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Carcinogenesis Advance Access originally published online on July 13, 2006
Carcinogenesis 2007 28(1):107-111; doi:10.1093/carcin/bgl126
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cancer incidence in Nijmegen breakage syndrome is modulated by the amount of a variant NBS protein

Lars Krüger1, Ilja Demuth1, Heidemarie Neitzel1, Raymonda Varon1, Karl Sperling1, Krystyna H. Chrzanowska2, Eva Seemanova3 and Martin Digweed1,*

1 Institut für Humangenetik, Charité—Universitätsmedizin Berlin Campus—Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
2 Department of Genetics, Memorial Hospital-Child Health Center Al. Dzieci Polskich 20, 04-730 Warsaw, Poland
3 Department of Clinical Genetics, Institute of Biology and Medical Genetics, 2nd Medical School of Charles University V Úvalu 84, 150 06 Prague 5 -Motol, Czech Republic

*To whom correspondence should be addressed. Tel. +49 (0)30 450 566 016; Fax +49 (0)30 450 566 904; Email martin.digweed{at}charite.de


   Abstract
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 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
The human genetic disorder, Nijmegen breakage syndrome (NBS), is characterized by radiosensitivity, immunodeficiency and an increased risk for cancer, particularly B-cell non-Hodgkin lymphoma. The NBS1 gene codes for a protein, nibrin, involved in the processing/repair of DNA double-strand breaks and in cell cycle checkpoints. The majority of patients are homozygous for a founder mutation, a 5 bp deletion. This mutation is actually hypomorphic, since a functionally relevant truncated protein, of ~70 kDa, is produced by alternative translation. Null mutation of the homologous gene in mice is lethal; however, null-mutant murine cells can be rescued by a human NBS1 cDNA carrying the founder mutation. Clearly, the truncated p70-nibrin is able to sustain vital cellular functions of the full-length protein. We have used semi-quantitative immunoprecipitation to examine a panel of 26 lymphoblastoid B-cell lines from NBS patients for their level of p70-nibrin expression and correlate this with details of clinical phenotype provided by the two contributing centres. We find considerable variation in the amount of p70-nibrin in cell lines from different patients. Examination of clinical history indicated a clear and statistically significant correlation between p70-nibrin expression levels and lymphoma incidence. The variation in p70-nibrin levels between patients probably reflects the susceptibility of the alternative translation process to other genetic and non-genetic factors. Patients whose cells are able to maintain particularly high levels of the truncated p70-nibrin protein are at a lower risk for lymphoma than those patients with low levels of p70-nibrin in their cells.

Abbreviations: NBS, Nijmegen breakage syndrome


   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Patients affected by the autosomal recessive Nijmegen breakage syndrome [NBS (MIM 251260 [OMIM] )] have possibly the highest risk of developing a malignancy of all the chromosomal instability syndromes (1,2). This reflects the profound disturbance to genomic integrity and cellular homeostasis that is caused by the mutation of the essential mammalian gene, NBS1. Indeed, null mutation of NBS1 is lethal in the mouse (3,4), and NBS patients survive only owing to the fact that the common human mutation found in over 90% of patients (5,6) is in fact hypomorphic and leads to production of a partially functional C-terminal protein fragment. This 555 amino acid protein migrates on sodium dodecyl sulphate–polyacrylamide gels with 70 kDa (7,8) and is termed p70-nibrin here.

The full-length protein product of the NBS1 gene, nibrin, or here, p95-nibrin, is found in the cell in a complex with the proteins RAD50 and MRE11. This complex has been ascribed multiple roles in DNA repair (9–11) and cell cycle checkpoints (12). This dual gatekeeper/caretaker (13) character of nibrin almost certainly contributes to the particularly high incidence of malignancy in NBS patients. Even so, there is considerable variation in the clinical phenotype of NBS; for example, age at manifestation of malignancy varies significantly from 7 to 29 years under the patients described here.

Since viability is clearly dependent on the expression of a nibrin protein fragment, we postulated that the clinical course of the disease might be modulated by the amount of p70-nibrin protein produced. We have used immunoprecipitation to measure the relative amounts of p70-nibrin in lymphoblastoid B-cell lines established from a panel of 26 NBS patients and attempted to correlate the expression level with clinical phenotype. We find that low expression levels correlate with a more severe disease with malignancy and cancer death whilst higher expression levels of p70-nibrin were found in lymphoblastoids established from NBS patients who are currently cancer-free.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Cell lines
Peripheral blood was submitted to Berlin by the participating centres in Prague and Warsaw. B-lymphocytes were prepared and immortalized by infection with Epstein Barr Virus (EBV) as described previously (14). Lymphoblastoid cell lines were grown in RPMI with 10% fetal calf serum and antibiotics at 37°C, 5% CO2. Logarithmic growth of cells was ensured by regular cell counting and subculture.

Immunoprecipitation
Whole cell lysates were prepared from NBS lymphoblastoid cells and a control cell line using standard techniques. Lysates were incubated for 90 min at 4°C with protein G-coated magnetic beads (Dynabeads) preloaded with equal quantities of polyclonal rabbit antibodies directed against MRE11 (Novus Biologicals; immunogen: full-length Mre11 fusion protein) and nibrin (Novus Biologicals; immunogen: amino acids 395–742). After washing, the beads were boiled in gel loading buffer and the proteins released were separated on a 4–12% polyacrylamide gel (NuPAGE) and transferred to a Hybond ECL nitrocellulose membrane. MRE11 was detected using the murine monoclonal antibody 12D7 (GeneTex; immunogen: amino acids 182–582) diluted 1 : 2000 and nibrin with the murine monoclonal antibody p95/NBS1-1D7 (GeneTex; immunogen: full-length nibrin fusion protein) diluted 1 : 1000. Each immunoblot included the same control cell line freshly immunoprecipitated in parallel as a gel-to-gel internal control. The formula for calculating p70-nibrin levels in lymphoblastoid cell lines from individual patients based on immunoblot signal intensities was

Formula
Several exposures of each immunoblot were made in order to ensure that scanning and digital quantification were performed in the linear response range of the photographic film. Films were scanned using the ScanMaker scanner (Mikrotek) and the images were quantified using ImageQuant software (Molecular Dynamics).

Clinical data and statistical analyses
The same standardized questionnaire was used in both participating centres to collect data on 42 NBS patients from their physicians. The subset of 28 patients from whom cell lines were established was chosen randomly with no knowledge of clinical status. Patient data were collected before the immunoprecipitation analysis and updated after its conclusion. Patient ages were projected to the study termination date of August 1, 2005. Statistical analysis was performed using the GraphPad QuickCalc Internet tools (http://www.graphpad.com/quickcalcs/index.cfm).


   Results
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 Materials and methods
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Discussion
 References
 
Clinical databank
The 28 lymphoblastoid cell lines examined here were established from blood samples from NBS patients all homozygous for the major NBS1 mutation, 657del5. The cell lines were established between 1989 and 1998. Clinical data for the patients were provided in a standard questionnaire format from the two participating centres in Warsaw and Prague and entered into a databank in Berlin. The analyses of p70-nibrin levels in the lymphoblastoid cell lines was concluded in the summer of 2005, at which point updates of the clinical data were obtained and entered into the databank. Current data could not be obtained for two patients; these cell lines were subsequently removed from the study.

Table I shows details of the 26 NBS patients included in this analysis. On August 1, 2005, 13 patients were still alive with an average age of 17 years. Thirteen patients had died. Nine deaths were due to cancer, three due to respiratory insufficiency and one due to sepsis. Altogether, 14 patients had developed a cancer, and of these, 11 were lymphoma, with B-cell non-Hodgkin's lymphoma the most frequent malignancy (8 cases). Malignancy occurred at an average age of 12.6 years (range: 7–29). The average age of patients at death from cancer was 14.5 years (range: 7–29). Exactly one half of the patients were male, one half were female.


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  		Table I Data on the NBS patients included in this study

 
The immunoglobulin (Ig) status of the patients was compared with that of age-matched controls. Only three patients (14%) had IgG and IgA levels within the normal range. Combined IgA and IgG deficiency was found in 57% of the patients whilst deficiency of either IgG or IgA was found in 14% of the patients each.

Semi-quantitative immunoprecipitation
Figure 1A shows representative immunoprecipitation results for five NBS lymphoblastoid cell lines in comparison with a control cell line homozygous for wild-type NBS1. In each analysis, nibrin and MRE11 were simultaneously immunoprecipitated with specific antibodies. MRE11 was chosen as an internal standard since it has been previously established that the RAD50/MRE11 complex is undiminished in NBS patient cells despite the absence of nibrin (5,15,16). In control cells, a 95 kDa nibrin product is detected whilst in each NBS cell line a 70 kDa product detected by anti-nibrin antibody is observed; its amount, however, varies considerably from patient to patient. Immunoblots such as the one shown in Figure 1A were scanned and the relative amounts of MRE11 and p70-nibrin were measured using ImageQuant software. These were then normalized to the amounts of MRE11 and p95-nibrin found in the same control cells loaded on every immunoblot. We employed immunoprecipitation rather than western blotting because we anticipated that p70 levels might in some cases be lower than the sensitivity threshold of western blots. Furthermore, the use of two independent nibrin antibodies for precipitation and for detection offers a further guarantee of specificity. The NBS cell lines were immunopreciptated on average four times and the measurements were pooled (mean standard deviation: 5.55).


Figure 1
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  		Fig. 1 Relative p70-nibrin levels in NBS patient lymphoblastoid cell lines. (A) Immunoprecipitation of nibrin and MRE11 from lysates of one control and five NBS lymphoblastoid cell lines. p95-nibrin and p70-nibrin are indicated. (B) Bar chart of the relative p70-nibrin levels in the panel of 26 NBS cell lines; error bars indicate the standard error of the mean of multiple measurements. The 95% confidence limits of the panel-mean are shown as dotted lines.

 
The average level of p70-nibrin in the collection of NBS lymphoblastoid cell lines examined here was 21.1% of p95-nibrin in control cells; the range, however, was large: from 7 to 50% (Figure 1B). We have never observed such a large variation in the expression of p95-nibrin in lymphoblastoid cells from control individuals (data not shown). The expression of p70-nibrin is clearly subject to other restraints and influencing factors than full-length nibrin is.

Correlation of p70-nibrin levels with clinical phenotype
NBS patients have cellular and humoral immunoinsufficiency, but there is considerable variability. We have recently demonstrated that nibrin is involved in Ig class switching (11), thus explaining the characteristically low levels of IgG and IgA, but normal levels of IgM, found in patient serum (1,2). Since p70-nibrin can maintain some of the functions of p95-nibrin (8), we compared the levels of p70-nibrin in patients with normal Ig levels, with IgG or IgA deficiency and with combined IgA and IgG deficiency. There was no significant difference in p70-nibrin levels between these four groups; 15.35, 16.39, 26.58 and 23.78% of control p95-nibrin, respectively. Although the numbers are low, differences in Ig levels apparently do not correlate with the amount of p70-nibrin measured in patient cell lines, and variations in these levels are presumably due to variations in other components of the class-switching process.

A further examination of the data shown in Figure 1B suggested that p70-nibrin levels were below average in the majority of cell lines from those patients who had developed a malignancy whilst cells from cancer-free patients had generally above average p70-nibrin levels. To examine this statistically, the 95% confidence limits (17.48 and 24.65%) for the sample average were used to partition the lymphoblastoid cell lines, and the patients, into three groups: below the lower 95% confidence limit, within the 95% confidence limits and above the upper 95% confidence limit (dotted lines in Figure 1B). Projected age for the low p70-nibrin group was 15.7 years, not significantly different from the high p70-nibrin group (18.6 years) or the sample as a whole (18.1 years). The male-to-female ratio in the low p70-nibrin group was 0.43 in comparison with 1.7 in the high p70-nibrin group or 1.0 in the panel as a whole; these differences are, however, not statistically significant. The cancer occurrence in these three groups is detailed in Table II.


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  		Table II Cancer, lymphoma and cancer deaths in NBS patients in comparison with p70-nibrin levels in their lymphoblastoid cell lines

 
There is a clear and significant correlation between cancer occurrence in patients and p70-nibrin levels in their lymphoblastoid cell lines. Cancer is significantly more frequent amongst patients with low levels of p70-nibrin in their lymphoblastoid cell lines in comparison with patients with high p70-nibrin levels (P = 0.0152 in Fischer's Exact Test). There was no significant difference in age of occurrence of malignancy, 11.3 years, and death from malignancy, 15.1 years, in the low p70-nibrin group in comparison with the sample as a whole.

In the high p70-nibrin group there was no death from malignancy in comparison with seven deaths in the group with low levels of p70-nibrin (P = 0.0040 in Fischer's Exact Test). The age of occurrence of malignancy in the only cancer patient in the high p70-nibrin group was relatively late at 24 years in comparison with 12.1 years in the low p70-nibrin group or 12.6 years in the patients as a whole. This single value cannot be tested for significance but it clearly substantiates the previously described and statistically significant differences.


   Discussion
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 Introduction
 Materials and methods
 Results
 Discussion
References
 
The critical importance of the 70 kDa C-terminal nibrin protein fragment found in cells from NBS patients is illustrated by the fact that null-mutant mice are non-viable and die early in embryonic development (3,4). Furthermore, mice expressing truncated proteins similar to p70-nibrin are viable (17,18) and null-mutant murine cells can be rescued from death by transfer of a human cDNA carrying the major human mutation and expressing a 70 kDa protein fragment (8). Clearly, the presence of p70-nibrin is sufficient to uphold many of p95-nibrin's cellular functions. Indeed, it has been demonstrated that this protein fragment can bind to its molecular partners MRE11 and RAD50 and stimulate activation of ATM and ATM's downstream targets (15,19–21).

The 70 kDa C-terminal nibrin fragment is produced by alternative translation from two cryptic start codons upstream from the 5 bp deletion through which they are brought into frame (7). The molecular basis of this alternative translation is poorly understood. It was shown in an in vitro reporter system that internal ribosome entry occurred at the cryptic start codons; however, the sequence upstream of these ATGs could not function as an internal ribosome entry site (IRES) in the same system (7). In any case, the significance of such IRES sequences in the mammalian cell in vivo is still controversial (22).

Alternatively, leaky ribosome scanning of the NBS1 mRNA might allow significant initiation of translation at downstream sites, as described previously for other mRNAs (23). Whatever the mechanism, it is clearly much less efficient than normal translation from the first ATG, and it is reasonable to expect that it is dependent upon many cellular factors and will be more sensitive to perturbation. It was therefore of interest to question whether the amount of p70-nibrin produced in cells from different patients varied and whether the expression level correlated with any aspect of the disease phenotype.

We find that this is indeed the case. There is a 7-fold variation in p70-nibrin expression levels in a sample of 26 patient lymphoblastoid cells. Furthermore, those cell lines with particularly high levels of p70-nibrin were isolated from patients most of whom have not developed a malignancy within the timeframe of this study.

Conversely, those lymphoblastoid cell lines with significantly low levels of p70-nibrin, below the 95% confidence level, were from patients many of whom had developed a malignancy and died. Interestingly, the patient with the lowest p70-nibrin level measured (94P0195) and who was 18 years old at the end of the study without developing cancer is one of the few patients with a normal Ig status. It is tempting to speculate that better immunosurveillance in this patient has compensated for critically low levels of p70-nibrin. The majority of cancers in the patient group were B-cell non-Hodgkin's lymphoma, as reported previously for NBS (2,24,25). Thus, the EBV-immortalized lymphoblastoid B-cell lines employed here might have been particularly pertinent for correlation with clinical phenotype.

There is increasing evidence that the expression level of nibrin is critical. Firstly, mice heterozygous for null mutation of NBS1 develop more tumours and die earlier than wild-type mice, and this has been ascribed to a haploinsufficiency effect (4). Secondly, human NBS1 heterozygotes are similarly cancer-prone (26,27), NBS1 mutations have been found in patients with acute lymphoblastic leukaemia (28) and breast cancer (29), and allelic imbalance for NBS1 has been reported in colon cancer (30). Finally, we recently presented NBS patients who were compound heterozygotes for the major 657del5 mutation and the missense mutation R215W. This latter mutation leads to a marked destabilization of the protein and, together with 657del5, results in a phenotype even more severe than the classical NBS patient homozygous for NBS1-657del5 (31). Furthermore, in the yeast Saccharomyces cerevisiae, reductions in the expression level of the NBS1 functional analogue, Xrs2, have recently been shown to result in defects in meiotic DSB formation and telomere maintenance (32).

In conclusion, the expression of p70-nibrin is critical for survival of NBS patients. Nibrin is a protein with both caretaker and gatekeeper functions in the prevention of tumourigenesis (13) and these roles are partially upheld by the 70 kDa C-terminal protein fragment (8,19,33). In consequence, low levels of p70-nibrin expression correlate with the development of malignancy, presumably reflecting the cumulative effects of chronic nibrin deficiency. Those patients with higher expression levels remain cancer-free longer. It will be important now to identify the mechanisms and factors responsible for alternative translation of NBS1 mRNA and expression of p70-nibrin.


   Acknowledgments
 
We thank the NBS families for participating in this study. The excellent technical assistance of Mrs Susanne Rothe is gratefully acknowledged. This research was supported by funding from the Deutsche Forschungsgemeinschaft (SFB577) to K.S. and M.D. and from the Committee for Scientific Research in Poland (3P05E12423) to K.H.C.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received April 28, 2006; revised June 12, 2006; accepted June 17, 2006.


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