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C Cybulski,
D Wokołorczyk,
W Kluźniak,
A Kashyap,
A Gołąb,
M Słojewski,
A Sikorski,
M Puszyński,
M Soczawa,
T Borkowski, [......],
J Gronwald, A Jakubowska,
B Górski,
T Dębniak,
B Masojć,
T Huzarski,
K R Muir,
A Lophatananon,
J Lubiński,
S A Narod
[show abstract]
[hide abstract]
ABSTRACT: Background:To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens.Methods:A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40-90. Three hundred and twenty-three men with an elevated PSA (4 ng ml(-1)) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs).Results:On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03).Conclusion:These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal.British Journal of Cancer advance online publication 30 May 2013; doi:10.1038/bjc.2013.261 www.bjcancer.com.
British Journal of Cancer 05/2013; · 5.04 Impact Factor
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F J Couch,
X Wang,
L McGuffog,
A Lee,
C Olswold,
K B Kuchenbaecker,
P Soucy,
Z Fredericksen,
D Barrowdale,
J Dennis, [......],
D G Evans,
L Izatt,
R A Eeles,
J Adlard,
D M Eccles,
J Cook,
C Brewer,
F Douglas,
S Hodgson,
others
[show abstract]
[hide abstract]
ABSTRACT: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7x10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4x10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4x10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2x10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
01/2013: pages e1003212;
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C Cybulski,
D Wokołorczyk,
W Kluźniak, A Jakubowska,
B Górski,
J Gronwald,
T Huzarski,
A Kashyap,
T Byrski,
T Dębniak, [......],
A Paradysz,
K Jersak,
J Niemirowicz,
P Słupski,
P Jarzemski,
M Skrzypczyk,
J Dobruch,
P Domagała,
S A Narod,
J Lubiński
[show abstract]
[hide abstract]
ABSTRACT: Background:To establish the contribution of eight founder alleles in three DNA damage repair genes (BRCA1, CHEK2 and NBS1) to prostate cancer in Poland, and to measure the impact of these variants on survival among patients.Methods:Three thousand seven hundred fifty men with prostate cancer and 3956 cancer-free controls were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA, C61G), four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), and one allele in NBS1 (657del5).Results:The NBS1 mutation was detected in 53 of 3750 unselected cases compared with 23 of 3956 (0.6%) controls (odds ratio (OR)=2.5; P=0.0003). A CHEK2 mutation was seen in 383 (10.2%) unselected cases and in 228 (5.8%) controls (OR=1.9; P<0.0001). Mutation of BRCA1 (three mutations combined) was not associated with the risk of prostate cancer (OR=0.9; P=0.8). In a subgroup analysis, the 4153delA mutation was associated with early-onset (age 60 years) prostate cancer (OR=20.3, P=0.004). The mean follow-up was 54 months. Mortality was significantly worse for carriers of a NBS1 mutation than for non-carriers (HR=1.85; P=0.008). The 5-year survival for men with an NBS1 mutation was 49%, compared with 72% for mutation-negative cases.Conclusion:A mutation in NBS1 predisposes to aggressive prostate cancer. These data are relevant to the prospect of adapting personalised medicine to prostate cancer prevention and treatment.British Journal of Cancer advance online publication, 13 November 2012; doi:10.1038/bjc.2012.486 www.bjcancer.com.
British Journal of Cancer 11/2012; · 5.04 Impact Factor
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A Jakubowska,
D Rozkrut,
A Antoniou,
U Hamann,
R J Scott,
L McGuffog,
S Healy,
O M Sinilnikova,
G Rennert,
F Lejbkowicz, [......],
Z Fredericksen,
V S Pankratz,
P Peterlongo,
B Bonanni,
S Fortuzzi,
B Peissel,
C Szabo,
P L Mai,
J T Loud,
J Lubinski
[show abstract]
[hide abstract]
ABSTRACT: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.
To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.
There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.
The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.
British Journal of Cancer 06/2012; 106(12):2016-24. · 5.04 Impact Factor
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Hereditary Cancer in Clinical Practice 04/2012; 9:1-5. · 1.68 Impact Factor
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J Lubiński,
T Huzarski, A Jakubowska,
J Gronwald,
K Jaworska,
M Muszyńska,
G Sukiennicki,
K Durda,
C Cybulski,
T Dębniak,
A Tołoczko,
O Oszurek,
P Serrano-Fernandez,
R Scott,
S Narod
Hereditary Cancer in Clinical Practice 01/2012; 10 Suppl 1:A11. · 1.68 Impact Factor
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K Jaworska, A Jakubowska,
T Huzarski,
K Durda,
P Serrano-Fernandez,
G Sukiennicki,
M Muszyńska,
T Byrski,
J Gronwald,
S Gupta,
J J Lubiński
Hereditary Cancer in Clinical Practice 01/2012; 10 Suppl 1:A8. · 1.68 Impact Factor
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Hereditary Cancer in Clinical Practice 01/2012; 10 Suppl 1:A7. · 1.68 Impact Factor
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K. M. Im,
T. Kirchhoff,
X. Wang,
T. Green,
C. Y. Chow,
J. Vijai,
J. Korn,
M. M. Gaudet,
Z. Fredericksen,
V. Shane Pankratz, [......],
R. J. Klein,
M. J. Daly,
E. Friedman,
M. Dean,
A. G. Clark,
D. M. Altshuler,
A. C. Antoniou,
F. J. Couch,
K. Offit,
B. Gold
[show abstract]
[hide abstract]
ABSTRACT: Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
Human genetics. 01/2011; 130(5):685-99.
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P Willems,
V Magri,
M Cretnik,
M Fasano, A Jakubowska,
S Levanat,
J Lubinski,
E Marras,
V Musani,
H Thierens,
V Vandersickel,
G Perletti,
A Vral
[show abstract]
[hide abstract]
ABSTRACT: In the Milan area (Northern Italy), we identified a family characterized by a high prevalence of ovarian and breast cancer cases (5 out of 6 subjects, over 3 generations), and a predominant prevalence of ovarian lesions (4 out of 5 patients). Analysis of BRCA1 and BRCA2 genes allowed the identification of the missense c.190T>C mutation in codon 64 (Cys64Arg) of BRCA1. The aims of the present investigation were to characterize the functional implications of the c.190T>C mutation at the molecular level, and to search whether additional polymorphisms might be linked to the peculiar phenotypic features observed in the Italian pedigree. Molecular modelling studies suggested that substitution of the cysteine 64 with an arginine likely disrupts the architecture of the BRCA1 RING finger domain, responsible for the interaction with BARD1, essential for the tumor-suppressor activity of the BRCA1-BARD1 complex. By splicing site information analysis, exonic splicing enhancer site characterization, and analysis of transcript fragment length and sequence, we showed that the c.190T>C mutation was able to modulate the splicing of exon 5 in a fashion opposite to the c.190T>G transversion, responsible for the functionally-related Cys64Gly amino acid substitution. Genotyping of BRCA1 and BRCA2 in the Italian family revealed the presence of two significant polymorphisms: the cancer-associated c.2612C>T SNP in BRCA1, and the c.-26G>A SNP in the BRCA2 gene, acting as an ovarian cancer risk modifier in carriers of deleterious BRCA1 mutations. Analysis of these SNPs in a genotypically-unrelated Polish family, characterized by prevalent breast neoplasms in carriers of the c.190T>C mutation, revealed a genetic profile consistent with the hypothetic role of both polymorphisms.
International Journal of Oncology 05/2009; 34(4):1005-15. · 2.40 Impact Factor
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C Cybulski,
T Huzarski,
T Byrski,
J Gronwald,
T Debniak, A Jakubowska,
B Górski,
D Wokołorczyk,
B Masojć,
S A Narod,
J Lubiński
[show abstract]
[hide abstract]
ABSTRACT: To investigate the relationship between CHEK2 mutation status and estrogen receptor (ER) status in unselected cases of early-onset breast cancer from Poland, we screened 4441 women diagnosed with breast cancer younger than 51 years and 7217 controls for three inherited mutations in CHEK2 (1100delC, IVS2+1G>A, del5395). ER status was compared between CHEK2-positive and CHEK2-negative breast cancer cases. A truncating mutation in CHEK2 was seen in 140 of 4441 cases and in 70 of 7217 controls [odds ratio (OR) = 3.3; 95% CI = 2.5-4.4; p < 0.0001]. ER status was available for 92 of 140 mutation carriers and for 3001 of 4301 non-carriers with breast cancer. The OR was higher for ER-positive cancers (OR = 3.9; 95% CI = 2.7-5.4; p < 0.0001) than for ER-negative cancers (OR = 2.1; 95% CI = 1.3-3.3; p = 0.002). Sixty-six of the 92 breast cancers in carriers of CHEK2 truncating mutations were ER positive compared with 1742 of the 3001 breast cancers in non-carriers (72% vs 58%; p = 0.01). Women with a CHEK2 mutation face a fourfold increase in the risk of ER-positive breast cancer and might be candidates for tamoxifen chemoprevention.
Clinical Genetics 12/2008; 75(1):72-8. · 3.13 Impact Factor
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A Osorio,
M Poll|[aacute]|n,
G Pita,
R K Schmutzler,
B Versmold,
C Engel,
A Meindl,
N Arnold,
S Preisler-Adams,
D Niederacher, [......],
B Peissel,
P Peterlongo,
P Radice,
T Heikkinen,
H Nevanlinna,
P L Mai,
J T Loud,
L McGuffog,
A C Antoniou,
J Benitez
[show abstract]
[hide abstract]
ABSTRACT: The close functional relationship between p53 and the breast cancer susceptibility genes BRCA1 and BRCA2 has promoted the investigation of various polymorphisms in the p53 gene as possible risk modifiers in BRCA1/2 mutation carriers. Specifically, two polymorphisms in p53, c.97-147ins16bp and p.Arg72Pro have been analysed as putative breast cancer susceptibility variants, and it has been recently reported that a p53 haplotype combining the absence of the 16-bp insertion and the presence of proline at codon 72 (No Ins-72Pro) was associated with an earlier age at the onset of the first primary tumour in BRCA2 mutation carriers in the Spanish population. In this study, we have evaluated this association in a series of 2932 BRCA1/2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.Keywords: BRCA1, BRCA2, p53, breast cancer
British Journal of Cancer 09/2008; 99(6):974-977. · 5.04 Impact Factor
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T Debniak,
R J Scott,
B Górski,
C Cybulski,
T van de Wetering,
P Serrano-Fernandez,
T Huzarski,
T Byrski,
L Nagay,
B Debniak,
E Kowalska, A Jakubowska,
J Gronwald,
D Wokolorczyk,
R Maleszka,
J Kładny,
J Lubinski
[show abstract]
[hide abstract]
ABSTRACT: In the current study, we evaluated the possible associations of seven common variants of the DNA repair and cell cycle control genes BRCA2 and CHEK2 with malignant melanoma (MM). We genotyped 630 unselected MM patients and over 3700 controls (newborns, age- and sex-matched healthy adults with negative cancer family histories, and the adults selected at random by family doctors) for the prevalence of three common variants of the BRCA2 (T1915M, N991D and N372H) and four common variants of the CHEK2 (1100delC, VS2+1G --> A, I157T and del5395). Our study strongly suggests that the common variant of the BRCA2 gene -- the N991D variant is associated with malignant melanoma risk (OR=1.8, p=0.002 after Bonferroni correction). Patients homozygote for the N991D variant were present in 0.32% of cases and only 0.13% of controls. The other variants studied were not over-represented among MM patients when compared to the general population. In conclusion, we report an increased melanoma risk among carriers of the N991D change of the BRCA2 and no association of the CHEK2 changes with malignant melanoma.
European Journal of Cancer 01/2008; 44(1):110-4. · 5.54 Impact Factor
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C Cybulski,
D Wokołorczyk,
T Huzarski,
T Byrski,
J Gronwald,
B Górski,
T Debniak,
B Masojć, A Jakubowska,
B Gliniewicz, [......],
P Sikorska-Radek,
K Bar,
R Klijer,
R Zdrojowy,
B Małkiewicz,
A Borkowski,
T Borkowski,
M Szwiec,
S A Narod,
J Lubiński
[show abstract]
[hide abstract]
ABSTRACT: Germline mutations in the Chek2 kinase gene (CHEK2) have been associated with a range of cancer types. Recently, a large deletion of exons 9 and 10 of CHEK2 was identified in several unrelated patients with breast cancer of Czech or Slovak origin. The geographical and ethnic extent of this founder allele has not yet been determined.
We assayed for the presence of this deletion, and of three other CHEK2 founder mutations, in 1864 patients with prostate cancer and 5496 controls from Poland.
The deletion was detected in 24 of 5496 (0.4%) controls from the general population, and is the most common CHEK2 truncating founder allele in Polish patients. The deletion was identified in 15 of 1864 (0.8%) men with unselected prostate cancer (OR 1.9; 95% CI 0.97 to 3.5; p = 0.09) and in 4 of 249 men with familial prostate cancer (OR 3.7; 95% CI 1.3 to 10.8; p = 0.03). These ORs were similar to those associated with the other truncating mutations (IVS2+1G-->A, 1100delC).
A large deletion of exons 9 and 10 of CHEK2 confers an increased risk of prostate cancer in Polish men. The del5395 founder deletion might be present in other Slavic populations, including Ukraine, Belarus, Russia, Baltic and Balkan countries. It will be of interest to see to what extent this deletion is responsible for the burden of prostate cancer in other populations.
Journal of Medical Genetics 12/2006; 43(11):863-6. · 6.36 Impact Factor
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G Kurzawski,
J Suchy,
M Lener,
E Kłujszo-Grabowska,
J Kładny,
K Safranow,
K Jakubowska, A Jakubowska,
T Huzarski,
T Byrski, [......],
I Brozek,
B Wysocka,
J Limon,
A Jawień,
Z Banaszkiewicz,
H Janiszewska,
J Kowalczyk,
D Czudowska,
R J Scott,
J Lubiński
[show abstract]
[hide abstract]
ABSTRACT: Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.
Clinical Genetics 02/2006; 69(1):40-7. · 3.13 Impact Factor
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G Kurzawski,
J Suchy,
M Lener,
E Kłujszo-Grabowska,
J Kładny,
K Safranow,
K Jakubowska, A Jakubowska,
T Huzarski,
T Byrski, [......],
I Brożek,
B Wysocka,
J Limon,
A Jawień,
Z Banaszkiewicz,
H Janiszewska,
J Kowalczyk,
D Czudowska,
RJ Scott,
J Lubiński
[show abstract]
[hide abstract]
ABSTRACT: Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.
Clinical Genetics 12/2005; 69(1):40 - 47. · 3.13 Impact Factor
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B Górski,
C Cybulski,
T Huzarski,
T Byrski,
J Gronwald, A Jakubowska,
M Stawicka,
S Gozdecka-Grodecka,
M Szwiec,
K Urbański, [......],
O Haus,
H Janiszewska,
T Debniak,
A Tołoczko-Grabarek,
K Medrek,
B Masojć,
M Mierzejewski,
E Kowalska,
S A Narod,
J Lubiński
[show abstract]
[hide abstract]
ABSTRACT: Mutant alleles of several genes in the DNA repair pathway have been found to predispose women to breast cancer. From a public health perspective, the importance of a given allele in a population is determined by the frequency of the allele and by the relative risk of breast cancer that it confers. In Poland founder alleles of the BRCA1, CHEK2 and NBS1 genes have been associated with an increased risk of breast cancer, but the relative contribution of each of these alleles to the overall breast cancer burden has not yet been determined. We screened 2012 unselected cases of breast cancer and 4000 population controls for 7 different mutations in these genes. Overall, a mutation was found in 12% of the cases and in 6% of the controls. Mutations in BRCA1 and CHEK2 contributed in approximately equal measure to the burden of breast cancer in Poland. A BRCA1 mutation was present in 3% of the cases. The missense BRCA1 mutation C61G was associated with a higher odds ratio for breast cancer (OR=15) than were either of the truncating BRCA1 mutations 4153delA (OR=2.0) and 5382insC (OR=6.2). In contrast, a higher odds ratio was seen for truncating CHEK2 mutations (OR=2.1) than for the missense mutation I157T (OR=1.4). This study suggests that cancer risks may be specific for particular alleles of a susceptibility gene and that these different risks should be taken into account by genetic counselors.
Breast Cancer Research and Treatment 08/2005; 92(1):19-24. · 4.43 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Currently genetic testing for BRCA1 and BRCA2 susceptibility genes is performed throughout Europe and North America. In Poland three founder mutations in BRCA1 account for 14% of all invasive ovarian cancers and oophorectomy is frequently recommended to mutation carriers as a preventive measure. The purpose of the present study was to evaluate patient acceptance of the recommendation for prophylactic oophorectomy in a hereditary cancer clinic. Seventy-two women over the age of 40 and who carried a BRCA1 mutation were advised to undergo prophylactic oophorectomy. After a mean follow-up period of 19 months, 43 of the women (60%) had undergone the procedure. Of the 29 women who had not had an oophorectomy, five indicated that they did not intend to do so, 19 indicated that they intended to have the operation in the near future and five were undecided. In conclusion, preventive oophorectomy is acceptable to most Polish women at high risk of hereditary ovarian cancer and should be among the range of services offered in cancer genetics clinics.
European journal of gynaecological oncology 02/2004; 25(1):93-5. · 0.47 Impact Factor
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J Menkiszak,
J Gronwald,
B Górski,
T Byrski,
T Huzarski, A Jakubowska,
M Foszczyńska-Kłoda,
M Brzosko,
J Fliciński,
I Rzepka-Górska,
S A Narod,
J Lubiński
[show abstract]
[hide abstract]
ABSTRACT: The purpose of the present study was to identify the clinical and pathologic features of ovarian cancers in patients who have a family history of breast or ovarian cancer but who do not have a mutation in the BRCA1 or BRCA2 gene.
303 patients with ovarian cancer were reviewed for clinical features and for cancer family histories. After the exclusion of 51 patients known to carry BRCA1 or BRCA2 mutations, 24 patients with familial cancer were compared with 228 patients with non-familial cancer.
Patients with familial cancer were more likely to have grade 2 tumors, Stage II disease and to present between ages 51 and 60 than were non-familial controls. Ten of 24 patients in the familial group presented between ages 51 and 60 with a grade 2 tumor compared to 3.0 expected (p = 0.001).
Families of women who present with grade 2 ovarian cancer between the ages of 51 and 60 may have an unidentified ovarian cancer susceptibility gene.
European journal of gynaecological oncology 02/2004; 25(1):99-100. · 0.47 Impact Factor
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C Cybulski,
B Górski,
T Debniak,
B Gliniewicz,
M Mierzejewski,
B Masojć, A Jakubowska,
J Matyjasik,
E Złowocka,
A Sikorski,
S A Narod,
J Lubiński
[show abstract]
[hide abstract]
ABSTRACT: To evaluate whether an inactivating mutation in the gene for the Nijmegen breakage syndrome (NBS1) plays a role in the etiology of prostate cancer, we compared the prevalence of the 657del5 NBS1 founder allele in 56 patients with familial prostate cancer, 305 patients with nonfamilial prostate cancer, and 1500 control subjects from Poland. Loss of heterozygosity analysis also was performed on DNA samples isolated from 17 microdissected prostate cancers, including 8 from carriers of the 657del5 mutation. The NBS1 founder mutation was present in 5 of 56 (9%) patients with familial prostate cancer (odds ratio, 16; P < 0.0001), 7 of 305 (2.2%) patients with nonfamilial prostate cancer (odds ratio, 3.9; P = 0.01), and 9 of 1500 control subjects (0.6%). The wild-type NBS1 allele was lost in seven of eight prostate tumors from carriers of the 657del5 allele, but loss of heterozygosity was seen in only one of nine tumors from noncarriers (P = 0.003). These findings suggest that heterozygous carriers of the NBS1 founder mutation exhibit increased susceptibility to prostate cancer and that the cancers that develop in the prostates of carriers are functionally homozygous for the mutation.
Cancer Research 02/2004; 64(4):1215-9. · 7.86 Impact Factor
