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

生物 端粒 癌症 癌症的体细胞进化 遗传学 种系突变 生殖系 体细胞 突变 癌症研究 基因
作者
Fernanda Gutierrez‐Rodrigues,Emma M. Groarke,Natthakan Thongon,Juan Jose Rodriguez-Sevilla,Luiz Fernando Bazzo Catto,Marena R. Niewisch,Ruba Shalhoub,Lisa J. McReynolds,Diego V. Clé,Bhavisha A. Patel,Xiaoyang Ma,Dalton Hironaka,Flávia S. Donaires,Nina Spitofsky,Bárbara A. Santana,Tsung‐Po Lai,Lemlem Alemu,Sachiko Kajigaya,Ivana Darden,Weiyin Zhou
出处
期刊:Blood [Elsevier BV]
卷期号:144 (23): 2402-2416 被引量:4
标识
DOI:10.1182/blood.2024025023
摘要

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.
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