BACKGROUND: Nijmegen breakage syndrome (NBS) is an autosomal-recessive chromosome instability disorder characterized by, among others, hypersensitivity to X-irradiation and an exceptionally high risk for lymphoid malignancy. The vast majority of NBS patients is homozygous for a common Slavic founder mutation, c.657del5, of the NBN gene, which is involved in the repair of DNA double-strand breaks (DSBs). The founder mutation also predisposes heterozygous carriers to cancer, apparently however, with a higher risk in the Czech Republic/Slovakia (CS) than in Poland. AIM: To examine whether the age of cancer manifestation and cancer death of NBN homozygotes is different between probands from CS and Poland. METHODS: The study is restricted to probands born until 1989, before replacement of the communist regime by a democratic system in CS and Poland, and a substantial transition of the health care systems. Moreover, all patients were recruited without knowledge of their genetic status since the NBN gene was not identified until 1998. RESULTS: Here, we show that cancer manifestation of NBN homozygotes is at a significantly earlier age in probands from CS than from Poland. This is explained by the difference in natural and medical radiation exposure, though within the permissible dosage. CONCLUSION: It is reasonable to assume that this finding also sheds light on the higher cancer risk of NBN heterozygotes in CS than in Poland. This has implications for genetic counseling and individualized medicine also of probands with other DNA repair defects.
The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.
- MeSH
- detekce genetických nosičů MeSH
- dospělí MeSH
- efekt zakladatele * MeSH
- haplotypy MeSH
- jaderné proteiny genetika MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace * MeSH
- oprava DNA MeSH
- poškození DNA MeSH
- proteiny buněčného cyklu genetika MeSH
- rozmnožování genetika MeSH
- syndrom Nijmegen breakage etnologie genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
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.
- MeSH
- delece genu MeSH
- detekce genetických nosičů MeSH
- dospělí MeSH
- efekt zakladatele MeSH
- financování organizované MeSH
- genetická predispozice k nemoci MeSH
- heterozygot MeSH
- kolorektální nádory epidemiologie genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutační analýza DNA MeSH
- nádory prsu epidemiologie genetika MeSH
- nádory ženských pohlavních orgánů epidemiologie genetika MeSH
- odds ratio MeSH
- proteiny buněčného cyklu genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- zárodečné mutace MeSH
- zlomy chromozomů MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Geografické názvy
- Česká republika MeSH
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) that codes for a cAMP-regulated chloride channel. The R347P is a missense mutation located within the first membrane spanning domain (MSD1) of the CFTR protein. This mutation occurs with an overall worldwide frequency of about 0.2%. The patients, originally described with this mutation were compound heterozygotes with the delta F508 mutation and had a very mild course of CF, suggesting that R347P, similar to other missense mutations affecting the MSD1 domain, causes a mild phenotype. We report here a group of 19 CF patients with the R347P mutation of German, Bulgarian, Czech, and Slovak origin, including two homozygotes. Most patients presented with early disease onset, pancreas insufficiency (PI), and early pulmonary involvement, suggesting that this mutation can lead to a severe course of CF. Most R347P alleles in the group studied share a common polymorphic haplotype. In addition, these analyses gave evidence for recurrence of the mutation in two CF patients of German and Czech origin.
- MeSH
- cystická fibróza * genetika patologie MeSH
- exokrinní pankreatická insuficience * komplikace MeSH
- genotyp MeSH
- lidé MeSH
- mutace MeSH
- plicní nemoci * komplikace MeSH
- polymerázová řetězová reakce MeSH
- polymorfismus konformace jednovláknové DNA MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Geografické názvy
- Česká republika MeSH
- Německo MeSH
