Shared and distinct genetic etiologies for different types of clonal hematopoiesis

被引：15

作者：

Brown, Derek W. ^{[1
,2
]}

Cato, Liam D. ^{[3
,4
,5
]}

Zhao, Yajie ^{[6
]}

Nandakumar, Satish K. ^{[3
,4
,5
,7
]}

Bao, Erik L. ^{[3
,4
,5
]}

Gardner, Eugene J. ^{[6
]}

Hubbard, Aubrey K. ^{[1
]}

Depaulis, Alexander ^{[1
]}

Rehling, Thomas ^{[1
]}

Song, Lei ^{[1
]}

Yu, Kai ^{[1
]}

Chanock, Stephen J. ^{[1
]}

Perry, John R. B. ^{[6
,8
]}

Sankaran, Vijay G. ^{[3
,4
,5
]}

Machiela, Mitchell J. ^{[1
]}

机构：

[1] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA

[2] NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Rockville, MD USA

[3] Harvard Med Sch, Div Hematol Oncol, Boston Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA

[4] Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[5] Broad Inst & Harvard, Cambridge, MA 02142 USA

[6] Univ Cambridge, Wellcome MRC Inst Metab Sci, MRC Epidemiol Unit, Sch Clin Med, Cambridge CB2 0QQ, England

[7] Albert Einstein Coll Med, Montefiore Med Ctr, Ruth L & David S Gottesman Inst Stem Cell Res & R, Bronx, NY 10461 USA

[8] Univ Cambridge, Wellcome MRC Inst Metab Sci, Metab Res Lab, Sch Clin Med, Cambridge CB2 0QQ, England

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

美国国家卫生研究院;

关键词：

MENDELIAN RANDOMIZATION; MOSAIC LOSS; GENOMIC ABERRATIONS; SOMATIC MUTATIONS; CHRONIC PHASE; CHROMOSOME Y; COMMON; IDENTIFICATION; INACTIVATION; NEOPLASMS;

D O I：

10.1038/s41467-023-41315-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Clonal hematopoiesis (CH)-age-related expansion of mutated hematopoietic clones-can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk. Types of clonal hematopoiesis (CH) differ in frequency and fitness. These findings uncover shared genetic architecture, suggest evolutionary trade-offs between CH types, and detail elevated leukemia risk in individuals with overlapping types of CH.

引用

页数：13

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