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8 Genetic Diseases with a High Risk of Lymphoma: Ataxia-Telangiectasia and Nijmegen Breakage-Syndrome

8 Genetic Diseases with a High Risk of Lymphoma: Ataxia-Telangiectasia and Nijmegen Breakage-Syndrome

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22.8 Genetic Diseases with a High Risk of Lymphoma

At the cellular level, A-T and NBS show many similarities. Cells from patients

with both diseases have a high rate of spontaneous chromosome breakage. Characteristic of lymphocytes are clonal and non-clonal rearrangements involving the

T-cell receptor and immunoglobulin genes. Occasionally, fusions of chromosome

ends, so-called telomere fusions, are also observed. Cellular sensitivity towards

ionizing radiation is remarkable, particularly the failure to arrest DNA synthesis

after irradiation (radio resistant DNA synthesis).

Both genes are express ubiquitously. The NBS gene product, nibrin, is part of

a trimeric complex together with MRE11 and RAD50 (the MRN complex). This

complex is evolutionarily highly conserved, and in yeast consists of the proteins

Mre11, Rad50, and Xrs2, whereby Xrs2 represents the functional ortholog of

nibrin [3]. In yeast, and also in human cells, the MRN complex is involved in

DSB repair by both HR and NHEJ. Only seconds after irradiation, the MRN

complex relocates to the sites of DSBs where it holds the open DNA ends together.

The protein product of the AT gene, ATM, is recruited to the DSBs and converted

from an inactive dimer to an active, auto-phosphorylated monomer. The DNAbound MRN complex is a prerequisite for the activation of ATM. This protein

belongs to a highly conserved family of DNA-dependent protein kinases and,

indeed, phosphorylates a large number of target proteins, including nibrin, p53,

MDM2, CHK1, CHK2, BRCA1, and the histone, H2AX [4, 5]. However these

proteins are also phosphorylated in ATM-deficient cells, albeit at much slower

rates, by the related protein ATR. Particularly critical is the phosphorylation on

the transcription factor and tumor suppressor p53, which regulates both cell cycle

arrest and apoptosis.

As shown in Figure 22.3, the MRN complex is involved in the response to DNA

damage upstream and downstream of ATM. Nibrin performs apparently as a

sensor, since a complex of MRE11 and RAD50 alone does not relocate to DSBs

after irradiation. In consequence, ATM is not activated, thus nibrin also clearly

has a transducer function. Finally, nibrin is also an effector, since it is directly

involved in DSB repair by HR and NHEJ, and in checkpoint control through its

facilitating effect on ATM target phosphorylation.

In addition, ATM and nibrin are involved in the processing of DSBs, which

occur during the maturation of immuno-competent cells. ATM is clearly involved

in V(D)J recombination in T- and B-cells, whilst nibrin is never involved in this

process: the sensor of DSBs and transducer to ATM during immune gene rearrangement is apparently a different protein. On the other hand, nibrin is clearly

involved in immunoglobulin class switching, explaining the deficiencies in serum

IgG and IgA observed in NBS patients. In both A-T and NBS patients, there is

also a shift in the naive to memory T-cell ratio [6].

All these results can be assembled to obtain a greatly simplified pathophysiology

of the diseases, A-T and NBS. Thus, because of the gene mutations, the mutation

rate in rapidly proliferating lymphatic cells is particularly high with coincident

deficiencies in cell cycle checkpoints and apoptosis induction. The development

of T- and B-cell lymphoma during childhood is the almost inevitable outcome,

particularly in immunodeficient patients. It remains to be explained why T-cell



22 DNA-Repair Deficiency and Cancer: Lessons from Lymphoma

Figure 22.3 The MRE11/RAD50/nibrin complex and its role in the DNA double-strand break

response. The diagram highlights the role of the MRN complex and ATM in DSB repair and

checkpoint control. Some important critical phosphorylations are shown (-p). DSBs occur in

mammalian cells not only after IR exposure, but also as a result of physiological processes,

such as rearrangement of immunoglobulin genes and meiotic crossing over (after [1]).

For details, see text.

lymphoma is four times more frequent than B-cell lymphoma among A-T patients.

Under NBS patients, the B- and T-cell lymphomas occur equally often, but together

much more frequently than in A-T patients.

The chromosome instability inherent in NBS and A-T affects all cells and, in

both diseases, the risk for other haematological malignancies and for solid tumors

is also increased. Patients with a deficiency in DNA repair are generally sensitive

towards exogenous and endogenous mutagens. In this respect, free oxygen radicals generated during energy metabolism may pose a particular threat.


Lymphoma in Ataxia-Telangiectasia and Nijmegen Breakage Syndrome

Cancer is the most common cause of death in patients with NBS [7], and the

second most common in A-T patients [8, 9]. The precise molecular classification

22.9 Lymphoma in Ataxia-Telangiectasia and Nijmegen Breakage Syndrome

of lympho-proliferative disease and lymphomas occurring in A-T and NBS is still

incomplete, and it is often difficult to make a clear distinction between lymphoproliferation and overt lymphoma. Nevertheless, the calculated risk for developing

lymphoma is clearly dramatically increased to over 1000-fold, and 252-fold for NBS

and A-T patients, respectively (Boffetta et al., personal communication and [8]).

The life-time cancer risk of developing malignancy among A-T patients has been

estimated as about 38% [8], whilst in NBS it ranges from 40 to 65% in various

reports [7, 10]. Roughly, 80 to 85% of all the malignancies in A-T patients, and 85

to 90% in NBS patients are either lymphoma or leukemia. The incidence of lymphoma, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL),

is lower in A-T patients (50–60%) than in NBS patients (∼80%) [8–10]. Median age

of lymphoma development in A-T and NBS patients is about 8.5 and 9.5 years,

respectively (Chrzanowska, unpublished materials and [11]).

In October 2007, an examination of the Polish NB.S. Registry, with 105 patients

representing the largest national sample, revealed 51 lymphoid malignancies

among 56 primary cancers. Among the 51 lymphoid malignancies, there were 46

lymphomas, including 44 cases of NHL and 2 of HL. A slight predominance of

T-cell NHL (55%) over B-cell NHL (45%) was noted. Further analysis of the available data showed a high frequency of two morphological subtypes: T-cell lymphoblastic lymphoma (T-LBL) and diffuse large B-cell lymphoma (DLBCL), which

were diagnosed in 13 of 23 patients (57%) and 10 of 19 patients (53%), respectively.

Five Burkitt-like and one angio-immunobastic type T-cell lymphoma were also

diagnosed; the histological subtypes of the remaining tumors were not specified.

The ratio of T- to B-cell lymphoid malignancies in A-T patients is more difficult

to assess since many reports do not discriminate between the two. Some studies

show a clear predominance of T-cell over B-cell tumors; however, when only lymphomas are considered, the proportions are almost equal [12, 13]. Other authors

have pointed out that the histological origin of leukemia and lymphoma in A-T

patients may be different, with the latter being predominantly of B-cell origin [14].

This situation will only be clarified by the publication of the characteristics of all

tumors occurring in A-T patients in the future. Collectively, these data suggest the

predominance of two phenotypes of lymphomas in NBS, those of precursor T-cell

origin, and those representing mature large B-cell lymphomas.

In the general population, the majority of pediatric lymphomas stem from

B-cells (B-NHL), and the most prevalent are Burkitt lymphoma (43%) and diffuse

large B-cell lymphoma (13%) [15]. In comparison, in adults, DLBCL accounts for

30 to 40% of NHL [16]. Currently, DLBCL are grouped into three prognostically

distinct types: the germinal center B-cell type (GCB), the activated B-cell type

(ABC), and Type 3 or primary mediastinal DLBCL [17, 18]. A multicenter study of

altogether 63 cases of DLBCL in pediatric patients revealed a striking predominance (83%) of the germinal center B-cell-like (GCB) type, indicating that pediatric

DLBCL differs from adult DLBCL where this subtype makes up less than half of

the cases [19]. In this connection it is interesting to note that sporadic childhood

DLBCL has a generally more favorable prognosis than DLBCL in adulthood.

A thorough analysis of eight NBS-associated DLBCL tumors collected at one

center (CMHI) revealed that all cases are of the BCL6−/CD10− ABC type of DLBCL



22 DNA-Repair Deficiency and Cancer: Lessons from Lymphoma

(Gladkowska-Dura, personal communication). This tumor type exhibits a particularly aggressive biological behavior, and is associated with a much poorer prognosis. These findings are in line with an earlier report pointing out that the spectrum

of lympho-proliferative disease in NBS patients appears to be more characteristic

for adults than for children, and has an unfavorable clinical outcome [20, 21]. In

addition, B-cell monoclonality was confirmed by gene rearrangement studies in

all DLBCL tumors of these eight NBS patients, again showing a difference to other

primary or secondary immuno-deficiencies in which around 60% of B-cell lymphoproliferations are oligoclonal and polymorphic in nature [22].

Patients with A-T and NBS are known to be at risk of developing secondary

neoplasia; however, precise data have not been published. Earlier investigations

of the additional risk for A-T patients already diagnosed with one type of neoplasm

indicated that approximately 25% of patients with solid tumors subsequently

developed NHL or leukemia. In contrast, when the primary tumor was lymphoid

in origin, there was only a low risk of subsequent neoplasia [9]. In the Polish NBS

Registry, nine patients with lymphoma developed a second malignancy. Among

the secondary lympho-proliferations, there were seven lymphomas (6 B-cell and 1

T-cell) and two leukemias (T-ALL). It is striking that in all cases of lymphoma followed by a further lympho-proliferation, the primary lymphoma was Hodgkin

lymphoma or NHL of B-cell origin; no subsequent neoplasia were observed in

patients with NHL of T-cell origin. The median age at diagnosis of the second

lympho-proliferation was 13 years.

In a further detailed analysis of six multiple lympho-proliferations in NBS

patients, two types of secondary lymphomas could be defined. In four patients,

the second tumor was a reoccurrence of the initial lymphoma, DLBCL. This could

be a consequence of the relatively mild chemotherapy protocols employed due to

their toxic complications in NBS patients: this is naturally of great concern. In two

further patients, also with primary DLBCL, a true secondary lymphoma was found,

including one peripheral T-cell lymphoma (Gladkowska-Dura, personal communication). These new malignancies reflect the higher mutation rate with its potential for cancer development in NBS patients.

Of the 35 Czech NBS patients born between 1960 and 2004, 15 have died from

malignancies, 3 from infections, and 1 from congenital CNS malformation. Of the

surviving patients, 5 have a malignancy, which they have survived for an average of

11 years (range 6–16) since diagnosis. Eleven patients are cancer-free at an average

age of 11 years (range 1–33). The mean age at death from malignancy has increased

to 12 years (range 1–29) since the introduction of modified treatment protocols.

In 2 of these patients, there were 2 or 3 secondary malignancies 3 to 4 years

after diagnosis of the primary neoplasia. One boy had ALL at the age of 14, HL at

the age of 17, and at 26, he developed a hepatic tumor. A girl who manifested with

B-cell NHL at the relatively late age of 25 years, developed a T-cell NHL 3 years

later. Three patients are living after successful treatment of their malignancy: the

above-mentioned boy with three independent malignancies, a girl after malignant

meningeoma, and a boy who had a rhabdomyosarcoma. Two patients, a boy and

a girl, are alive at 20 years of age with NHL.

22.10 Treatment of Malignancies in Nijmegen Breakage Syndrome

In conclusion, the spectrum of lymphoma NBS patients differs clearly not only

from that of sporadic pediatric NHL, which are predominantly either Burkitt

lymphoma or large cell anaplastic/diffuse lymphoma, but also from NHL in

immunodeficient patients where oligoclonal B-cell proliferation predominates.

Clearly, this reflects a different mechanism of lymphomagenesis in NBS



Treatment of Malignancies in Nijmegen Breakage Syndrome

Twenty years ago, the oldest known Czech patient with NBS was 12 years of age;

of 8 patients, 5 died, 4 from lymphoreticular malignancy. Survival ranged from a

few days to weeks after diagnosis of malignancy. The former standard therapy for

lymphoreticular malignancy including radiotherapy led to rapidly progressive

organ insufficiency and death. Hyper-radiosensitivity of NBS patient cells was first

reported in 1989 [23], and from that time, malignancy in children with NBS was

treated by modified protocols completely avoiding ionizing radiation and radiomimetics. Initial doses of cytostatic drugs are considerably lower and are raised

very slowly under careful clinical observation. Survival is now for several years

after diagnosis and some patients have survived more than one malignancy

(see Table 22.2).

Table 22.2 Treatment of malignancy in NBS



Number of patients ascertained

Number of patients with malignancies

Total number of malignancies







Number of deceased patients

Death from malignancy

Death from infections

Death from congenital CNS malformation






11 + 4



Mean age at death from malignancy


5.5 y


12 y


Mean survival after diagnosis of malignancy

Number of patients surviving after

treatment of malignancy

0.1 y

3.3 y



Number of patients free from malignancy

Mean age






11 y




22 DNA-Repair Deficiency and Cancer: Lessons from Lymphoma

A further major factor in the improvement of the clinical prognosis of NBS since

1998 is the possibility of very early and exact diagnosis by direct detection of the

so-called Slavic mutation, 657del5, in exon 6 of the NBS gene [24]. Thus, confirmed

homozygotes can be appropriately protected from mutagens, and particularly from

ionizing radiation. Prior to identification of the NBS gene, the mean age at diagnosis was 7 years and was made solely on the basis of microcephaly, lymphoreticular malignancy, and toxic complications of standard tumor therapy. Since 1998,

the mean age at diagnosis in the Czech Republic has dropped to 4 months (range

2–5 months) due to the routine analysis of the NBS gene in all infants with congenital microcephaly [25].

Needless to say, the prognosis for lympho-proliferative disease and malignant

tumors in general has improved considerably over the past 20 years. For example,

in the Czech Republic, the proportion of surviving patients has increased from

40% in 1985 to 80% in 2006, due to progress in combined therapy protocols. Thus,

the successes in treating recurrent malignancies and modifications to chemotherapy have substantially improved the clinical prognosis for NBS patients.


Somatic Mutations in Sporadic Lymphoma

One of the most frequent deletions in lymphoid neoplasia is on the long arm of

chromosome 11, leading to loss of the ATM gene at 11q22.3 [26]. More than 50%

of mantel cell lymphomas (MCL) and 10 to 20% of chronic B-cell lymphocytic

leukemia (B-CLL) have this deletion. Similarly, T-cell prolymphocytic leukemia

(T-PLL) is often accompanied by a partial or complete loss of 11q. Inactivation

of the second ATM allele could be demonstrated in all six T-PLLs, showing that

ATM can behave as a typical “two-hit” tumor suppressor gene [27]. In the meantime, there is ample evidence that in many MCLs, B-CLLs, and T-PLLs, both

ATM alleles are defective [26]. Inactivation of ATM clearly plays an important

role in pathogenesis and tumor progression. Surprisingly, in NHL, which is

common in A-T patients, mutation in both ATM alleles is only rarely observed.

Similarly, mutations in the NBS gene play little or no role in sporadic lymphoma


It is well documented that a large number of lymphoid neoplasias, particularly

of the B-cell and myeloid lineages, are characterized by translocations of a more

or less specific nature. In the case of Burkitt lymphoma, the translocation breakpoints are located in intron 1 of the proto-oncogene, c-myc, and in the Sμ switch

region of the immunoglobulin heavy chain locus (IgH). In consequence, the c-myc

gene is regulated by the promoter/enhancer of the IgH gene; a critical first step

in the development of this lymphoma. Translocations can also lead to the generation of chimaeric proteins, such as the BCR-ABL tyrosine kinase in chronic

myelogenous leukemia (CML).

Such specific translocations suggest that the chromosomes involved are topologically connected. Indeed, in B-cells, the IgH and c-myc loci are neighbors. In

22.12 Outlook and Perspectives

CD34+ cells, the ABL gene and BCR region on chromosomes 9 and 22, respectively, are also in close proximity. However, it seems unlikely that this closeness

is sufficient to explain the high specificity of such translocations in the development of some lymphomas.

Many of the breakpoints of chromosome translocations involve genes involved

either in haematopoiesis, or in the regulation of the cell cycle [29]. A particularly instructive example is the translocation t(11;14)(q13;q32), which is highly

characteristic for MCL. This translocation brings the cyclin D1 gene, a central

regulator of the G1-phase of the cell cycle on 11q13, under the control of the

promoter of the immunoglobulin heavy chain gene on 14q32. Cyclin D1 is

overexpressed in cells carrying this translocation, with predictable effects on

cell proliferation.

Interestingly, haematological neoplasia often have two translocations, one affecting a gene involved in haematopoiesis whose disturbance blocks further differentiation, and one affecting a gene which leads to increased cell proliferation. In the

case of MCL, the frequent inactivation of the ATM gene leads to loss of DNA repair

processes and disturbances in cell cycle checkpoints, cumulating in the initiation

of the malignancy [30].


Outlook and Perspectives

The relationship between increased mutation rates and carcinogenesis touches a

central problem of tumor biology. Based on theoretical considerations of the

spontaneous mutation rate, Loeb proposed that a cell accumulates less than three

specific mutations within a normal lifetime: too few, considering the multistep

nature of tumor initiation. He concluded that an increase in the mutation rate

is a prerequisite for the malignant transformation of a cell [31]. Others were of a

somewhat different opinion. Tomlinson and Bodmer stressed the importance of

selection, leading to clonal expansion of those cells with a growth advantage. Just

as selection is the driving force of evolution among organisms, so it is for the

persistence of cells during tumorigenesis [32]. In this case, the normal spontaneous mutation rate is adequate, and an increased mutation rate can accelerate, but

not cause, the emergence of a tumor. With respect to diseases with a defect in

DNA repair, a constitutively increased mutation rate results in the early manifestation of cancer.

Knowledge of the molecular origin of hereditary and spontaneous lymphomas

also has consequences for therapy. Before elucidation of the molecular defect, NBS

and A-T patients with lymphoma were treated with radiotherapy, from which some

of them died. Nowadays, these patients can be successfully treated with low dose


In sporadic neoplasia, therapy sometimes depends on the particular chromosome translocation present. In case of the t(9;22) translocation in CML, the tyrosine kinase inhibitor Imatinib is the medication of choice since it inactivates the



22 DNA-Repair Deficiency and Cancer: Lessons from Lymphoma

BCR-AB.L. kinase. Patients with acute myeloid leukemia (AML) and a t(15;17)

translocation are treated with all-trans retinoic acid, which is directed towards the

chimaeric fusion receptor, PML-RAR. AML patients with inv(16) or t(8;21) respond

better to treatment with high doses of Cytarabine than those patients without these

chromosome rearrangements [29].

A great deal has been learned about cancerogenesis from the study of lymphoma, and the genes affected in haematological neoplasia. However, many questions still remain open – there is still much to be learned.


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Familial Leukemias

Christa Fonatsch


Leukemias and other hematological neoplasias are frequently observed in association with different genetic disorders, as DNA repair deficiency syndromes, tumor

predisposition syndromes, immunodeficiency syndromes, cancer family syndromes, and bone marrow failure syndromes, as well as in connection with several

constitutional chromosome anomalies. Recently, in families with increased leukemia incidence, constitutional mutations have been identified in genes that are also

affected by somatic mutations in sporadic leukemias. In addition to these high

penetrance mutations, gene alterations with a low penetrance and polymorphisms

seem to predispose to leukemia and/or modify the clinical course of the leukemia.

Predisposing and modifying polymorphisms can be found in genes involved in

cell proliferation, apoptosis, DNA repair, detoxification, and so on. A novel class

of small RNA molecules, the so-called microRNAs, also play a role in cancer and

presumably in leukemia pathogenesis. The findings on constitutional genetic

alterations predisposing to leukemia start to close the gap between inborn and

acquired genetic diseases.



The frequent occurrence of leukemias and lymphomas in association with DNA

repair deficiency syndromes (also called chromosome instability syndromes), and

also with Down’s syndrome represents a well established fact. But, most of the

leukemias and lymphomas occur sporadically and only a small number of hematopoietic neoplasias are due to constitutional genetic diseases. Research has demonstrated that a number of monogenic diseases as well as syndromes caused by

chromosome anomalies and also genetic polymorphisms, correlate with an

increased risk to neoplasias of the hematopoietic system. These new findings

create a bridge between leukemogenesis based on somatic (acquired) mutations

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