https://orcid.org/0000-0003-3116-4588
Key Points
Clonal signatures of TBD associate with age and the underlying genotype, and are markers of malignant clonal evolution and poor survival.
In contrast to POT1/PPM1D/TERTp mutations, Chr1q+, U2AF1S34, and TP53 somatic mutations are key drivers of cancer development in TBD.
Abstract
Telomere biology disorders (TBDs), caused by pathogenic germ line variants in telomere-related genes, present with multiorgan disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBDs is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 patients with TBD 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 were associated with poorer overall survival. Chr1q+ and splicing factor or TP53 mutations significantly increased the risk of hematologic malignancies, regardless of clonal burden. Chr1q+ and U2AF1S34 mutated clones were premalignant events associated with the secondary acquisition of mutations in genes related to hematologic malignancies. Similar to the 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 mutations 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 for the identification of patients at a higher risk of cancer development.
References
1.
Alter
BP
, Giri
N
, Savage
SA
, Rosenberg
PS
. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up
. Haematologica
. 2018
;103
(1
):30
-39
.2.
Niewisch
MR
, Giri
N
, McReynolds
LJ
, et al. Disease progression and clinical outcomes in telomere biology disorders
. Blood
. 2022
;139
(12
):1807
-1819
.3.
Niewisch
MR
, Savage
SA
. An update on the biology and management of dyskeratosis congenita and related telomere biology disorders
. Expert Rev Hematol
. 2019
;12
(12
):1037
-1052
.4.
Revy
P
, Kannengiesser
C
, Bertuch
AA
. Genetics of human telomere biology disorders
. Nat Rev Genet
. 2023
;24
(2
):86
-108
.5.
Jaiswal
S
, Fontanillas
P
, Flannick
J
, et al. Age-related clonal hematopoiesis associated with adverse outcomes
. N Engl J Med
. 2014
;371
(26
):2488
-2498
.6.
Revy
P
, Kannengiesser
C
, Fischer
A
. Somatic genetic rescue in Mendelian haematopoietic diseases
. Nat Rev Genet
. 2019
;20
(10
):582
-598
.7.
Gutierrez-Rodrigues
F
, Sahoo
SS
, Wlodarski
MW
, Young
NS
. Somatic mosaicism in inherited bone marrow failure syndromes
. Best Pract Res Clin Haematol
. 2021
;34
(2
):101279
.8.
Nicoletti
E
, Rao
G
, Bueren
JA
, et al. Mosaicism in Fanconi anemia: concise review and evaluation of published cases with focus on clinical course of blood count normalization
. Ann Hematol
. 2020
;99
(5
):913
-924
.9.
Sebert
M
, Gachet
S
, Leblanc
T
, et al. Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia
. Cell Stem Cell
. 2023
;30
(2
):153
-170.e9
.10.
Sahoo
SS
, Pastor
VB
, Goodings
C
, et al. Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes
. Nat Med
. 2021
;27
(10
):1806
-1817
.11.
Kennedy
AL
, Myers
KC
, Bowman
J
, et al. Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome
. Nat Commun
. 2021
;12
(1
):1334
.12.
Tan
S
, Kermasson
L
, Hilcenko
C
, et al. Somatic genetic rescue of a germline ribosome assembly defect
. Nat Commun
. 2021
;12
(1
):5044
.13.
Largeaud
L
, Collin
M
, Monselet
N
, et al. Somatic genetic alterations predict hematological progression in GATA2 deficiency
. Haematologica
. 2023
;108
(6
):1515
-1529
.14.
Schratz
KE
, Haley
L
, Danoff
SK
, et al. Cancer spectrum and outcomes in the Mendelian short telomere syndromes
. Blood
. 2020
;135
(22
):1946
-1956
.15.
Kirschner
M
, Maurer
A
, Wlodarski
MW
, et al. Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita
. Leukemia
. 2018
;32
(8
):1762
-1767
.16.
Maryoung
L
, Yue
Y
, Young
A
, et al. Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations
. J Clin Invest
. 2017
;127
(3
):982
-986
.17.
Gutierrez-Rodrigues
F
, Donaires
FS
, Pinto
A
, et al. Pathogenic TERT promoter variants in telomere diseases
. Genet Med
. 2019
;21
(7
):1594
-1602
.18.
Schratz
KE
, Gaysinskaya
V
, Cosner
ZL
, et al. Somatic reversion impacts myelodysplastic syndromes and acute myeloid leukemia evolution in the short telomere disorders
. J Clin Invest
. 2021
;131
(18
):e147598
.19.
Ferrer
A
, Lasho
T
, Fernandez
JA
, et al. Patients with telomere biology disorders show context specific somatic mosaic states with high frequency of U2AF1 variants
. Am J Hematol
. 2023
;98
(12
):E357
-E359
.20.
Gutierrez-Rodrigues
F
, Santana-Lemos
BA
, Scheucher
PS
, Alves-Paiva
RM
, Calado
RT
. Direct comparison of flow-FISH and qPCR as diagnostic tests for telomere length measurement in humans
. PLoS One
. 2014
;9
(11
):e113747
.21.
Lai
TP
, Zhang
N
, Noh
J
, et al. A method for measuring the distribution of the shortest telomeres in cells and tissues
. Nat Commun
. 2017
;8
(1
):1356
.22.
Gutierrez-Rodrigues
F
, Munger
E
, Ma
X
, et al. Differential diagnosis of bone marrow failure syndromes guided by machine learning
. Blood
. 2023
;141
(17
):2100
-2113
.23.
Nykamp
K
, Anderson
M
, Powers
M
, et al. Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria
. Genet Med
. 2017
;19
(10
):1105
-1117
.24.
Gutierrez-Rodrigues
F
, Kusne
Y
, Fernandez
J
, et al. Spectrum of clonal hematopoiesis in VEXAS syndrome
. Blood
. 2023
;142
(3
):244
-259
.25.
Ganan-Gomez
I
, Yang
H
, Ma
F
, et al. Stem cell architecture drives myelodysplastic syndrome progression and predicts response to venetoclax-based therapy
. Nat Med
. 2022
;28
(3
):557
-567
.26.
Alder
JK
, Stanley
SE
, Wagner
CL
, Hamilton
M
, Hanumanthu
VS
, Armanios
M
. Exome sequencing identifies mutant TINF2 in a family with pulmonary fibrosis
. Chest
. 2015
;147
(5
):1361
-1368
.27.
Miller
PG
, Sperling
AS
, Mayerhofer
C
, et al. PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy
. Blood
. 2023
;142
(24
):2079
-2091
.28.
Kleiblova
P
, Shaltiel
IA
, Benada
J
, et al. Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint
. J Cell Biol
. 2013
;201
(4
):511
-521
.29.
Harland
M
, Petljak
M
, Robles-Espinoza
CD
, et al. Germline TERT promoter mutations are rare in familial melanoma
. Fam Cancer
. 2016
;15
(1
):139
-144
.30.
Gu
P
, Wang
Y
, Bisht
KK
, et al. Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis
. Oncogene
. 2017
;36
(14
):1939
-1951
.31.
Chiba
K
, Lorbeer
FK
, Shain
AH
, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism
. Science
. 2017
;357
(6358
):1416
-1420
.32.
Thongon
N
, Ma
F
, Santoni
A
, et al. Hematopoiesis under telomere attrition at the single-cell resolution
. Nat Commun
. 2021
;12
(1
):6850
.33.
Sahin
E
, Colla
S
, Liesa
M
, et al. Telomere dysfunction induces metabolic and mitochondrial compromise
. Nature
. 2011
;470
(7334
):359
-365
.34.
Zink
F
, Stacey
SN
, Norddahl
GL
, et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly
. Blood
. 2017
;130
(6
):742
-752
.35.
Bick
AG
, Weinstock
JS
, Nandakumar
SK
, et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes
. Nature
. 2020
;586
(7831
):763
-768
.36.
Nakao
T
, Bick
AG
, Taub
MA
, et al. Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential
. Sci Adv
. 2022
;8
(14
):eabl6579
.37.
Brown
DW
, Zhou
W
, Wang
Y
, et al. Germline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis
. Nat Commun
. 2022
;13
(1
):5284
.38.
Xia
J
, Miller
CA
, Baty
J
, et al. Somatic mutations and clonal hematopoiesis in congenital neutropenia
. Blood
. 2018
;131
(4
):408
-416
.39.
Catto
LFB
, Borges
G
, Pinto
AL
, et al. Somatic genetic rescue in hematopoietic cells in GATA2 deficiency
. Blood
. 2020
;136
(8
):1002
-1005
.40.
Yoshizato
T
, Dumitriu
B
, Hosokawa
K
, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia
. N Engl J Med
. 2015
;373
(1
):35
-47
.41.
Patel
BA
, Groarke
EM
, Lotter
J
, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study
. Blood
. 2022
;139
(1
):34
-43
.42.
Groarke
EM
, Patel
BA
, Shalhoub
R
, et al. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia
. Leukemia
. 2022
;36
(9
):2328
-2337
.43.
Thol
F
, Kade
S
, Schlarmann
C
, et al. Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes
. Blood
. 2012
;119
(15
):3578
-3584
.44.
Perdigones
N
, Perin
JC
, Schiano
I
, et al. Clonal hematopoiesis in patients with dyskeratosis congenita
. Am J Hematol
. 2016
;91
(12
):1227
-1233
.45.
Gutierrez-Rodrigues
F
, Thongon
N
, Williams
CL
, Colla
S
, Young
NS
, Bertuch
AA
. Blood count recovery and telomere elongation in a TINF2 patient under treatment with a gonadotropin-releasing hormone (GnRH) agonist
. Blood
. 2023
;142
(suppl 1
):2735
.46.
Watson
CJ
, Papula
AL
, Poon
GYP
, et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis
. Science
. 2020
;367
(6485
):1449
-1454
.47.
Fabre
MA
, Almeida
JGd
, Fiorillo
E
, et al. The longitudinal dynamics and natural history of clonal haematopoiesis
. bioRxiv
. Preprint posted online 21 August 2021
.48.
Schratz
KE
, Flasch
DA
, Atik
CC
, et al. T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers
. Cancer Cell
. 2023
;41
(4
):807
-817.e6
.49.
Gutierrez-Rodrigues
F
, Wells
KV
, Jones
AI
, et al. Clonal haematopoiesis across the age spectrum of vasculitis patients with Takayasu's arteritis, ANCA-associated vasculitis and giant cell arteritis
. Ann Rheum Dis
. 2024
;83
(4
):508
-517
.50.
Vicente
A
, Patel
BA
, Gutierrez-Rodrigues
F
, et al. Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndrome
. Haematologica
. 2020
;105
(12
):2785
-2794
.2024
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