inflammation. One such patient population comprises people living with HIV (PLWH) who also have substantially increased incidences of CVD and CH . We studied the association between CH and CVD in PLWH using samples from ACTG Study A5001 (or ALLRT), a prospective clinical trial of HIV-infected persons with long-term follow-up. We observed a positive association between CH and CVD in PLWH independent of traditional CVD risk factors. Moreover, in CVD cases, the CH clone was identifiable in the blood years before CVD diagnosis, unlike in PLWH with CH who did not have CVD. With the life span of PLWH increasing because of advances in treatment, our results indicate that the presence of CH and its clonal dynamics could be used as a prognostic biomarker of the risk for CVD in PLWH.
MeSH term(s)	Biomarkers ; Cardiovascular Diseases/etiology ; Cardiovascular Diseases/genetics ; Clonal Hematopoiesis/genetics ; HIV Infections/complications ; HIV Infections/epidemiology ; HIV Infections/genetics ; Hematopoiesis/genetics ; Humans ; Inflammation ; Mutation ; Prospective Studies
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-08-06
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	185107-x
ISSN	1873-2399 ; 0531-5573 ; 0301-472X
ISSN (online)	1873-2399
ISSN	0531-5573 ; 0301-472X
DOI	10.1016/j.exphem.2022.07.304
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Zs.A 922: Show issues

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Article ; Online: ArCH: improving the performance of clonal hematopoiesis variant calling and interpretation.

Chan, Irenaeus C C / Panchot, Alex / Schmidt, Evelyn / McNulty, Samantha / Wiley, Brian J / Liu, Jie / Turner, Kimberly / Moukarzel, Lea / Wong, Wendy S W / Tran, Duc / Beeler, J Scott / Batchi-Bouyou, Armel Landry / Machiela, Mitchell J / Karyadi, Danielle M / Krajacich, Benjamin J / Zhao, Junhua / Kruglyak, Semyon / Lajoie, Bryan / Levy, Shawn /

Patel, Minal / Kantoff, Philip W / Mason, Christopher E / Link, Daniel C / Druley, Todd E / Stopsack, Konrad H / Bolton, Kelly L

Bioinformatics (Oxford, England)

2024 Volume 40, Issue 4

Abstract: Motivation: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. ...

Abstract	Motivation: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. Results: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. Availability and implementation: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH.
MeSH term(s)	Adult ; Humans ; Clonal Hematopoiesis ; High-Throughput Nucleotide Sequencing ; Software ; Reproducibility of Results ; Mutation ; Hematologic Neoplasms ; Hematopoiesis/genetics
Language	English
Publishing date	2024-03-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btae121
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Article ; Online: Clonal Hematopoiesis and Risk of Incident Lung Cancer.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2022 Volume 41, Issue 7, Page(s) 1423–1433

Abstract: Purpose: To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer.: Methods: Among 200,629 UK Biobank (UKBB) participants with whole-exome sequencing, CH was identified in a nested case-control ... ...

Abstract	Purpose: To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer. Methods: Among 200,629 UK Biobank (UKBB) participants with whole-exome sequencing, CH was identified in a nested case-control study of 832 incident lung cancer cases and 3,951 controls (2006-2019) matched on age and year at blood draw, sex, race, and smoking status. A similar nested case-control study (141 cases/652 controls) was conducted among 27,975 participants with whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In parallel, we compared CH frequency in published data from 5,003 patients with solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. Results: In UKBB, the presence of CH was associated with increased risk of lung cancer (cases: 12.5% Conclusion: Independent of known risk factors, CH is associated with increased risk of lung cancer.
MeSH term(s)	Humans ; Clonal Hematopoiesis ; Case-Control Studies ; Hematopoiesis/genetics ; Lung Neoplasms ; Mutation ; Risk Factors
Chemical Substances	methylglyoxal bis(butylamidinohydrazone) (66002-88-8)
Language	English
Publishing date	2022-12-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.22.00857
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Zs.A 1847: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Estimation of intrafamilial DNA contamination in family trio genome sequencing using deviation from Mendelian inheritance.

Genome research

2022 Volume 32, Issue 11-12, Page(s) 2134–2144

Abstract: With the increasing number of sequencing projects involving families, quality control tools optimized for family genome sequencing are needed. However, accurately quantifying contamination in a DNA mixture is particularly difficult when genetically ... ...

Abstract	With the increasing number of sequencing projects involving families, quality control tools optimized for family genome sequencing are needed. However, accurately quantifying contamination in a DNA mixture is particularly difficult when genetically related family members are the sources. We developed TrioMix, a maximum likelihood estimation (MLE) framework based on Mendel's law of inheritance, to quantify DNA mixture between family members in genome sequencing data of parent-offspring trios. TrioMix can accurately deconvolute any intrafamilial DNA contamination, including parent-offspring, sibling-sibling, parent-parent, and even multiple familial sources. In addition, TrioMix can be applied to detect genomic abnormalities that deviate from Mendelian inheritance patterns, such as uniparental disomy (UPD) and chimerism. A genome-wide depth and variant allele frequency plot generated by TrioMix facilitates tracing the origin of Mendelian inheritance deviations. We showed that TrioMix could accurately deconvolute genomes in both simulated and real data sets.
MeSH term(s)	Humans ; DNA Contamination ; Chromosome Mapping ; Genome ; Uniparental Disomy ; Databases, Genetic
Language	English
Publishing date	2022-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.276794.122
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Zs.A 3729: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes.

Bolton, Kelly L / Chen, Denise / Corona de la Fuente, Rosario / Fu, Zhuxuan / Murali, Rajmohan / Köbel, Martin / Tazi, Yanis / Cunningham, Julie M / Chan, Irenaeus C C / Wiley, Brian J / Moukarzel, Lea A / Winham, Stacey J / Armasu, Sebastian M / Lester, Jenny / Elishaev, Esther / Laslavic, Angela / Kennedy, Catherine J / Piskorz, Anna / Sekowska, Magdalena /

Brand, Alison H / Chiew, Yoke-Eng / Pharoah, Paul / Elias, Kevin M / Drapkin, Ronny / Churchman, Michael / Gourley, Charlie / DeFazio, Anna / Karlan, Beth / Brenton, James D / Weigelt, Britta / Anglesio, Michael S / Huntsman, David / Gayther, Simon / Konner, Jason / Modugno, Francesmary / Lawrenson, Kate / Goode, Ellen L / Papaemmanuil, Elli

Clinical cancer research : an official journal of the American Association for Cancer Research

2022 Volume 28, Issue 22, Page(s) 4947–4956

Abstract: Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.: Experimental design: We profiled 421 primary CCOCs that passed quality control using a targeted deep ... ...

Abstract	Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.
MeSH term(s)	Female ; Humans ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Adenocarcinoma, Clear Cell/drug therapy ; Adenocarcinoma, Clear Cell/genetics ; Mutation ; Endometriosis/genetics ; Endometriosis/pathology
Language	English
Publishing date	2022-07-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-21-3817
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Article ; Online: Clonal hematopoiesis is associated with risk of severe Covid-19.

Bolton, Kelly L / Koh, Youngil / Foote, Michael B / Im, Hogune / Jee, Justin / Sun, Choong Hyun / Safonov, Anton / Ptashkin, Ryan / Moon, Joon Ho / Lee, Ji Yeon / Jung, Jongtak / Kang, Chang Kyung / Song, Kyoung-Ho / Choe, Pyoeng Gyun / Park, Wan Beom / Kim, Hong Bin / Oh, Myoung-Don / Song, Han / Kim, Sugyeong /

Patel, Minal / Derkach, Andriy / Gedvilaite, Erika / Tkachuk, Kaitlyn A / Wiley, Brian J / Chan, Ireaneus C / Braunstein, Lior Z / Gao, Teng / Papaemmanuil, Elli / Esther Babady, N / Pessin, Melissa S / Kamboj, Mini / Diaz, Luis A / Ladanyi, Marc / Rauh, Michael J / Natarajan, Pradeep / Machiela, Mitchell J / Awadalla, Philip / Joseph, Vijai / Offit, Kenneth / Norton, Larry / Berger, Michael F / Levine, Ross L / Kim, Eu Suk / Kim, Nam Joong / Zehir, Ahmet

Nature communications

2021 Volume 12, Issue 1, Page(s) 5975

Abstract: Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be ... ...

Abstract	Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; COVID-19/etiology ; COVID-19/immunology ; COVID-19/pathology ; Child ; Child, Preschool ; Clonal Hematopoiesis/genetics ; Clonal Hematopoiesis/immunology ; Cohort Studies ; Female ; Hematopoietic Stem Cells/virology ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Mutation/immunology ; Neoplasms/genetics ; Risk Factors ; SARS-CoV-2 ; Severity of Illness Index
Language	English
Publishing date	2021-10-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-26138-6
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