Journal ArticleDOI
Distinction of lymphoid and myeloid clonal hematopoiesis
Abhishek Niroula,Abhishek Niroula,Abhishek Niroula,Aswin Sekar,Mark A. Murakami,Mark Trinder,Mark Trinder,Mridul Agrawal,Waihay J. Wong,Waihay J. Wong,Alexander G. Bick,Alexander G. Bick,Mesbah Uddin,Mesbah Uddin,Christopher J. Gibson,Christopher J. Gibson,Gabriel K. Griffin,Gabriel K. Griffin,Michael C. Honigberg,Michael C. Honigberg,Seyedeh M. Zekavat,Seyedeh M. Zekavat,Kaavya Paruchuri,Pradeep Natarajan,Pradeep Natarajan,Benjamin L. Ebert,Benjamin L. Ebert,Benjamin L. Ebert +27 more
TLDR
In this article, the authors performed an integrated analysis of gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), and found that myeloid and lymphoid gene mutations were associated with risk of lineage-specific malignancy.Abstract:
Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies. Genomic analyses in the UK Biobank show that clonal hematopoiesis of indeterminate potential in the lymphoid lineage is associated with a higher risk of developing lymphoid malignanciesread more
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ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group.
Javier Pascual,Gerhardt Attard,François-Clément Bidard,Giuseppe Curigliano,Leticia De Mattos-Arruda,Maximilian Diehn,Antoine Italiano,Johan Lindberg,Jason D. Merker,Clara Montagut,Nicola Normanno,Klaus Pantel,George Pentheroudakis,Sanjay Popat,Jorge S. Reis-Filho,Jeanne Tie,Joan Seoane,Noelia Tarazona,Takayuki Yoshino,Nicholas C. Turner +19 more
TL;DR: Alix-Panabières et al. as discussed by the authors reviewed analytical and clinical validity and utility of circulating tumour DNA (ctDNA) assays and made recommendations for reporting of results, future development of ctDNA assays, and future clinical research are made.
Journal ArticleDOI
Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis
Siddhartha Kar,Pedro M. Quirós,Muxin Gu,Tao Jiang,Jan Mitchell,Ryan Langdon,Vivek Iyer,Clea Bárcena,M. S. Vijayabaskar,Margarete A. Fabre,Paul Carter,Slavé Petrovski,Stephen Burgess,George S. Vassiliou +13 more
TL;DR: The authors analyzed genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14.
Journal ArticleDOI
TET2-mutant clonal hematopoiesis and risk of gout
Mridul Agrawal,Abhishek Niroula,Pierre Cunin,Marie McConkey,Veronica Kovalcik,Peter G Kim,Waihay J. Wong,Lachelle D. Weeks,Amy E. Lin,Peter Miller,Christopher J. Gibson,Aswin Sekar,Inga-Marie Schaefer,Donna Neuberg,Richard Stone,Alexander G. Bick,Mesbah Uddin,Gabriel K. Griffin,Siddhartha Jaiswal,Pradeep Natarajan,Peter A. Nigrovic,Deepak A. Rao,Benjamin L. Ebert +22 more
TL;DR: It is shown that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1B levels in Tet2 knockout murine models.
Journal ArticleDOI
Common and rare variant associations with clonal haematopoiesis phenotypes
Michael D. Kessler,Amy Damask,Sean O’Keeffe,Nilanjana Banerjee,Dadong Li,Kyoko Watanabe,Anthony Marketta,Michael Van Meter,Stefan Semrau,Julie Horowitz,Jing Tang,Jack A. Kosmicki,Veera M. Rajagopal,Yuxin Zou,Yariv Houvras,Arkopravo Ghosh,Christopher Gillies,Joelle Mbatchou,Ryan R. White,Niek Verweij,Jonas Bovijn,Neelroop N. Parikshak,Michelle G. LeBlanc,Marcus B. Jones,David J. Glass,Luca A. Lotta,Michael Cantor,Gurinder S. Atwal,Adam E. Locke,Manuel A. R. Ferreira,Raquel P. Deering,Charles Paulding,Alan R. Shuldiner,Gavin Thurston,Adolfo A. Ferrando,William J Salerno,Jeffrey G. Reid,John D. Overton,Jonathan Marchini,Hyun Min Kang,Aris Baras,Gonçalo R. Abecasis,Eric Jorgenson +42 more
TL;DR: In this paper , exome sequence data from 628,388 individuals was used to identify 24 risk loci in 40,208 carriers of clonal haematopoiesis of indeterminate potential and link them to other conditions including COVID-19, cardiovascular disease and cancer.
Journal ArticleDOI
Genetics of smoking and risk of clonal hematopoiesis
Michael Levin,Tetsushi Nakao,Seyedeh M. Zekavat,Satoshi Koyama,Alexander G. Bick,Abhishek Niroula,Benjamin L. Ebert,Scott M. Damrauer,Pradeep Natarajan +8 more
TL;DR: In this paper , the role of smoking in mCAs and CHIP was investigated using two complementary analyses, using an observational study design among UK Biobank participants, and using two-sample Mendelian randomization, smoking was strongly associated with mCA but not with CHIP.
References
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Heng Li,Bob Handsaker,Alec Wysoker,T. J. Fennell,Jue Ruan,Nils Homer,Gabor T. Marth,Gonçalo R. Abecasis,Richard Durbin +8 more
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The mutational constraint spectrum quantified from variation in 141,456 humans
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Journal ArticleDOI
The UK Biobank resource with deep phenotyping and genomic data
Clare Bycroft,Colin Freeman,Desislava Petkova,Desislava Petkova,Gavin Band,Lloyd T. Elliott,Kevin Sharp,Allan Motyer,Damjan Vukcevic,Olivier Delaneau,Olivier Delaneau,Jared O'Connell,Adrian Cortes,Adrian Cortes,Samantha Welsh,Alan Young,Mark Effingham,Gil McVean,Stephen Leslie,Naomi E. Allen,Peter Donnelly,Jonathan Marchini +21 more
TL;DR: Deep phenotype and genome-wide genetic data from 500,000 individuals from the UK Biobank is described, describing population structure and relatedness in the cohort, and imputation to increase the number of testable variants to 96 million.
Journal ArticleDOI
Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes
Siddhartha Jaiswal,Pierre Fontanillas,Jason Flannick,Jason Flannick,Alisa K. Manning,Peter V. Grauman,Brenton G. Mar,Brenton G. Mar,R. Coleman Lindsley,Craig H. Mermel,Noël P. Burtt,Alejandro Chavez,John M. Higgins,Vladislav Moltchanov,Vladislav Moltchanov,Frank C. Kuo,Michael J. Kluk,Brian E. Henderson,Leena Kinnunen,Heikki A. Koistinen,Heikki A. Koistinen,Claes Ladenvall,Gad Getz,Adolfo Correa,Benjamin F. Banahan,Stacey Gabriel,Stacey Gabriel,Sekar Kathiresan,Heather M. Stringham,Mark I. McCarthy,Michael Boehnke,Jaakko Tuomilehto,Jaakko Tuomilehto,Jaakko Tuomilehto,Christopher A. Haiman,Leif Groop,Gil Atzmon,James G. Wilson,Donna Neuberg,David Altshuler,Benjamin L. Ebert +40 more
TL;DR: Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease.