Journal of the National Cancer Institute Advance Access originally published online on December 11, 2007
JNCI Journal of the National Cancer Institute 2007 99(24):1875-1880; doi:10.1093/jnci/djm251
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Cancer Risk of Heterozygotes With the NBN Founder Mutation
Affiliations of authors: Department of Clinical Genetics, Institute of Biology and Medical Genetics (ES) and Department of Pediatric Neurology (PS), 2nd Medical School, Charles University, Prague, Czech Republic; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (PJ); Institute of Human Genetics, Charité—Universitätsmedizin Berlin, Humboldt-University, Berlin, Germany (RV, MD, KS); Disease Insight Research Foundation, Ardsley, NY (MS)
Correspondence to: Eva Seemanová, DrSc, Department of Clinical Genetics, Charles University Hospital, 2nd Medical School of Charles University, V úvalu 84, 150 06 Praha 5 Motol, Czech Republic (e-mail: eva.seemanova{at}lfmotol.cuni.cz).
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ABSTRACT |
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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.
Prior knowledge Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability disorder that is associated with increased risk of lymphoid malignancies and other cancers. More than 90% of NBS patients are homozygous for a founder mutation in the NBN gene, 657del5. The frequency of the 657del5 mutation varies from a low of 0.2% to a high of at least 1% in various Slavic populations. Study design Family study among blood relatives (i.e., first- through fourth-degree relatives) of NBS patients to test the hypothesis that NBN heterozygotes have an increased risk of any cancer. Contribution The NBN 657del5 founder mutation appears to be associated with an increased risk of cancer in heterozygotes. Implications There may be more than a million 657del5 carriers worldwide and the development of several hundred new cancers may be associated with this NBN mutation. Limitations Cancer sites reported on death certificates may be inaccurate. The confidence intervals for the estimated odds ratios of the association between the mutation and the risk of cancer are wide.
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Patients with the autosomal-recessive chromosomal instability disorder Nijmegen breakage syndrome (NBS) have microcephaly, growth retardation, immunodeficiency, predisposition to malignancy, and hypersensitivity to x-irradiation (1). Few NBS patients survive to the age of 20 years. Among NBS patients, particularly among those in early childhood, lymphoreticular malignancies occur frequently; hepatoma, malignant meningioma, gonadoblastoma, medulloblastoma, and rhabdomyosarcoma have also been observed (2).
The gene mutated in NBS patients was identified in 1998 as NBS1 (3–5); the currently recommended symbol for this gene is NBN. Nibrin, the product of the NBN gene, is a component of the MRE11–RAD50 complex, which is involved in the repair of double-stranded DNA breaks. Most NBS patients are of Central or Eastern European origin, and more than 90% are homozygous for a common founder mutation in the NBN gene, 657del5 (6).
Family data published before molecular genotyping was developed indicated that NBN heterozygotes have an elevated cancer risk (7). We tested the hypothesis that the NBN mutation 657del5 predisposes heterozygous carriers to cancer by investigating the relationship between the mutation and the occurrence of cancer in 24 NBS families.
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Patients and Methods |
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Patients and Their Relatives
For more than 20 years, one of us (E. Seemanova) has supervised the clinical management of essentially all patients with clinically confirmed NBS in the Czech Republic and Slovakia. This study was based on the compiled medical information from 24 NBS families. Seven of these families were counseled and repeatedly interviewed for a period of 20–25 years (January 1, 1978, through December 31, 2003), and seven other families were counseled and repeatedly interviewed for a period of 10–15 years (January 1, 1988, through December 31, 2003). The affected child (i.e., the index individual) of the remaining 10 families was diagnosed with NBS from January 1, 1994, through December 31, 2003. These latter 10 families with a relatively recent diagnosis of NBS were also counseled and interviewed. The major difference between these 10 families and the other 14 was that age at determination of the NBN mutation was earlier, generally shortly after the birth of a microcephalic child. Although this difference naturally has consequences for the medical care of the affected individual, it has no bearing on the likelihood of cancer occurring among his or her relatives.
All NBS patients in this study were homozygous for the same founder mutation, 657del5, in exon 6 of the NBN gene, as shown by molecular testing after 1998 (6). After the index individual was identified, as many relatives as possible in each family were contacted with the help of the index individual's parents. Attempts were made to contact all grandparents, all great aunts and great uncles (if alive), aunts, uncles, and first and second cousins of the parents of the index patient living in the Czech Republic. Individuals younger than 20 years of age were excluded from the study because they were considered to be too young for the development of most cancers; thus, the index patient's generation was excluded. Approximately 100 relatives could not be contacted at all because a correct address could not be obtained, 103 individuals did not respond to the letter asking for an interview, 32 responded with a refusal, and 11 relatives responded positively but were not at home at the date of appointment. Thus, of the 490 individuals who could be contacted, 338 were interviewed directly and questionnaire data for six deceased grandparents were provided by the surviving spouse. Data were thus available for 344 NBS relatives—206 from the parent's generation (60%), 114 from the grandparent's generation (33%), and 24 from the great-grandparent's generation (7%).
All oral interviews were conducted by only one person (E. Seemanova), who used a structured questionnaire. The questionnaire covered the individual's general, gynecologic, and obstetric medical histories; family medical history; sociodemographics; lifestyle; and occupational history. Socioeconomic status was inferred from the highest education level achieved. Almost all interviews took place at the homes of the participants, and each interview required approximately 60 minutes to complete. After the interview, a blood sample was collected to assay for the 657del5 mutation. The data and blood samples for this study were collected from January 1, 1998, through December 31, 2003. At the time of the interview, the carrier status for none of the relatives was known. NBN genotyping was carried out as previously described (3,6). Medical records, death certificate, and histologic samples were sought for all reported cancers.
Statistical Methods
The risk of cancer for a heterozygous carrier of the mutation 657del5 compared with the risk for a noncarrier was estimated by the index-test method (8). Great grandparents and siblings of the grandparents were included in this analysis. The carrier status for each relative with cancer who was not an obligate heterozygote (i.e., a "test cancer patient" within the scope of this study) was determined by molecular analysis (3,6) or, for deceased grandparents, by inference from the carrier status of the available spouse. If the remaining living grandparent was a noncarrier, the deceased grandparent from this couple was scored as a carrier, and vice versa. Male and female relatives were not considered separately.
Each test cancer patient had a prior probability of carrying the 657del5 mutation that was based on his or her relationship to the index individual and the carrier frequency of the 657del5 allele in the population of the Czech Republic (i.e., 0.006). The parents had a prior probability of 1.0, which was based solely on the relationship to the index patient, because they must carry the mutation transmitted to their child; thus, each aunt, uncle, and grandparent (in nonconsanguineous families) had a 0.5 chance of carrying the mutation. The sum of these individual prior probabilities gave the expected number of 657del5 carriers among all relatives with cancer. The observed number of NBN 657del5 carriers among all relatives with cancer was then compared with the number expected. The odds ratio (OR) = [R/(1 – R)]/[>/(1 – >)], where R is the observed proportion of heterozygous cancer patients and > is the expected proportion, and z score were calculated as previously described (8).
All 40 grandparents in 10 families were alive and participated in this analysis. In another four families, seven of the eight grandparents were alive and the carrier status of the deceased grandparent could be inferred from the genotype of his or her spouse. Thus, the carrier status and cancer status of all 56 grandparents in these 14 families were known. The cancer risk associated with the 657del5 mutation among these grandparents was calculated by use of the index-test method, as described above.
The study was approved by the ethics committee of the 2nd Medical School of the Charles University in Prague. All the participating subjects provided signed informed consent. All statistical tests were two-sided.
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Results |
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Cancer Occurrence in Relatives of the Index Patients With Nijmegen Breakage Syndrome
The cohort of index individual's relatives consisted of 141 carriers of the NBN 657del5 mutation and 203 individuals who were homozygous for the wild-type NBN allele, for a total of 344 relatives. The mean ages of the carriers (48.5 years, range = 24–85 years) and of the normal homozygotes (44.1 years, range = 21–93 years) were statistically significantly different (two-sided P = .05). No statistically significant difference was observed between carriers and noncarriers with respect to school or university attendance. In addition, no differences were detected between carriers and noncarriers with respect to smoking, occupational hazards (i.e., exposure to metals such as lead, mercury, or cadmium or chemicals such as dyes, insecticides, fuel products, phenols, anesthetic gases, drugs, or pharmaceuticals), or any type of x-ray exposure (data not shown). No therapeutic radiation exposure, other than radiation therapy for the cancer patients, before or during the study period was reported. At the time of this analysis, 19 of the 344 relatives had developed cancer (17 carriers and two noncarriers). Six of these 19 relatives with cancer were not eligible for the index-test analysis as discussed below. For the 13 relatives with cancer who were included in the analysis, their cancers were confirmed by medical records or death certificates and six of these 13 cancers were also confirmed by histologic samples.
Characteristics of the 13 cancer patients who were eligible for the index-test analysis, as described by Swift et al. (8), are listed in Table 1. Eleven of these 13 cancer patients were heterozygous carriers. The observed proportion, R, of heterozygous cancer patients was therefore 0.85. However, by adding the individual probabilities of heterozygosity for all 13 individuals, as given in Table 1, 6.0 heterozygotes were expected in this group (> = 0.46; OR of cancer for an NBN 657del5 carrier compared with that of a noncarrier = 6.3, 95% confidence interval [CI] = 1.4 to 28.2; P = .005).
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Characteristics of the six remaining cancer patients identified in this study are shown in Table 2. The three obligate heterozygotes (two fathers and a paternal grandmother) with cancer contributed nothing to the index-test analysis because their carrier status was known before genotyping. The cousin of a maternal grandmother (subject 25) and the maternal great grandmother (subject 35) and her sister (subject 36) were not included in the index-test analysis because only first- through fourth-degree relatives of the index individual were permitted by data collection protocol. Their inclusion might result in the biased ascertainment of cancer patients.
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A Special Case: The Grandparents of Index Patients
For 14 of the 24 families, the genetic status of all grandparents was determined and all relevant medical and sociodemographic data were available. The age distributions of carriers (mean age = 66.03 years; range = 51–97 years) and noncarriers (mean age = 66.33 years; range = 49–89 years) were almost identical. All other potential confounders (including nutrition, exposure to environmental mutagens, and availability of medical care) were similarly concordant. However, a statistically significant difference was observed in cancer incidence, with 10 cancer patients among the 28 heterozygotes and only one cancer patient among the 28 normal homozygotes (OR for cancer risk among carriers of the NBN 657del5 mutation = 10.7, 95% CI = 1.4 to 81.5; P<.004).
In the 10 families in which all 40 grandparents were alive at the time of this analysis, four cancer patients were identified among the 20 657del5 carriers but only one was identified among the 20 noncarriers. However, among the four families in which one or two grandparents had died, six cancer patients were identified among the eight grandparent carriers (five of whom were deceased) but none were identified among the eight grandparent noncarriers. These results highlight the substantially elevated cancer-related mortality among 657del5 carriers. Additional support for the increased cancer risk associated with heterozygosity for 657del5 was provided by analyses of the 50 obligate heterozygotes (including 48 parents and two grandparents), three of whom developed cancer, and the 203 noncarriers, two of whom developed cancer (P = .05, Fisher's exact test).
The most frequently observed cancer in our study was stomach cancer, with four patients with stomach cancer among the 17 cancer patients who also carried the 657del5 mutation. Site-specific information could not be obtained for three gynecologic cancers that were confirmed through death certificates. Among all carriers, two developed colorectal cancer and two developed breast cancer. In addition, one carrier developed a second primary tumor 5 years after radiotherapy of the primary tumor.
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Discussion |
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The statistically significant excess of NBN 657del5 mutation carriers that we found among test cancer patients supports the hypothesis that this allele predisposes heterozygous carriers to cancer. Support for this hypothesis is strengthened because all cancer patients were included in this study before his or her NBN genotype was known. In addition, results from almost all previously published case–control studies and case series support this hypothesis (9–24). Although confounders, inappropriate control subjects, population stratification, genetic heterogeneity, poor statistical power, or reduced penetrance sometimes limit the interpretation of such studies, these factors do not affect the index-test method when applied to all relatives (8) or to the grandparents for whom complete ascertainment was obtained in 14 families. In the analysis restricted to the grandparents, we found no evidence for any relevant selection bias from nonconsideration of the 10 families in which too few grandparents were alive and available for DNA testing. In addition, the 28 carrier and 28 noncarrier grandparents in the analysis showed no difference in age distribution and environmental risk factors; the only difference was the high cancer incidence among carriers. We consider this second approach to be of special value for the analysis of late-onset diseases, such as cancer.
This study has several limitations. The estimated odds ratio has wide confidence intervals. For some cancer patients, the cancer site reported on a death certificate may be inaccurate; for example, stomach cancer could refer to any intra-abdominal cancer discovered at autopsy. Moreover, the number of observed cancers could differ from that expected from an analysis of population vital statistics because of the so-called healthy worker effect or healthy family effect.
In principle, the proportion of cancer patients carrying a specific mutation can be estimated by the product of the relative risk and the mutation frequency in the population minus a small correction factor (25). Thus, in Poland and the Czech Republic, for example, both of which have an NBN 657del5 allelic frequency (6,9–12) of 0.006, approximately 4.0% of cancer patients might carry this allele if the true relative risk was 6.3. Of course, such an estimate of the frequency has wide 95% confidence intervals because the estimated relative risk has wide 95% confidence intervals.
The risk of cancer associated with NBN 657del5 mutations appears to differ by cancer type (Table 3). One study (10) found that 3.3% of prostate cancer patients in Poland were NBN 657del5 carriers. Two other studies (11,12) found that 2% of breast cancer patients in Poland were NBN carriers. In Russia, with a population frequency for the NBN 657del5 mutation of less than 0.3%, 0.8% of breast cancer patients carried 657del5 (13). This mutation may also predispose carriers to melanoma (14,15) and adult lymphoid cancers (9,16). Evidence for an association between the 657del5 allele and an increased risk of childhood lymphoid cancers has been suggested by some (17,18,20), but not all (22,23), data. Stomach cancer was the most frequently diagnosed cancer among the 657del5 carriers in our analysis, but the frequency of this allele has not yet been measured in a population series of patients with stomach cancer.
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Patients with the progressive neurologic disorder ataxia-telangiectasia and patients with the NBN founder mutation share a high incidence of cancer and frequent chromosome breaks and rearrangements and a high sensitivity to ionizing radiation (26). In a study of ataxia-telangiectasia families, the index-test method estimated that the female carrier's relative risk for breast cancer, compared with noncarriers (27), was 3.8. Patients with ataxia-telangiectasia have truncating mutations on 60%–70% of their ataxia-telangiectasia chromosomes. In contrast, a substantial excess of ataxia-telangiectasia missense mutations has been found in population case–control studies of breast cancer (28–30).
The frequency of the NBN 657del5 founder mutation varies from a low of 0.2% to a high of at least 1% in various Slavic populations (6). Therefore, more than a million carriers may exist worldwide, and the development of several hundred new cancers every year may be associated with NBN 657del5.
Moreover, some cancer patients carry another NBN germline mutation, R215W. The population frequency of the NBN R215W missense mutation is approximately three times higher in the United Kingdom than in Poland (Table 3), and R215W has been detected at high frequency among cancer patients. In Poland, the R215W missense mutation was found in 1.3% of patients with colorectal cancer and in 0.6% of all cancer patients (9). In the Czech Republic, the R215W missense mutation was found in 2% of patients with colorectal cancer and in 0.9% of all cancer patients (19,20). This mutation has also been found in cancer patients from Germany (17) and the United Kingdom (23). Moreover, two monozygotic twins, who were compound heterozygotes for the NBN R215W and 657del5 mutations, had severe clinical manifestations including neurologic abnormalities and myoclonic seizures (31). Other NBN missense mutations, which may not have been detected in NBS patients because such mutations were lethal in compound heterozygotes, may also be associated with increased risks of cancer. Precise determination of the risks of specific cancers associated with the combination of NBN 657del5 and R215W mutations and measurements of the frequency of these alleles in diverse populations should provide a useful estimate of the associations of these two alleles with the cancer burden worldwide.
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Funding |
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Sander Stiftung (1198-04-049-1 to K. S. and E. S.); DFG (SFB 577 to K. S. and M. D.); IGA MZ CR (NH 6439-3/2002, NR 7916-4/2004 to E. S.); ENS fellowship (NE 6912-4/2003 to P. S.).
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NOTES |
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We thank the Czechoslovakian Self Support Group of Chromosomal Instability Syndromes for collaboration and Mrs Anna Baumgartnerová, Markéta Skalová, and Kate
ina Gebertová for technical assistance. The authors take full responsibility for the design of the study; the collection, analysis, and interpretation of data; the writing of the manuscript; and the decision to submit the manuscript for publication.
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Manuscript received June 8, 2007; revised October 9, 2007; accepted November 2, 2007.
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