Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease characterized by microcephaly, growth retardation, severe immunodeficiency, and predisposition to lymphoid malignancy. In this report, we describe a case of a 9-year-old boy, previously diagnosed with NBS and symptoms of dyspnea, dry cough, and fever. Despite initial recognition of pneumonia, there was no response to broad spectrum antimicrobial treatment, negative results from microbiological tests, and unclear changes in lung imaging were observed. Therefore, further diagnostics were focused on suspected lymphoid malignancy and involved lung biopsy. Unexpectedly, histopathological examination revealed noncaseating granulomas. The introduction of systemic steroids resulted in significant improvement of the patient's clinical condition. This is the first description of primary pulmonary noncaseating granulomas without nodular involvement in a child with NBS.

Nijmegen breakage syndrome (NBS, MIM #251260) is an autosomal recessive chromosomal instability disorder. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks repair. Clinically, this is characterized by a microcephaly, immunodeficiency and a high incidence of pediatric malignancies, mostly lymphomas and leukemias. Anticancer treatment among patients with NBS is challenging because of a high risk of life threatening therapy-related toxicity including severe infections, bone marrow failure, cardio- and nephrotoxicity and occurrence of secondary cancer. Based on systemic review of available literature and the Polish acute lymphoblastic leukemia database we concluded that among patients with NBS, these who suffered from clinically proven severe immunodeficiency are at risk of the complications associated with oncological treatment. Thus, in this group it reasonable to reduce chemotherapy up to 50% especially concerning anthracyclines methotrexate, alkylating agents and epipodophyllotoxines, bleomycin and radiotherapy should be omitted. Moreover, infection prophylaxis using intravenous immunoglobulin supplementation together with antifungal and antibacterial agent is recommended. To replace radiotherapy or some toxic anticancer agents targeted therapy using monoclonal antibodies and kinase inhibitors or bone marrow transplantation with reduced-intensity conditioning should be considered in some cases, however, this statement needs further studies.

Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder characterized by a high incidence of pediatric hematologic malignancies. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks (DSB) repair. We report a case of a pediatric patient with NBS, who developed t(9;11)/AF9-MLL-positive AML as a second malignancy after successful treatment of T-NHL. The coexistence of NBN and MLL mutations suggests that the profound dysfunction of NBN may promote alterations of MLL that is mediated by error-prone non-homologous end joining pathway particularly in patients treated with DNA topoisomerase II inhibitors.

In mammalian cells more than 90% of double-strand breaks are repaired by NHEJ. Impairment of this pathway is associated with cell cycle arrest, cell death, genomic instability and cancer. Human diseases such as Nijmegen breakage syndrome, due to mutations in the NBS1 gene, produce defects in resection of double-strand breaks. NBS1 hypomorphic mutant mice are viable, and cells from these mice are defective in S phase and G2/M checkpoints. NBS1 polymorphisms have been associated with increased risk of breast cancer. We previously demonstrated that estradiol protected estrogen receptor (ER)-positive (+) breast cancer cell lines against double-strand breaks and cell death. We now demonstrate that protection from double-strand break damage in ER+ cells is mediated via regulation by c-myc, p53, CBP and SRC1 coactivators in intron 1 of the NBS1 gene. We concluded that NBS1 is responsible for estradiol-mediated protection from double-strand breaks in ER+ breast cancer cells.

The XCIND syndrome is named after distinct hypersensitivity to ionizing (X-ray) irradiation, cancer susceptibility, immunodeficiency, neurological abnormality, and double-strand DNA breakage. The disorders comprising XCIND syndrome are usually inherited in an autosomal recessive manner. Ataxia telangiectasia (A-T) is one such disease, and is caused by biallelic germline mutation of the Ataxia telangiectasia mutated (ATM) gene. Heterozygous carriers of the ATM mutation, who do not show A-T-like clinical symptoms, are estimated to comprise 1 % of the population. Thus, understanding the biological basis of XCIND, including A-T, should help shed light on the pathogenesis of genetic diseases with cancer susceptibility.

The adaptive component of the immune system depends greatly on the generation of genetic diversity provided by lymphocyte-specific genomic rearrangements. V(D)J recombination, class switch recombination (CSR), and somatic hypermutation (SHM) constitute complex and vulnerable processes that are orchestrated by a multitude of DNA repair pathways. When inherited defects in certain DNA repair proteins are present, lymphocyte development can be compromised and, consequently, patients can develop primary immunodeficiencies (PIDs). PID patients often have a strong predisposition for cancer development as a result of genomic instability generated from defective DNA repair mechanisms. Tumors of lymphoid origin are one of the most common PID-associated cancers, likely due to DNA lesions resulting from defective V(D)J, CSR, and SHM. In this review, we describe PID syndromes that confer an increased risk for cancer development. Furthermore, we discuss the role of the affected proteins in tumorigenesis/lymphomagenesis.

Children with chromosomal instability syndromes have an increased risk of developing lymphoma and leukaemia. The treatment of these malignancies is hampered by therapy-associated toxicity and infectious complications. This retrospective analysis evaluated the therapy outcome of 38 children with Ataxia teleangiectasia or Nijmegen-breakage syndrome with acute lymphoblastic leukaemia (ALL, n = 9), Non-Hodgkin lymphoma (NHL, n = 28) and Hodgkin lymphoma (HL, n = 1). All patients with NHL or ALL were treated in accordance to Berlin-Frankfurt-Münster (BFM)- or Co-operative study group for childhood ALL (CoALL)-oriented chemotherapy schedules. 22 patients received significantly reduced-intensity chemotherapy. After a median follow-up of 3·7 years the 10-year overall survival was 58%. Dosage-reduction of chemotherapeutic drugs seemed to have no disadvantages and reduced toxic side effects. On the other hand, reduced-intensity chemotherapy did not prevent second malignancies, which occurred in ten patients with a 10-year incidence of 25%. After individual treatment approaches three of these patients with second malignancies were in complete clinical remission for more than 5 years. We conclude that BFM- or CoALL-oriented chemotherapy is effective and can be administered in children with AT or NBS. Moreover, we show that even second lymphoid malignancies can successfully be treated in these patients.

Members of the breast cancer 1 (BRCA1) carboxy-terminal (BRCT) superfamily are involved in the cellular response to the DNA damage sensing and repair, as well as in the cell cycle control. All proteins are characterized by one or more BRCT domain(s), which provides a flexible framework representing scaffolding element(s) in multi-protein complexes. In particular, BRCA1, nibrin (NBN), and microcephalin (MCPH1), generally considered as molecular models for cancer-prone syndromes, contain BRCT domains able to bind phosphorylated proteins. Mutations within the BRCT domains of BRCA1, NBN, and MCPH1 are responsible for cancer susceptibility, both at the homozygous and heterozygous status. Here, we report a critical analysis of: (i) the BRCT domain structure, (ii) the role of BRCA1, NBN, and MCPH1 in DNA damage sensing and repair as well as in cell cycle control, and (iii) the pathological effects of mutations within the BRCT domains of BRCA1, NBN, and MCPH1.

Central nervous system (CNS) involvement is an independent risk factor for poor event-free survival and relapse confined to the CNS. Knock-out mice deprived of RAG2, the protein involved in DNA repair, developed leukemic infiltration within leptomeninges. Therefore, we hypothesized that DNA repair deficiencies in humans, such as Nijmegen breakage syndrome (NBS), may constitute a risk factor for CNS dissemination of acute lymphoblastic leukemia (ALL). Having analyzed the incidence of CNS2/CNS3 status at diagnosis of ALL in two independent cohorts from the Polish Pediatric Leukemia/Lymphoma Study Group, we noticed that among children with NBS CNS involvement was significantly frequent.

BACKGROUND: Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, microcephaly, and growth retardation. The NBS gene product, NBS1 (p95) or nibrin, is a part of the MRN complex, a central player associated with double-strand break (DSB) repair. We previously demonstrated that NBS1 overexpression contributes to transformation through the activation of PI 3-kinase/Akt. NBS1 overexpression also induces epithelial-mesenchymal transition through the Snail/MMP2 pathway.
METHODS: RT-PCR, Western blot analysis, in vitro migration/invasion, soft agar colony formation, and gelatin zymography assays were performed.
RESULTS: Here we show that heat shock protein family members, A4 and A14, were induced by NBS1 overexpression. siRNA mediated knockdown of HSPA4 or HSPA14 decreased the in vitro migration, invasion, and transformation activity in H1299 cells overexpressing NBS1. However, HSPA4 or HSPA14 induced activity was not mediated through MMP2. NBS1 overexpression induced the expression of heat shock transcription factor 4b (HSF4b), which correlated with the expression of HSPA4 and HSPA14.
CONCLUSION: These results identify a novel pathway (NBS1-HSF4b-HSPA4/HSPA14 axis) to induce migration, invasion, and transformation, suggesting the activation of multiple signaling events induced by NBS1 overexpression.

Selected viruses and immune parameters were monitored in 57 patients with Nijmegen breakage syndrome as a proposed tool for early detection of changes preceding development of malignancy. The following parameters were analysed: (1) viral infections; (2) monoclonal proteins; and (3) B-cell and T-cell receptor gene rearrangements in peripheral blood lymphocytes. Viral infections were detected in 68.4% of patients with a predominance of EBV (63.2%), followed by HBV (19.2%) and HCV (8.8%). Monoclonal gammopathy detected in 38.6% of cases correlated with the presence of EBV DNA (p=0.002) and HCV RNA (p=0.04). Clonal Ig and/or TCR gene rearrangements occurred in 73.9% of patients. The presence of at least one of the studied parameters preceded the development of malignancy in 22 patients. Systematic PCR analysis for viral infections and Ig/TCR gene rearrangements, supplemented by detection of monoclonal proteins, is advantageous in monitoring NBS patients before severe complications of the disease, including cancer, appear.

The NBN (NBS1) gene belongs to a group of double-strand break repair genes. Mutations in any of these genes cause genome instability syndromes and contribute to carcinogenesis. NBN gene mutations cause increased tumor risk in Nijmegen breakage syndrome (NBS) homozygotes as well as in NBN heterozygotes. NBS patients develop different types of malignancies; among solid tumors, medulloblastoma (MB), an embryonal tumor of the cerebellum, has been reported most frequently. The majority of medulloblastomas occur sporadically, some of them manifest within familial cancer syndromes. Several signaling pathways are known to be engaged in hereditary and sporadic MB. The aim of our study was to identify mutations in selected exons of the NBN gene and to determine the frequency of the most common NBN gene mutations in pediatric patients with different types of medulloblastoma. We screened a total of 104 patients with MB and identified 7 heterozygous carriers (6.7%) of two different germ-line mutations of NBN gene; all of them had classic MB. Our results indicate that heterozygous carriers of the germ-line NBN gene mutations (c.511A>G and c.657_661del5) may exhibit increased susceptibility to developing MB. The risk of medulloblastoma is estimated to be 3.0 (for c.511A>G) and 4.86 (for c.657_661del5) times higher than in the general Polish population (p<0.05). These results suggest that heterozygous NBN germ-line mutations may contribute to the etiology of medulloblastoma.

Nijmegen breakage syndrome (NBS) is a rare DNA repair disorder characterized by microcephaly, immunodeficiency, and predisposition to malignancy. We report on a 5-year-old patient with NBS who presented with nodular sclerosing type of Hodgkin disease stage IVB. Chemotherapy consisting of COPP/ABV regimen with reduction at 75% of full doses was employed. During this treatment, no major toxic or infectious complications were observed. Complete remission was achieved lasting now for 20 months. In DNA repair disorders, prognosis of Hodgkin disease is poor as opposed to excellent overall prognosis in general pediatric population. Better survival may be achieved both with adopted, disease-specific regimens, and individualized approach considering patient's clinical condition. Also, better recognition and treatment of infections during chemotherapy may reduce early deaths in patients with DNA repair disorders.

BACKGROUND: Due to small number of patients with Nijmegen Breakage Syndrome (NBS) and Non-Hodgkin lymphoma (NHL) experience in their treatment is limited.
PROCEDURE: Since 1996, 17 patients with a median age of 9.5 years who had NBS, were treated for NHL. NHL type, stage, chemotherapy, dose modifications, chemotherapy delays, response to chemotherapy, toxicity, outcome and correlation of drug reduction with response to treatment and outcome were analyzed.
RESULTS: Nine patients had TNHL, eight BNHL. TNHL patients received BFM and BNHL LMB type protocols. Doses of cytostatics were reduced in the first chemotherapy courses. Further modifications depended on severity of complications. None of the patients complied with timing of chemotherapy. Complete remissions after induction were achieved in 8 of 9 TNHL and 3 out 8 of BNHL patients. All patients experienced grade 4 toxicities. Two patients died from complications. Six of 17 patients are alive. All received more than 80% of recommended doses of chemotherapy. No differences in the type, number of responses or grade 3 and 4 toxicities between patients receiving less or more than 80% of drug doses were observed. Treatment related deaths concerned patients who received less than 80% of drug doses.
CONCLUSIONS: Patients with NBS develop both T and B cell lymphomas. Treatment outcome is poor and might be improved by administering over 80% of drug doses. Although toxicity often depends upon drug doses, our patients experienced equal grade 3 and 4 toxicities whether they received more or less than 80% of the chemotherapeutic agents.

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by microcephaly, immunodeficiency, radiation hypersensitivity, chromosomal instability and increased incidence of malignancies. In Poland 105 NBS cases showing mutations in the NBS gene (nibrin, NBN), have been diagnosed, approximately 53% of which have developed cancer, mainly (>90%) lymphoid malignancies. This study is based upon the largest reported group of NBS-associated lymphomas. The predominant lymphoma types found in these 14 NBS children were diffuse large B cell lymphoma (DLBCL) and T cell lymphoblastic lymphoma (T-LBL/ALL), all showing monoclonal Ig/TCR rearrangements. The spectrum of NBS lymphomas is completely different from sporadic paediatric lymphomas and lymphomas in other immunodeficient patients. Morphological and molecular analysis of consecutive lymphoproliferations in six NBS patients revealed two cases of true secondary lymphoma. Furthermore, 9/13 NBS patients with lymphomas analysed by split-signal FISH showed breaks in the Ig or TCR loci, several of which likely represent chromosome aberrations. The combined data would fit a model in which an NBN gene defect results in a higher frequency of DNA misrejoining during double-strand break (DSB) repair, thereby contributing to an increased likelihood of lymphoma formation in NBS patients.

PURPOSE: Cerebellar medulloblastoma is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutations is a rare autosomal recessive disease with clinical features that include microcephaly, mental and growth retardation, immunodeficiency, increased radiosensitivity, and predisposition to cancer. There may be functional interactions between NBS1 and the TP53 pathways. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of sporadic medulloblastomas.
EXPERIMENTAL DESIGN: Forty-two cases of medulloblastomas were screened for mutations in the NBS1 gene (all 16 exons) and the TP53 gene (exons 5-8) by single-stranded conformational polymorphism followed by direct DNA sequencing.
RESULTS: Seven of 42 (17%) medulloblastomas carried a total of 15 NBS1 mutations. Of these, 10 were missense point mutations and 5 were intronic splicing mutations. None of these were reported previously as germ-line mutations in NBS patients. No NBS1 mutations were detected in peritumoral brain tissues available in two patients. Of 5 medulloblastomas with TP53 mutations, 4 (80%) contained NBS1 mutations, and there was a significant association between TP53 mutations and NBS1 mutations (P = 0.001).
CONCLUSIONS: We provide evidence of medulloblastomas characterized by NBS1 mutations typically associated with mutational inactivation of the TP53 gene.

Approximately 1-5 percent of cancer patients suffer from significant side effects in normal tissue after radiotherapy (RT). Although RT is an effective cancer therapy, treatment dose intensities are restricted to minimize the incidence of such normal tissue reactions. Therefore, most patients receive lower dose intensities than can be tolerated in normal tissue. A primary aim for radiation oncology is to identify radiosensitive (RS) individuals prior to treatment. Such predictive ability should result in an improvement in tumor control rates and/or a reduction in the incidence of RT side effects. Recent evidence suggests a link between RS and telomere length. A positive correlation between cellular RS and telomere length in a cohort of breast cancer patients has been reported. Furthermore,individuals with cancer-prone recessive RS syndromes, such as ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome(NBS), have shortened telomeres. To determine whether the association between telomere length and RS could be used as a predictive assay to prospectively identify RS cancer patients, we utilized a bank of lymphoblastoid cell lines (LCLs) derived from 33 RS patients, along with 18 LCL samples from RT patients who did not have severe reactions, to assess the link between RS and telomere length. We found a subset of RS patient LCLs had abnormally long telomere lengths, so these data suggest that RS could potentially be predicted for a subset of RS patients based on telomere length in LCLs, and contribute to therapy individualization.

A 17-year-old Croatian boy with Nijmegen breakage syndrome (NBS) who developed diffuse large B-cell non-Hodgkin lymphoma is presented. The majority of the patients with this rare autosomal recessive disease are of Slavic origin and, in most of them, the disease is caused by NBS1 mutation 657del5, as was found in our patient. Nijmegen breakage syndrome is characterized by microcephaly, growth retardation, abnormal facial appearance, spontaneous chromosomal rearrangements, immunodeficiency, and a high predisposition to cancer development, predominantly lymphoma. Because of increased sensitivity to radiation therapy and chemotherapy, the treatment of malignancies in patients with NBS can be difficult. To our knowledge, our patient is the first with NBS reported in the literature who was successfully treated for diffuse large B-cell lymphoma with the anti-CD20 monoclonal antibody rituximab in addition to a modified dose of CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) chemotherapy. He has been in complete remission for 3 years after finishing the treatment.

BACKGROUND: The autosomal recessive chromosomal instability disorder Nijmegen breakage syndrome (NBS) is associated with increased risk of lymphoid malignancies and other cancers. Cells from NBS patients contain many double-stranded DNA breaks. More than 90% of NBS patients are homozygous for a founder mutation, 657del5, in the NBN gene. We investigated the 657del5 carrier status of cancer patients among blood relatives (i.e., first-, through fourth-degree relatives) of NBS patients in the Czech Republic and Slovakia to test the hypothesis that NBN heterozygotes have an increased cancer risk.
METHODS: Medical information was compiled from 344 blood relatives of NBS patients in 24 different NBS families from January 1, 1998, through December 31, 2003. The 657del5 carrier status of subjects was unknown at the time of their recruitment but was later determined from blood samples collected at the time of the interview. Medical records and death certificates were used to confirm a diagnosis of cancer. For the relatives with cancer who are not obligate heterozygotes (such as parents and two grandparents in consanguineous families), the observed and expected number of mutation carriers were compared by use of the index-test method, which estimated the risk of cancer associated with carrying the mutation. All P values were two-sided.
RESULTS: Thirteen of the 344 blood relatives had confirmed cases of any type of cancer; 11 of these 13 cancer patients carried the NBN 657del5 mutation, compared with 6.0 expected (P = .005). Among the 56 grandparents with complete data from 14 NBS families, 10 of the 28 carriers of 657del5, but only one of the 28 noncarriers, developed cancer (odds ratio = 10.7, 95% CI = 1.4 to 81.5; P<.004).
CONCLUSIONS: The NBN 657del5 mutation appears to be associated with an elevated risk of cancer in heterozygotes.

Mutations in the NBS1 gene have been identified as disease-causing mutations in patients with Nijmegen Breakage Syndrome (NBS), but their clinical impact on breast cancer susceptibility has remained uncertain. We determined the frequency of 2 NBS mutations, 657del5 and R215W, in two large series of breast cancer cases and controls from Northern Germany and from the Republic of Belarus. The 5-bp-deletion 657del5 was identified in 15/1,588 cases (0.9%) from Belarus and in 1/1,076 cases (0.1%) from Germany but in only 1/1,014 population controls from Belarus and 0/1017 German controls (p < 0.01). The missense substitution R215W was observed in 9/1,588 Byelorussian and 9/1,076 German patients (0.6% and 0.8%, respectively) but was also present in 5/1,014 Byelorussian and 2/1,017 German control individuals (adjusted OR = 1.9, 95%CI 0.8-4.6, p = 0.18). Studies of lymphoblastoid cell lines revealed that NBS1/p95 protein levels were reduced to 70% in cells from a heterozygous breast cancer patient carrying R215W and to 15% in cells from a NBS patient compound heterozygous for 657del5/R215W suggesting that the R215W substitution may be associated with protein instability. Levels of radiation-induced phosphorylation of Nbs1/p95(Ser343) were reduced to 60% and 35% of wildtype, respectively. Neither age at diagnosis nor family history of breast cancer differed significantly between carriers and noncarriers of NBS mutations. The combined data are in line with an about 3-fold increase in breast cancer risk for female NBS heterozygotes (OR 3.1; 95%CI 1.4-6.6) and indicate that the 657del5 deletion and perhaps the R215W substitution contribute to inherited breast cancer susceptibility in Central and Eastern Europe.

We found that the peripheral T lymphocytes from four of eight patients with the lymphoma predisposing Nijmegen Breakage Syndrome (NBS) acquired an unlimited growth potential following in vitro mitogen stimulation and subsequent interleukin-2-dependent propagation. The immortal T cell lines revealed morphological and other features typical for anaplastic large cell lymphoma (ALCL). In addition, multiple copies of ALK, but with no ALK gene rearrangements were found in a subpopulation of cells of one of the immortalized lines. These cell lines may be useful for the in vitro elucidation of mechanisms involved in the development of ALCL.

PURPOSE: Local failure and toxicity to adjacent critical structures is a significant problem in radiation therapy of cancers of the head and neck. We are developing a gene therapy based method of sensitizing head/neck squamous cell carcinoma (HNSCC) to radiation treatment. As patients with the rare hereditary disorder, Nijmegen breakage syndrome, show radiation sensitivity we hypothesized that tumor-specific disruption of the function of the Nbs1 protein would lead to enhanced cellular sensitivity to ionizing radiation.
EXPERIMENTAL PROCEDURES: We constructed two recombinant adenoviruses by cloning the full-length Nbs1 cDNA as well as the C-terminal 300 amino acids of Nbs1 into an adenovirus backbone under the control of a CMV promoter. The resulting adenoviruses were used to infect HNSCC cell line JHU011. These cells were evaluated for expression of the viral based constructs and assayed for clonogenic survival following radiation exposure.
RESULTS: Exposure of cells expressing Nbs1-300 to ionizing radiation resulted in a small reduction in survival relative to cells infected with control virus. Surprisingly, expression of full-length Nbs1 protein resulted in markedly enhanced sensitivity to ionizing radiation. Furthermore, the use of a fractionated radiation scheme following virus infection demonstrates that expression of full-length Nbs1 protein results in significant reduction in cell survival.
CONCLUSIONS: These results provide a proof of principle that disruption of Nbs1 function may provide a means of enhancing the radiosensitivity of head and neck tumors. Additionally, this work highlights the Mre11 complex as an attractive target for development of radiation sensitizers.

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 approximately 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.

During the past 20 years, the MRE11-RAD50-NBS1 complex has become an increasingly important focus in basic and clinical cancer research. One main conceptual step forward was made with the discovery of NBS1 and the understanding of its critical pathophysiological role in Nijmegen breakage syndrome. Major efforts were carried out to define the role in DNA repair of this complex. Recently, basic research has continuously extended our understanding of the complexity of the NBS1 complex. MRE11-RAD50-NBS1 complex can no longer be viewed as having a single role in DNA damage repair since it also serves as a sensor and a mediator in cell cycle checkpoint signaling. Meanwhile, studies have challenged the concept that NBS1 only functions as a tumor suppressor in preserving genome integrity in the nucleus. It may also provide an oncogenic role in the cytoplasm which is associated with the PI3-kinase/AKT-activation pathway. Consistent with this aspect, a growing body of clinical evidence suggests that NBS1 contains a deleterious character that depends on its subcellular localization. This review focuses on recent experimental evidences demonstrating how NBS1 is translocated into the nucleus by an importin KPNA2 which mediates NBS1 subcellular localization and the functions of the NBS1 complex in tumorigenesis.

The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples.

Nijmegen breakage syndrome (NBS) is a rare autosomal-recessive disorder characterized by microcephaly, immunodeficiency and predisposition to cancer, mainly B-cell lymphomas. Our 10-years-old female patient with NBS developed T-cell lymphoblastic leukemia/lymphoma (TLBL/ALL). The use of standard chemotherapy in our patient, except for cranial irradiation, led to complete and sustained remission of TLBL/ALL. In patients with chromosomal instability syndromes chemotherapy must be modified and radiotherapy must be omitted because of potentially serious toxic complications. Careful prevention of infections, including the use of intravenous immunoglobulin is also essential for successful treatment of lymphoid malignancies in NBS. Immunodeficiency in NBS is profound affecting both humoral and cellular immune system. During long-term follow-up after treatment of malignancy our patient remained free of major infections However, the rise of oligoclonal serum IgM was detected recently. Monitoring of serum IgM concentration may be a useful indicator for early detection of lymphomas in NBS.