Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescuing and cancer mutations.

Autor:	Gutierrez-Rodrigues F; National Heart, Lung, and Blood Institute (NHLBI)/NIH, Bethesda, Maryland, United States., Groarke EM; National Heart, Lung and Blood Institute, Bethesda, Maryland, United States., Thongon N; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Rodriguez-Sevilla JJ; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Bazzo Catto LF; National Heart Lung and Blood Institute, Bethesda, Maryland, United States., Niewisch MR; Medizinische Hochschule Hannover, Hannover, Germany., Shalhoub RN; NIH, Vienna, Virginia, United States., McReynolds LJ; National Cancer Institute, Bethesda, Maryland, United States., Clé DV; University of Sao Paulo, Ribeirao Preto, Brazil., Patel BA; National Institute of Health, Bethesda, Maryland, United States., Ma X; Georgetown University, Washington, District of Columbia, United States., Hironaka D; National Heart, Lung, and Blood Institute (NHLBI)/NIH, Bethesda, Maryland, United States., Donaires FS; Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil., Spitofsky NR; National Heart, Lung, and Blood Institute (NHLBI)/NIH, Bethesda, Maryland, United States., Santana BA; University of Sao Paulo, Ribeirao Preto, Brazil., Lai TP; Rutgers New Jersey Medical School, Newark, New Jersey, United States., Alemu L; NHLBI, Bethesda, United States., Kajigaya S; NIH, Bethesda, Maryland, United States., Darden I; National Institute of Health, Bethesda, Maryland, United States., Zhou W; NCI, Rockville, Maryland, United States., Browne PV; Department of Haematology, Trinity College Dublin, Dublin, Ireland, Dublin, Ireland., Paul S; NIAID/NIH, Bethesda, Maryland, United States., Lack J; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States., Young DJ; Translational Stem Cell Biology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, Bethesda, Maryland, United States., DiNardo CD; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Aviv A; Rutgers New Jersey Medical School, Newark, New Jersey, United States., Ma F; The University of California, Los Angeles, Los Angeles, California, United States., Michels de Oliveira M; Universidade Federal do Parana, Curitiba, Brazil., Azambuja AP; Universidade Federal do Parana, Curitiba, Brazil., Dunbar CE; National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States., Olszewska M; Icahn School of Medicine at Mount Sinai, New York, New York, United States., Olivier E; Icahn School of Medicine at Mount Sinai, New York, New York, United States., Papapetrou EP; Icahn School of Medicine at Mount Sinai, New York, New York, United States., Giri N; National Cancer Institute, NIH, Rockville, Maryland, United States., Alter BP; National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States., Bonfim CMS; Hospital Pequeno Principe/Pele Pequeno Príncipe Research Institute, Curitiba, Brazil., Wu CO; National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA, Bethesda, Maryland, United States., Garcia-Manero G; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Savage SA; National Cancer Institute, Bethesda, Maryland, United States., Young NS; NHLBI, NIH, Bethesda, Maryland, United States., Colla S; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Calado RT; University of Sao Paulo, Ribeirao Preto, Brazil.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Sep 24. Date of Electronic Publication: 2024 Sep 24.
DOI:	10.1182/blood.2024025023
Abstrakt:	Telomere biology disorders (TBD), caused by pathogenic germline variants in telomere-related genes, present with multi-organ disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBD is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 TBD patients with a broad range of age and phenotype. CH occurred predominantly in symptomatic patients and in signature genes typically associated with cancers: PPM1D, POT1, TERT promoter (TERTp), U2AF1S34, and/or TP53. Chromosome 1q gain (Chr1q+) was the commonest karyotypic abnormality. Clinically, multiorgan involvement and CH in TERTp, TP53, and splicing factor genes associated with poorer overall survival. Chr1q+, and splicing factor or TP53 mutations significantly increased the risk of hematologic malignancies, regardless of the clonal burden. Chr1q+ and U2AF1S34 mutated clones were pre-malignant events associated with the secondary acquisition of mutations in genes related to hematologic malignancies. Like known effects of Chr1q+ and TP53-CH, functional studies demonstrated that U2AF1S34 mutations primarily compensated for aberrant upregulation of TP53 and interferon pathways in telomere-dysfunctional hematopoietic stem cells, highlighting the TP53 pathway as a canonical route of malignancy in TBD. In contrast, somatic POT1/PPM1D/TERTp-CH had distinct trajectories unrelated to cancer development. With implications beyond TBD, our data show that telomere dysfunction is a strong selective pressure for CH. In TBD, CH is a poor prognostic marker associated with worse overall survival. The identification of key regulatory pathways that drive clonal transformation in TBD allows the identification of patients at a higher risk of cancer development. (Copyright © 2024 American Society of Hematology.)
Databáze:	MEDLINE
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