CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY

Hematopoietic Stem Cell Transplantation Positively

Affects the Natural History of Cancer in Nijmegen
Breakage Syndrome
Beata Wolska-Kusnierz1, Agata Pastorczak2, Wojciech Fendler3,4, Anna Wakulinska5,
Bozena Dembowska-Baginska5, Edyta Heropolitanska-Pliszka1, Barbara Pi˛a tosa6, Barbara Pietrucha1,
Krzysztof Kałwak7, Marek Ussowicz7, Anna Pieczonka8, Katarzyna Drabko9, Monika Lejman9,
Sylwia Koltan10, Jolanta Gozdzik11, Jan Styczynski10, Alina Fedorova12, Natalia Miakova13,
Elena Deripapa14, Larysa Kostyuchenko15, Zdenka Krenova16, Eva Hlavackova16,17, Andrew R. Gennery18,
Karl-Walter Sykora19, Sujal Ghosh20, Michael H. Albert21, Dmitry Balashov22, Mary Eapen23, Peter Svec24,
Markus G. Seidel25, Sara S. Kilic26, Agnieszka Tomaszewska27, Ewa Wiesik-Szewczyk28,
Alexandra Kreins29, Johann Greil30, Jochen Buechner31, Bendik Lund32, Hanna Gregorek33,
Krystyna Chrzanowska34, and Wojciech Mlynarski2

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ABSTRACT
◥
Purpose: Nijmegen breakage syndrome (NBS) is a DNA repair
disorder with a high predisposition to hematologic malignancies.
Experimental Design: We describe the natural history of NBS,
including cancer incidence, risk of death, and the potential effec-
tiveness of hematopoietic stem cell transplantation (HSCT)
in preventing both pathologies: malignancy and immunodeficiency.
Results: Among 241 patients with NBS enrolled in the study
from 11 countries, 151 (63.0%) patients were diagnosed with
cancer. Incidence rates for primary and secondary cancer, tumor
characteristics, and risk factors affecting overall survival (OS)
were estimated. The cumulative cancer incidence was 40.21%

3.5% and 77.78%
3.4% at 10 years and 20 years of follow-up,
respectively. Most of the tumors n ¼ 95 (62.9%) were non-
Hodgkin lymphomas. Overall, 20 (13.2%) secondary malignan-
cies occurred at a median age of 18 (interquartile range, 13.7–
21.5) years. The probability of 20-year overall survival (OS) for
the whole cohort was 44.6%
4.5%. Patients who developed
cancer had a shorter 20-year OS than those without malignancy
(29.6% vs. 86.2%; P < 105). A total of 49 patients with NBS
underwent HSCT, including 14 patients transplanted before
malignancy. Patients with NBS with diagnosed cancer who
received HSCT had higher 20-year OS than those who did not
(42.7% vs. 30.3%; P ¼ 0.038, respectively). In the group of
patients who underwent preemptive transplantation, only 1
patient developed cancer, which is 6.7 times lower as compared
with nontransplanted patients [incidence rate ratio 0.149 (95%
confidence interval, 0.138–0.162); P < 0.0001].
Conclusions: There is a beneficial effect of HSCT on the long-
term survival of patients with NBS transplanted in their first
complete remission of cancer.

1
Department of Immunology, Children’s Memorial Health Institute, Warsaw,
Poland. 2Department Pediatrics, Oncology and Hematology, Medical Univer-
sity of Lodz, Lodz, Poland. 3Department of Biostatistics and Translational
Medicine, Medical University of Lodz, Lodz, Poland. 4Department of Radiation
Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 5Department
of Oncology, Children’s Memorial Health Institute, Warsaw, Poland. 6Histo-
compatibility Laboratory, Children’s Memorial Health Institute, Warsaw,
Poland. 7Department of Pediatric Hematology, Oncology and Bone Marrow
Transplantation, Wroclaw Medical University, Wroclaw, Poland. 8Department
of Pediatric Oncology, Poznan University of Medical Sciences, Poznan, Poland.
9
Department of Pediatric Hematology, Oncology and Transplantology, Med-
ical University of Lublin, Poland. 10Department of Pediatric Hematology and
Oncology, Collegium Medicum, Nicolaus Copernicus University Torun,
Bydgoszcz, Poland. 11Department of Transplantation, Institute of Pediatrics,
Jagiellonian University Medical College, Krakow, Poland. 12Belarusian
Research Center for Pediatric Oncology and Hematology, Minsk, Belarus.
13
Department of Pediatric Oncology and Hematology, Federal Research Cen-
ter for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
14
Department of Immunology and Hematopoietic Stem Cell Transplantation,
Federal Research Center for Pediatric Hematology, Oncology and Immunol-
ogy, Moscow, Russia. 15Department of Pediatric Immunology, Western Ukrai-
nian Specialized Children’s Medical Centre, Lviv, Ukraine. 16Department of
Pediatric Oncology, University Hospital and Faculty of Medicine, Masaryk
University, Brno, Czech Republic. 17Department of Clinical Immunology and
Allergology, St. Anne’s University Hospital in Brno and Faculty of Medicine,
Masaryk University, Brno, Czech Republic. 18Translational and Clinical
Research Institute, Newcastle University and Newcastle upon Tyne Hospitals
NHS Foundation Trust, Newcastle, United Kingdom. 19Department of Pediat-
rics, Hannover Medical School (MHH), Hannover, Germany. 20Department of
Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty,
Center of Child and Adolescent Health, Heinrich-Heine-University, Du €sseldorf,
Germany. 21Dr. von Hauner University Children’s Hospital, Ludwig-Maximi-
lians-University, Munich, Germany. 22Department of Hematopoietic Stem Cell
Transplantation, Dmitriy Rogachev National Center for Pediatric Hematology,
Oncology, and Immunology, Moscow, Russia. 23Center for International Blood
and Marrow Transplant, Department of Medicine, Medical College of Wiscon-
sin, Milwaukee, Wisconsin. 24Department of Pediatric Hematology and Oncol-
ogy, Comenius University and National Institute of Children’s Diseases, Bra-
tislava, Slovakia. 25Research Unit Pediatric Hematology and Immunology,
Division of Pediatric Hematology-Oncology, Department of Pediatrics and
Adolescent Medicine, Medical University Graz, Graz, Austria. 26Pediatric Immu-
nology Division, Department of Pediatrics, Uludag University Medical Faculty,
Bursa, Turkey. 27Department of Hematology, Oncology and Internal Medicine,
Medical University of Warsaw, Warsaw, Poland. 28Department of Internal
Medicine, Pneumonology, Allergology and Clinical Immunology, Central Clin-
ical Hospital of the Ministry of National Defense, Military Institute of Medicine,
Warsaw, Poland. 29Great Ormond Street Hospital for Children NHS Foundation
Trust, London, United Kingdom. 30Department of Pediatric Hematology and

AACRJournals.org | 575
 Wolska-Kusnierz et al.
Translational Relevance
Nijmegen breakage syndrome (NBS) is a rare autosomal-
recessive primary immunodeficiency and tumor predisposition
syndrome caused by mutations of the NBN gene on chromosome
8q21. The majority of patients are of central and eastern European
descent. In the study, we have collected exhaustive clinical and
genetic data from 241 patients within three international cohorts:
Inborn Errors Working Party of the European Society for Blood
and Marrow Transplantation, the I-BFM Genetic Variation Task
Force, and within the LEGEND of the EU COST action (CA16223)
over a span of an up to 40-year-long observation period. The work
shows accurate prognosis of patients with NBS in terms of overall
survival, details a cancer incidence, shows hazard dynamics of
developing cancer, and presents the predisposition to secondary
cancers of survivors. The study is practice changing, as we con-
clusively show that allogeneic hematopoietic stem cell transplan-
tation prolongs survival and reduces the risk of malignancies.
Introduction
Nijmegen breakage syndrome (NBS; Online Mendelian Inheri-
tance in Man, #251260) is a rare autosomal-recessive primary
immunodeficiency and tumor predisposition syndrome caused by
mutations of the NBN gene on chromosome 8q21 (1, 2). The NBN
gene encodes the nibrin protein which is a crucial component of the
Mre11-Rad50-Nbs1 complex involved in DNA double- and single-
strand break repair and in the activation of cell-cycle checkpoints
via ataxia telangiectasia mutated (ATM; ref. 3). The exact preva-
lence value of NBS is not given, but according to the European
Society for Immunodeficiencies (ESID) database, which is the
largest registry for primary immunodeficiencies, 195 patients have
been diagnosed with this syndrome, including 110 patients of Polish
origin. The majority of these patients are of central and eastern
Europe descent and share the founder homozygous five base pair
deletion within the NBN gene (c.657_661del5, p.Lys219Asnfs;
ref. 1). This deletion probably occurred in the Middle Ages,
resulting in a particularly high (1/177) mutation carrier frequency
in the Slavic populations (Poland, Ukraine, Czech Republic; ref. 3).
The essential phenotypic features describing patients with NBS are
microcephaly at birth, a distinct dysmorphic facial appearance (prom-
inent midface, receding forehead, and mandible), growth retardation,
combined immunodeficiency, radiosensitivity, and an increased risk
of cancer, especially of hematologic origin (1, 4). According to data
published so far, the incidence of malignancy is extremely high,
reaching 40%, but the population-based occurrence in NBS remains
Oncology, University Hospital, Heidelberg, Germany. 31Department of Pedi-
atric Hematology and Oncology, Oslo University Hospital, Oslo, Norway.
32
Pediatric Department, St Olav University Hospital, Trondheim, Norway.
33
Department of Microbiology and Clinical Immunology, The Children’s Memo-
rial Health Institute, Warsaw, Poland. 34Department of Medical Genetics, The
Children’s Memorial Health Institute, Warsaw, Poland.
Note: Supplementary data for this article are available at Clinical Cancer
Research Online (http://clincancerres.aacrjournals.org/).
B. Wolska-Kusnierz and A. Pastorczak contributed equally as co-first authors of
this article.
K. Chrzanowska and W. Mlynarski contributed equally as co-senior authors of
this article.
576 Clin Cancer Res; 27(2) January 15, 2021
unknown (5). In addition, patients with NBS are also prone to develop
secondary malignancies, but data on this aspect are scarce.
In addition, patients with NBS with cancer have poorer outcomes
than patients with cancer without underlying DNA repair defects.
Disease progression, relapses, and secondary malignancies are the
primary causes of death in most patients with NBS who developed
leukemias or lymphomas and contribute to their shortened life
expectancy (5–7). Moreover, inherited chromosomal instability with
a combination of primary and secondary immune defects make
patients with NBS prone to developing severe infectious and excessive,
toxic treatment-related complications. Notably, the reduction in che-
motherapy dosages was not associated with reduced rates of side effects
but contributed to a higher risk of disease recurrence and poorer
overall survival (8). There are currently no dedicated protocols of
cancer treatment for patients with NBS or recommendations of
chemotherapy reduction. Formulation of each one requires accurate,
wide-ranging, and long-term data on the natural history of the disease,
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outcomes, and effectiveness of therapeutic interventions attempted in
patients with NBS.
Allogeneic hematopoietic stem cell transplantation (HSCT) pro-
vides a chance to bring clinical benefit for both immunodeficiency and
hematologic cancer in patients with NBS. However, no studies have
investigated the impact of HSCT on the first complete remission of
malignancy on the long-term survival of patients with NBS and long-
term complications, especially the risk of malignancies after trans-
plantation. Clearly, the failure of previous studies was due to small
sample sizes and short follow-up time.
The aim of this study was to present comprehensive, complete, and
long-term data on cancer incidence, mortality, tumor characteristics,
and the role of HSCT as a therapeutic option for malignancy and as a
preemptive approach in patients with NBS.
Materials and Methods
Patients and genotype
Data of patients with NBS diagnosed between 1993 and 2018 were
collected as result of an international collaboration in a frame of the
Inborn Errors Working Party of the European Society for Blood and
Marrow Transplantation, the I-BFM Genetic Variation Task Force,
and within the LEGEND COST (CA16223) action. Inclusion criteria of
the study were defined as clinical (according to the diagnostic criteria
for NBS developed by Clinical Working Party of ESID) and/or
genetically confirmed NBS and available information about cancer
incidence during the observation time. Detailed clinical and biological
data were gathered in the university hospitals located in the following
countries: Poland, Belarus, Russia, Czech Republic, Slovakia, Turkey,
United Kingdom, Germany, Ukraine, Pakistan, United States of
America, and Austria. In these centers, patients with NBS were
Joint report on behalf of the Inborn Errors Working Party of the European
Society for Blood and Marrow Transplantation and the Host Genetic Variation
Study Group of I-BFM and the LEGEND COST action.
Corresponding Author: Wojciech Mlynarski, Medical University of Lodz, Sporna
36/50, Lodz 91-738, Poland. Phone: 484-2617-7791; Fax: 484-2617-7798; E-mail:
wojciech.mlynarski@umed.lodz.pl
Clin Cancer Res 2021;27:575–84
doi: 10.1158/1078-0432.CCR-20-2574
2020 American Association for Cancer Research.
CLINICAL CANCER RESEARCH

clinically characterized according to the genotype, patient demograph-
ic, primary and secondary cancer incidence, histopathologic diagnosis
of malignancies, treatment, immunodeficiency, transplantation, over-
all survival, and cause of death. The study was approved by the
Bioethics Committee of Children’s Memorial Health Institute, War-
saw, Poland, and by the local institutional review boards of the
participating centers. Epidemiologic data on the number of children
in Poland throughout the study period were obtained from the Local
Data Bank of Poland (https://bdl.stat.gov.pl/BDL/start, accessed
December 14, 2018). An informed written consent was obtained from
each subject or each subject’s guardian. The study was conducted in
accordance with the Declaration of Helsinki.
Cancer characterization
Cancers were classified according to the national pathology reports.
Acute leukemias were categorized according to the current World
Health Organization criteria of hematologic malignancies, including
lineage and immunophenotype specification. With respect to lym-
phomas, we distinguished between Hodgkin lymphoma and non-
Hodgkin lymphoma (NHL). NHL was further classified according to
immunophenotype as B-cell [diffuse large B-cell lymphoma (DLBCL),
other B-cell], T-cell (peripheral T-NHL, other T-cell), and unknown. A
central pathology review was available for 81 (53.6%) patients with
NBS with cancer. The nonhematologic group of cancers was catego-
rized according to their histologic diagnosis described in the pathology
reports. The outcome of cancer was reported as complete remission,
relapse, and progression. Second cancer was defined as a different type
in comparison with the first diagnosis or the same cancer type, which
occurred after more than 5 years from diagnosis of the first malignancy
among patients who achieved complete remission.
HSCT
We collected the following data in patients who underwent HSCT:
indication for transplantation, type and source of HSC, conditioning
regimen, incidence and severity of acute and chronic GVHD, severe
transplant-related complications, survival post-HSCT, and incidence
of cancer after HSCT. Patients who underwent HSCT before devel-
oping cancer were considered transplanted beacause of preemptive
indications, usually because of clinically relevant combined immuno-
deficiency (9). Patients transplanted because of malignancies were
classified according to achievement of complete remission of cancer
before HSCT. For the 26 patients who are included in this study, the
results of HSCT with a shorter follow-up time have already been
reported (Supplementary Table S1). We included them in this analysis
because of significantly longer follow-up compared with previously
published studies.
Outcome analysis
The incidence of cancer and death due to any cause was treated as
a primary outcome measure in the study. Overall survival (OS) time
was defined as the time elapsed from birth to the last follow-up.
Patients still alive at the end of the study were treated as a censored
observation. Individuals were considered lost to follow-up if the
period between the last visit and the date of analysis (January 2019)
exceeded 2 years. Secondary reported outcomes were time to
developing cancer presented as a cumulative incidence and the
probability of second cancer, evaluated using a competing risk
approach, with death included in the competing incidence rates
model as a competing factor. In addition, treatment-related mor-
tality for the first-line therapy and transplant-related mortality was
also calculated.
AACRJournals.org
HSCT Improves Survival of Patients with NBS with Cancer
Statistical analysis
OS probabilities were compared using the log-rank test. Kaplan–
Meier survival curves were used to represent probabilities of survival
over time. Multivariate analysis of survival was performed using Cox
proportional hazard regression models. Competing incidence rate
models were used for secondary cancer development with death as
an interfering outcome and for death as the primary outcome with
secondary cancer as the interfering outcome. Analyses were performed
in Statistica (Statsoft, TIBCO) and STATA (StataCorp LLC). P values <
0.05 were considered statistically significant.
Results
NBS cohort for analysis of the natural history of cancer
The study flow chart illustrating the natural history of cancer in
the NBS cohort and the inference of HSCT in the course of
malignancies is presented in Fig. 1. A total of 241 patients with
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NBS were initially enrolled in the study. Because of the lack of
information about cancer incidence, one individual was excluded,
and eventually, 240 patients were included in the final study
group. After the exclusion of patients transplanted before malig-
nancy (n ¼ 14), the final number of 226 patients was enrolled in the
analysis of the natural history of cancer occurrence. The median
follow-up time of the entire cohort was 12.63 [interquartile range
(IQR), 7.9–17.45] years, accounting for 3,342 person-years. Overall,
14 (5.8%) patients were classified as lost to follow-up. The median
age at NBS diagnosis was 5.0 (IQR, 1.73–10.25) years, and 4 patients
were diagnosed postmortem. Genetic diagnosis of biallelic mutation
within the NBN gene was confirmed in 229 (95.4%) patients. All but 3
Pakistani patients, who were homozygous carriers of the c.1089C>A
(p.Tyr363Ter) mutation, harbored a homozygous deletion
(c.657_661del5, p.Lys219Asnfs; NM_001024688, NP_002476.2) with-
in exon 6 of the NBN gene. Detailed patient characteristics within the
entire cohort and within the subgroups are presented in Table 1
and Fig. 1.
Primary malignancies in NBS
Cancer was diagnosed in 151 (63.0%) patients, which corresponded
to 4,743 events per 100,000 patient-years, with a median age at
presentation of 9.31 (IQR, 6.0–14) years (Table 1). In 27% of patients,
NBS was diagnosed after the cancer developed. The median follow-up
time of patients with NBS who developed malignancies was 13.6 (IQR,
9.1–17.51) years. The cumulative cancer incidence was 40.21%
3.5%
and 77.78%
3.4% at 10 years and 20 years of follow-up, respectively
(Fig. 2A).
With respect to the tumor type, we observed n ¼ 95 (62.9%) NHLs,
n ¼ 32 (21.2%) acute leukemias, n ¼ 9 (6.0%) Hodgkin lymphomas,
and n ¼ 11 (7.2%) other types of solid malignancies (medulloblastoma
n ¼ 3, neuroblastoma n ¼ 2, thyroid carcinoma n ¼ 1,
gastric carcinoma n ¼ 1, low-grade glioma n ¼ 1, rhabdomyosarcoma
n ¼ 1, unspecified liver tumor n ¼ 1, and dysgerminoma n ¼ 1). For 4
patients (2.6%), the type of malignancy was unknown (Fig. 3). Both
carcinomas and gliomas were diagnosed in early adulthood before the
age of 25 years. The cumulative cancer incidence depending on the
type of malignancy is presented in Fig. 2B.
Among patients with NBS diagnosed with NHL, there was a similar
number of lymphoid tumors of B-cell origin n ¼ 49 (51.5%), including
n ¼ 25 cases of DLBCL, and lymphomas developed from abnormal T
cells n ¼ 43 (45.2%). In 3 and 2 patients, peripheral T-NHL and
anaplastic large cell lymphomas were identified, respectively. The
phenotype of NHL was unclassified in 3 patients (3.2%). The median
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578 Clin Cancer Res; 27(2) January 15, 2021

Figure 1.
Flow chart of the study group: number of patients with NBS in each study subgroups according to cancer incidence and treatment with HSCT. The median follow-up time in years was assessed and compared for each
subgroup.  , P ¼ 0.041; #, P ¼ 0.0002.

CLINICAL CANCER RESEARCH

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 HSCT Improves Survival of Patients with NBS with Cancer

Table 1. Patients characteristics.

Entire cohort Malignanciesa No malignanciesa

Characteristic N ¼ 241 N ¼ 151 N ¼ 75 P value

Sex n (%)
Male 120 (49.8) 84 (55.6) 44 (58.7) 0.77
Female 121 (50.2) 67 (44.4) 31 (41.3)
Year of birth median (IQR) 2000 (1991–2007) 1995 (1990–2003) 2007 (1995–2011) <105
Age at cancer diagnosis (years) median (IQR) 9.1 (5.9–14.0) 9.1 (5.9–14.0) NA NA
Status n (%)
Alive 131 (54.3) 49 (32.4) 67 (89.3) <105
Dead 110 (45.7) 101 (67.6) 8 (10.7)
Age at death (years) median (IQR) 13.8 (9.0–17.3) 13.0 (8.9–17.2) 13.4 (11.8–25.1) 0.34
Lost to follow-up n (%) 38 (15.8) 20 (13.2) 18 (24.0) 0.065
Follow-up time (years) median (IQR) 12.6 (7.8–17.5) 13.6 (9.1–18.3) 10.5 (6.4–20.9) 0.01
Number of person-years 3,315.2 2,165.9 1,149.2 NA
Transplantation n (%) 49 (20.3) 35 (23.2) 14 (18.7) 0.55
Age at transplantation (years) 9.0 (5.7–14.5) 11.0 (7.5–15.6) 4.9 (2.3–7.9) 0.0005

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Abbreviations: IQR, interquartile range; NA, not applicable.
a
Patients with no cancer status known (n ¼ 1) and patients transplanted preemptively (n ¼ 14) were excluded.

age at diagnosis of lymphoma in NBS was 9.35 (IQR, 6–13.6) years. respectively (P ¼ 0.041). Hodgkin lymphoma in patients with NBS
Tumors of B-cell origin occurred earlier in a lifetime in comparison developed at adolescence with a median age at diagnosis of 13 (IQR,
with T-NHL 8.2 (IQR, 5.1–11.9) versus 10.53 (IQR, 8–14.2) years, 7.53–18) years.

Figure 2.
A, Cumulative incidence of primary cancer among patients with NBS. B, Cumulative incidence of different types of malignancies in patients with NBS (AL, acute
leukemia; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; other). C, Prevalence of NBS (orange line) in the Polish population ages 0–35 years (blue line) over
the 1995–2017 period. D, Cumulative incidence of cancer in patients with NBS depending on the patients' origin (Polish vs. non-Polish).

AACRJournals.org Clin Cancer Res; 27(2) January 15, 2021 579

 Wolska-Kusnierz et al.
Figure 3.
The incidence of the specific subtypes of primary and secondary malignancies in patients with NBS (NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; AL, acute
leukemias).
Regarding leukemic cell origin, patients with NBS predomi-
nantly developed T-cell acute lymphoblastic leukemia (T-ALL),
n ¼ 23 (71.8%) at different maturation stages. Only three cases of
B-cell precursor ALL and single patients diagnosed with acute
myelogenous leukemia (AML) and acute bilineage leukemia were
observed in the cohort. For 4 patients, the immunophenotype of
leukemia was not specified. Similarly, acute leukemias occurred in
patients with NBS on average at approximately 9 (IQR, 5.9–12.3)
years of age.
Analysis of the nationally representative Polish NBS cohort
Because the results of our study could be biased by the lack of
group representativeness for populations within the particular
countries, we selected the Polish NBS cohort as possibly the most
complete cohort for further separate analysis. Overall, 137 out of
241 (56.8%) patients with NBS were of Polish origin. Four patients
in this group were transplanted before cancer was diagnosed. First,
we aimed to assess whether this group is truly representative of the
Polish population. Next, we verified whether significant associations
that were observed in the entire study cohort reflect similar trends
in Polish patients only. The prevalence of NBS apparently increased
over the 1995–2017 period in the Polish population (r ¼ 0.7401, P <
0.0001; Fig. 2C). This was, however, caused by a negative trend of
the population ages 0–35 years in Poland (r ¼ 0.9937, P < 0.0001).
After adjusting for the current population, a negative but nonsig-
nificant trend was noted (rpartial ¼ 0.3527, P ¼ 0.114). These
observations confirmed our assumptions of the Polish registry
completeness. Within the Polish cohort, 86 (out of 133) patients
(64.7%) developed malignancies (4,254 events per 100,000 patient-
years) with a median age at presentation of 9.2 (IQR, 6.8–14) years.
The 20-year cumulative incidence of cancer was 71.64%
4.5% in
Polish patients with NBS, which was nonsignificantly lower than the
87.9%
4.5% observed in the non-Polish cohort (Fig. 2D).
However, in both the Polish and international cohorts, a three-stage
joint-point model of cancer incidence fit the data better than a two-
stage or continuous model (P < 0.0001 in all instances; Supplementary
Fig. S1). In both cohorts, an initial rapid increase phase was noted (b ¼
580 Clin Cancer Res; 27(2) January 15, 2021
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0.39 and b ¼ 0.66, both P < 0.0001) and ended at 7 [95% confidence
interval (CI), 5–8] and 4 (95% CI, 4–9) years in the Polish and non-
Polish cohorts, respectively. This was followed by a second, linear
increase phase lasting until 13 years (95% CI, 11–16) in both cases, with
trend coefficients of 0.09 and 0.14, respectively (both P < 0.0001).
Afterward, the incidence showed a miniscule increase per year: 0.03
and 0.02, confirming that after 13 years, the risk of developing cancer
decreases dramatically and significantly against earlier periods (P <
0.0001 in both cohorts). Curiously, the dynamics of the initial years of
observation resulted in a statistically significant difference between the
two cohorts (P ¼ 0.032), which may result from different diagnostic
strategies, genetic counseling or varied familial clustering patterns in
the Polish and foreign patients. In this group, we observed the
following subtypes of cancer: n ¼ 57 (66.3%) NHLs, n ¼ 15 (17%)
acute leukemias, n ¼ 6 (7.0%) Hodgkin lymphomas, and n ¼ 8 (9.3%)
other types of solid tumors. There were 16 HSCTs performed in Polish
patients with NBS, including four preemptive transplantations. The
remaining 9 and 3 patients were transplanted because of primary and
secondary malignancies, respectively.
Survival
Overall, 110 patients with NBS out of 240 (45.8%) without pre-
emptive HSCT transplantation died, including 102 patients diagnosed
with malignancies and 8 patients without cancer after a median follow-
up of 13 (IQR, 8.94–17.2) years and 13.4 (IQR, 11.5–25.72) years,
respectively (P < 105).
The probability of 20-year OS for the whole group was 44.6%

4.5% (Fig. 4A). Patients who developed cancer had a shorter 20-year
OS than those without malignancy (29.6% vs. 86.2%; P <
105; Fig. 4B). This association also remained significant when we
analyzed OS in patients treated because of malignancies before and
after 2000 (Supplementary Fig. S2). In addition, 20-year OS was
marginally higher in Polish patients with NBS versus non-Polish
individuals (Fig. 4C). We also analyzed OS after cancer diagnosis in
the deceased patients finding that the patients die within the median
time of 1.23 (
0.36  3.03) year from the first presentation of the
tumor (Supplementary Fig. S3).
CLINICAL CANCER RESEARCH

Figure 4.
A, Overall survival of the entire NBS study cohort. B, Overall survival of patients with NBS according to cancer incidence. C, Overall survival of patients with NBS
depending on their origin (Polish vs. non-Polish). D, Cause of death reported in whole NBS cohort with subdivision of infectious basis.
Information about the cause of death was recorded for 99 (90%)
patients with NBS. The main cause of death was cancer progression
(61%) and infections (34%; Fig. 4D). Treatment-related mortality in
the first line of anticancer therapy was 9.2%, which was mostly
associated with infectious complications (85%). Transplant-related
mortality was 18.3%, with an infection as the most frequent cause of
death (67%).
HSCT in NBS
Between 2000 and 2018, 49 patients with NBS underwent HSCT in
17 BMT centers in nine countries (Supplementary Table S1). The
transplantation procedure was performed twice due to rejection of the
first graft in 2 patients. The median age at the time of HSCT was 9.0
(IQR, 5.7–14.5) years. In the transplanted group, 14 patients were
transplanted before malignancy, 30 after the primary cancer diagnosis,
and the remaining 5 after secondary tumors. A clinically relevant
immunodeficiency with severe or chronic infections or immune
dysregulation was the indication for HSCT in patients transplanted
preemptively. The majority of patients with NBS (n ¼ 31) obtained
hematopoietic stem cells from matched donors [n ¼ 30 and matched
family donors (MFD) n ¼ 1], 11 from matched sibling donors (MSD)
and 2 from mismatched family donors (MMFD). For 5 patients, the
information about the donor was unknown. Most patients received
reduced conditioning regimens, adopted from protocols used in
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HSCT Improves Survival of Patients with NBS with Cancer
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patients with Fanconi anemia. Detailed data on the HSCT procedure
are presented in the Supplementary Materials (Supplementary
Table S1).
In total, 13 patients died after HSCT, including 6 patients who
developed fatal infections and 4 patients with cancer progression.
In 3 additional cases, toxic complications of HSCT (GVHD with
microangiopathy and bleeding, GVHD of gut followed by fatal respi-
ratory infection and venooclussive disease with cooccurred infection)
were the primary causes of death. Three relapses of malignancies
occurred in transplanted patients, two of the primary lymphomas and
one of the secondary T-NHL. Both patients who developed relapse of
primary lymphoma were in partial remission of cancer at the time of
transplantation.
In the entire cohort, 20-year OS in transplanted patients did not
significantly differ from the one observed in the nontransplanted
group (45.1% vs. 44.2%; P ¼ 0.172; Fig. 5A). However, patients
with NBS with diagnosed cancer who received HSCT had significantly
higher 20-year OS than those who did not (42.7% vs. 30.3%; P ¼ 0.038,
respectively; Fig. 5B). Moreover, the difference in OS remained
significant when we analyzed the cancer group depending on treat-
ment before and after 2000 (Supplementary Fig. S2). Interestingly, in
the group of patients who underwent preemptive transplantation, only
1 patient (1 per 14) developed kidney carcinoma with fatal outcomes,
which corresponded to 708 (95% CI, 658–763) events per 100,000
Clin Cancer Res; 27(2) January 15, 2021 581
 Wolska-Kusnierz et al.
Figure 5.
A, Overall survival in the entire NBS cohort according to transplantation. B, Cancer incidence in patients with or without preemptive bone marrow transplantation.
C, Overall survival in patients with NBS with cancer depending on transplantation. D, Cumulative risk of death with the occurrence of secondary malignancy as a
competing event in patients with NBS with cancer according to transplantation status.
patient-years. This is 6.7 times lower than in the group of patients who
were not transplanted [incidence rate ratio 0.149 (95% CI, 0.138–
0.162), P < 0.0001; Fig. 5C].
Secondary malignancies in NBS
Overall, 20 (13.2%) patients with NBS developed secondary
malignancies at a median age of 18 (IQR, 13.7–21.5) years. The
most frequent subsequent cancer occurred in those patients whose
primary diagnosis was B-cell leukemia/lymphoma (n ¼ 12). Sec-
ondary malignancies were rarely diagnosed in patients with primary
T-NHL/ALL (n ¼ 3), Hodgkin lymphoma (n ¼ 3), AML (n ¼ 1),
and ALL with an unspecified immunophenotype (n ¼ 1). T-cell
leukemia/lymphoma were confirmed as half of secondary tumors
(n ¼ 9), and the remaining types of cancer were DLBCL, Burkitt
lymphoma, large cell anaplastic lymphoma, AML, meningioma, and
ganglioglioma diagnosed in 5, 2, 1, 1, 1, and 1 cases, respectively
(Fig. 3). All but 5 patients who developed secondary malignancies
died of tumor progression or infectious complications during che-
motherapy. Among the 5 patients who were still alive, 2 patients
were observed for a relatively short time period (<6 months) after
HSCT, and 1 who developed secondary T-NHL after transplantation
had just started chemotherapy treatment. Two others were success-
fully transplanted from MSD or MMFD, and they remained in the
remission of cancer for more than 5 years. Analysis of the impact of
HSCT on the cumulative risk of death in the presence of secondary
582 Clin Cancer Res; 27(2) January 15, 2021
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malignancy as a competing event showed that the risk for death was
reduced 2-fold in transplanted patients compared with nontrans-
planted individuals [sub-distribution hazard ratio (SHR) ¼ 0.42,
95% CI (0.21–0.85), P ¼ 0.016; Fig. 5D].
Discussion
This report describes, on an unprecedented scale, the natural
history of NBS; details on cancer incidence, risk of death, and
secondary cancer; and the potential effectiveness of HSCT in
preventing either death or cancer. The 20-year cumulative inci-
dence of cancer in NBS was considerably higher than reported in
previous studies (1). Interestingly, this figure is almost three times
more than the 20-year cumulative incidence of cancer described in
ataxia telangiectasia and it is similar to the one reported for
constitutional mismatch repair deficiency (CMMRD; refs. 10–13).
However, in contrast to CMMRD, patients with NBS develop
almost exclusively malignancies of hematologic origin (90%). The
median age at diagnosis of most neoplasms is 9 years, which is
similar to the age observed in ataxia telangiectasia. However,
temporal differences in the cumulative incidences of the various
cancers that were reported in ataxia telangiectasia differ from the
ones we could identify in NBS (10). Apart from carcinomas, all
malignancies occurred up to 25 years of age in patients with NBS. In
addition, half of the patients with NBS (51%) developed first cancer
CLINICAL CANCER RESEARCH

before 10 years of age. Nevertheless, genetic heterogeneity of ATM
mutation types in patients with ataxia telangiectasia affect the risk
and spectrum of malignancies (14).
Consistent with previous smaller studies, most tumors diagnosed in
NBS (62.5%) were NHLs with similar frequencies of B-cell lymphomas
and tumors of abnormal T-cell origin (15). Inefficient elimination of
damaged cells in patients with NBS and the fact that nibrin is involved
in class switch recombination and alternative end joining DNA repair
pathways contribute to the specific targeting of B cells by genomic
instability (4). In addition, an increased chromosomal instability is also
mediated by the extreme telomere attrition observed among homo-
zygous carriers of NBN mutation (16). Telomere shortening was
previously identified in patients with Fanconi anemia in whom the
extent of telomere shortening correlated with the degree of bone
marrow failure, but not with the presence of clonal abnormalities (17).
There is a significant variation of telomere length dynamics in
particular T-cell and B-cell lymphomas depending on the histologic
subtype, the presence of specific translocation (e.g., involving TERT,
BCL6), and germinal centre experience in case of B cells (18). There-
fore, lymphoproliferative disorders with telomere dependent pattern
of carcinogenesis may be more easily promoted in NBS. Because
genomic data from tumors in NBS have not been published yet, we
speculate that both telomere attrition together with hypermutability
facilitate clonal selection of abnormal cells leading to early-onset
malignancy.
Interestingly, among T-NHL’s three cases of lymphomas of periph-
eral T-cell origin, tumors rarely diagnosed in the nonsyndromic
pediatric population were identified (19). T-cell ALL was the second
most common malignancy diagnosed in patients with NBS (10).
Recently published data showed a high frequency of chromothriptic
events in ALL in ataxia telangiectasia individuals, but to our knowl-
edge, chromothripsis has not been identified in T-ALL and in any other
tumors in patients with NBS (20).
Although HSCT can correct both essential characteristics in NBS,
immunodeficiency and susceptibility to hematologic malignancies, it
has not been traditionally attempted in patients with NBS. The first
encouraging results of HSCT among patients with NBS have already
been provided by small case series (5, 21). Moreover, a recent study
performed on a large group of patients with DNA repair syndromes
who underwent HSCT demonstrated that HSCT can improve the
survival of these patients, particularly when reduced intensity condi-
tioning is applied (9). In contrast to the lack of beneficial effects of
HSCT reported for patients with ataxia telangiectasia, transplantation
improved OS in NBS individuals diagnosed with cancer. Moreover,
preemptive HSCT performed in 14 individuals resulted in a more than
6-fold reduction in cancer incidence compared with patients with NBS
selected for natural history of cancer incidence. There were no
transplant-related deaths in the group of patients transplanted pre-
emptively. In future, probably other alternative treatment strategies
counteracting malignant transformation in NBS should be investigat-
ed. The example are substances which restore telomerase activity
already successfully used in patients with telomere diseases such as
dyskeratosis congenita (22).
In our study cohort, 13.2% of patients with NBS developed subse-
quent cancer. This frequency places NBS in the middle of the scale of
risk for second tumors in DNA repair disorders (12, 23). An exposure
to intensive chemotherapy was traditionally perceived to be a major
factor contributing to the development of second tumors (24). How-
ever, in our cohort, half of subsequent cancers occurred in patients
with NBS who obtained upfront reduced treatment, which should
theoretically result in a lower rate of second cancers.
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HSCT Improves Survival of Patients with NBS with Cancer
With respect to the recurrence of malignancy or the incidence of
secondary cancer after transplantation, three NHL relapses, one
subsequent lymphoma, and one case of renal carcinoma after
preemptive transplantation were observed. A year after HSCT, only
1 patient out of 49 (2.0%) developed posttransplant lymphoproli-
ferative disorder (PLTD). PLTDs are the most serious complication
of HSCT resulting from iatrogenically impaired immune surveil-
lance and Epstein–Barr virus primary infection/reactivation. On the
basis of our results, the overall incidence of PLTD among patients
with NBS seems to be similar as compared with nonsyndromic
recipients of HSCT, for which it was estimated to be 3.2% (25). In
addition, in contrast to patients with Fanconi anemia, patients with
NBS are probably less prone to developing secondary nonhemato-
logic tumors after HSCT (26). Only one primary solid tumor was
detected in patients with NBS 17 years after preemptive transplan-
tation. Although the median time of the follow-up after HSCT was
relatively short in our cohort, the probability of cancer is not high
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after transplantation.
One of the main limitations of our study is an ascertainment bias
resulting from the selection of NBS cases that were enrolled in the
study group from particular countries, including Germany, Czech
Republic, Slovakia, Serbia, Turkey, and Austria. To avoid possible
misinterpretation, we decided to analyze the Polish NBS cohort
separately as a possible representative group in which we investi-
gated the same associations as we could previously identify in the
entire cohort. Eventually, we managed to confirm both our assump-
tions of the Polish registry completeness and concordance of results
between Polish and entire NBS cohorts, which all together increased
the reliability of our observations. Finally, the selection of patients
for HSCT may have been affected by center-specific factors and
preferences with potential temporal bias. Patients who underwent
transplantation did so mostly after 2000, which may have affected
the quality of supportive and immunologic care provided. Never-
theless, the impact of transplantation persisted even if the year of
diagnosis was factored in the analysis, supporting our claim that
HSCT will contribute to longer OS without increasing the risk of
secondary cancers.
In summary, our results strongly support the notion of a beneficial
effect of HSCT in the first complete remission of cancer on the long-
term survival of patients with NBS. Although there are very promising
results after preemptive HSCT, there is still not enough data to estimate
its positive influence on long-term patient survival. Despite the above,
preemptive transplantation should be considered individually in every
patient considering the clinical severity of immune defects and other
comorbidities.
Authors’ Disclosures
A. Pastorczak reports grants and personal fees from National Science Centre and
grants from COST Action - CA16223 during the conduct of the study. K.-W. Sykora
reports grants and other from Medac GmbH outside the submitted work. M. Eapen
reports grants from NIH during the conduct of the study. M.G. Seidel reports personal
fees from Jazz Pharmaceuticals, Novartis, and Amgen, as well as nonfinancial support
from Shire outside the submitted work. No disclosures were reported by the other
authors.
Authors’ Contributions
B. Wolska-Kusnierz: Conceptualization, resources, supervision, investigation,
writing-original draft. A. Pastorczak: Conceptualization, resources, data curation,
formal analysis, investigation, writing-original draft. W. Fendler: Formal analysis,
investigation, methodology, writing-review and editing. A. Wakulinska: Resources,
writing-review and editing. B. Dembowska-Baginska: Conceptualization, resources,
writing-review and editing. E. Heropolitanska-Pliszka: Resources, writing-review
Clin Cancer Res; 27(2) January 15, 2021 583
 Wolska-Kusnierz et al.
and editing. B. Piatosa: Resources, writing-review and editing. B. Pietrucha:
Resources, writing-review and editing. K. Kalwak: Resources, writing-review and
editing. M. Ussowicz: Conceptualization, resources, writing-review and editing.
A. Pieczonka: Resources, writing-review and editing. K. Drabko: Resources,
writing-review and editing. M. Lejman: Resources, writing-review and editing.
S. Koltan: Resources, writing-review and editing. J. Gozdzik: Resources, writing-
review and editing. J. Styczynski: Resources, writing-review and editing.
A. Fedorova: Resources, writing-review and editing. N. Miakova: Resources,
writing-review and editing. E. Deripapa: Resources, writing-review and editing.
L. Kostyuchenko: Resources, writing-review and editing. Z. Krenova: Resources,
writing-review and editing. E. Hlavackova: Resources, writing-review and editing.
A.R. Gennery: Data curation, writing-review and editing. K.-W. Sykora: Resources,
writing-review and editing. S. Ghosh: Resources, writing-review and editing.
M.H. Albert: Resources, writing-review and editing. D. Balashov: Resources,
writing-review and editing. M. Eapen: Resources, writing-original draft. P. Svec:
Resources, writing-review and editing. M.G. Seidel: Resources, writing-review and
editing. S.S. Kilic: Resources, writing-review and editing. A. Tomaszewska:
Resources, writing-review and editing. E. Wiesik-Szewczyk: Resources, writing-
review and editing. A. Kreins: Resources, writing-review and editing. J. Greil:
Resources, writing-review and editing. J. Buechner: Resources, writing-review and
editing. B. Lund: Resources, writing-review and editing. H. Gregorek: Resources,
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Acknowledgments
This project has received funding from the European Union’s Horizon 2020
Research and Innovation Programme under ERA-NET Cofund action N643578 and
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