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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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M M Gaudet,
K B Kuchenbaecker,
J Vijai,
R J Klein,
T Kirchhoff,
L McGuffog,
D Barrowdale,
A M Dunning,
A Lee,
J Dennis, [......],
B Burwinkel,
P Guenel,
S E Bojesen,
R L Milne,
H Brenner,
M Lochmann,
K Aittomaki,
T Dork,
S Margolin,
others
[show abstract]
[hide abstract]
ABSTRACT: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9x10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
01/2013: pages e1003173;
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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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A Osorio,
R L Milne,
R Alonso,
G Pita,
P Peterlongo,
A Teulé,
K L Nathanson,
S M Domchek,
T Rebbeck,
A Lasa, [......],
X-C Chen,
J Beesley,
A B Spurdle, O M Sinilnikova,
S Healey,
L McGuffog,
A C Antoniou,
J Brunet,
P Radice,
J Benítez
[show abstract]
[hide abstract]
ABSTRACT: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2.
Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers.
An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.
British Journal of Cancer 03/2011; 104(8):1356-61. · 5.04 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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A Osorio,
R L Milne,
G Pita,
P Peterlongo,
T Heikkinen,
J Simard,
G Chenevix-Trench,
A B Spurdle,
J Beesley,
X Chen, [......],
R Varon-Mateeva,
D Schaefer,
U G Froster,
T Caldes,
M de la Hoya,
L McGuffog,
A C Antoniou,
H Nevanlinna,
P Radice,
J Ben|[iacute]|tez
[show abstract]
[hide abstract]
ABSTRACT: Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.
British Journal of Cancer 11/2009; 101(12):2048-2054. · 5.04 Impact Factor
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A Osorio,
R L Milne,
G Pita,
P Peterlongo,
T Heikkinen,
J Simard,
G Chenevix-Trench,
A B Spurdle,
J Beesley,
X Chen, [......],
R Varon-Mateeva,
D Schaefer,
U G Froster,
T Caldes,
M de la Hoya,
L McGuffog,
A C Antoniou,
H Nevanlinna,
P Radice,
J Benítez
[show abstract]
[hide abstract]
ABSTRACT: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.
We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach.
We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers.
This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
British Journal of Cancer 11/2009; 101(12):2048-54. · 5.04 Impact Factor
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O M Sinilnikova,
A C Antoniou,
J Simard,
S Healey,
M Léoné,
D Sinnett,
A B Spurdle,
J Beesley,
X Chen,
M H Greene, [......],
C Sutter,
H Deissler,
D Schaefer,
U G Froster,
K Aittomäki,
H Nevanlinna,
L McGuffog,
D F Easton,
G Chenevix-Trench,
D Stoppa-Lyonnet
[show abstract]
[hide abstract]
ABSTRACT: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.
To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.
No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.
There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.
British Journal of Cancer 09/2009; 101(8):1456-60. · 5.04 Impact Factor
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O M Sinilnikova,
A C Antoniou,
J Simard,
S Healey,
M L|[eacute]|on|[eacute,
D Sinnett,
A B Spurdle,
J Beesley,
X Chen,
M H Greene, [......],
C Sutter,
H Deissler,
D Schaefer,
U G Froster,
K Aittom|[auml]|ki,
H Nevanlinna,
L McGuffog,
D F Easton,
G Chenevix-Trench,
D Stoppa-Lyonnet
[show abstract]
[hide abstract]
ABSTRACT: Background: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.
British Journal of Cancer 08/2009; 101(8):1456-1460. · 5.04 Impact Factor
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F Casilli,
I Tournier, O M Sinilnikova,
F Coulet,
F Soubrier,
C Houdayer,
A Hardouin,
P Berthet,
H Sobol,
V Bourdon, [......],
D M Provencher,
C Dugast,
C Delvincourt,
T D Nguyen,
L Faivre,
V Bonadona,
T Frébourg,
R Lidereau,
D Stoppa-Lyonnet,
M Tosi
[show abstract]
[hide abstract]
ABSTRACT: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer.
To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects.
Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2.
We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum.
The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.
Journal of Medical Genetics 09/2006; 43(9):e49. · 6.36 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: BRCA2 (BReast CAncer susceptibility gene 2) germline mutation carriers are at increased risk for breast and ovarian cancers. Mutations occurring in the ovarian cancer cluster region (OCCR) are linked to higher ovarian cancer and/or lower breast cancer risk(s) than mutations occurring elsewhere in BRCA2. Most BRCA2 germline mutations introduce premature termination codons (PTCs), making their mRNAs likely targets of nonsense-mediated mRNA decay (NMD), a mechanism that eliminates PTC-bearing transcripts to prevent expression of truncated proteins. Contradictory evidence exists regarding whether NMD can be triggered by PTCs located far upstream of the nearest exon-exon junction (EEJ). Since the OCCR comprises a major portion of the 4.9 kb exon 11 of BRCA2, we investigated if transcripts bearing PTCs in this large exon are unable to trigger NMD, and if this might contribute to the phenotypic difference associated with the OCCR. We examined cDNA from 18 carriers of PTC-introducing germline mutations located throughout BRCA2, and found that PTC-bearing transcripts were 1.4-3.3-fold less prevalent than their nonmutated counterparts irregardless of PTC position. We conclude that NMD can recognize PTCs up to 4.5 kb upstream of the nearest EEJ, demonstrating that a general inability of NMD to recognize PTCs in exon 11 is unlikely to explain the genotype-phenotype correlation associated with the OCCR.
Oncogene 02/2006; 25(2):323-8. · 6.37 Impact Factor
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G Chenevix-Trench, O M Sinilnikova,
G Suthers,
N Pandeya,
S Mazoyer,
J F Sambrook,
S Goldup,
D Goldgar,
H T Lynch,
G M Lenoir,
G Cheetham
[show abstract]
[hide abstract]
ABSTRACT: A recent report based on 68 families, including 17 with mutations in BRCA1, suggested that there was an excess of female offspring born to BRCA1 mutation carriers. We have examined the gender ratio among offspring of 511 mutation carriers from 116 BRCA1 families, 77 and 39 from Australia and the United States, respectively. We found no evidence for a significant deviation from the expected proportion of female offspring in the Australian pedigrees, but there was an excess of female offspring in pedigrees from the USA. Ascertainment bias probably explains this bias, rather than a link with X-chromosome inactivation as previously suggested, because the families from the USA were ascertained for the purposes of linkage studies whereas those from Australia were ascertained through Familial Cancer Clinics to which they had been referred for clinical genetic counseling and mutation testing.
Familial Cancer 02/2005; 4(2):73-5. · 1.30 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: On the basis, chiefly, of anecdotal reports of cases of ocular melanoma (OM) occurring in families with inherited susceptibility to breast cancer due to brca2 germline mutations, we examined the frequency of brca2 alterations in a series of 62 ocular melanoma cases. These cases were preferentially selected on the basis of reported family history of breast or ovarian cancer, or OM, although the series also included a randomly selected set of cases without family history of cancer. A total of 7 germline alterations were found, of which 3 were likely to be associated with disease. While all 3 deleterious mutations were found in patients who also had a personal history of breast cancer, only 1 of the 3 families had a family history of breast/ovarian cancer or OM. Although germline brca2 mutations may account for a small proportion of all OM cases, there may be additional loci that contribute to familial aggregation of OM and to the familial association between OM and breast cancer.
International Journal of Cancer 08/1999; 82(3):325-8. · 5.44 Impact Factor
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The American Journal of Human Genetics 02/1999; 64(1):300-2. · 10.60 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Most previous BRCA1 mutation screening studies conducted on breast cancer families were aimed at identifying mutations in the coding sequence and splice sites. Mutations in the promoter and untranslated regions, and large rearrangements are missed by standard mutation detection strategies. To look specifically for such germ-line mutations in the BRCA1 gene, we have analyzed a series of 27 American and 51 French breast cancer families in which no BRCA1 mutation was identified by classical techniques. No mutations were detected in either the promoter or untranslated regions, and we did not find any deletion of the whole gene. Four families were found to carry distinct deletions. Two of them, probably generated by Alu-mediated homologous recombination, were internal deletions of 3 and 23.8 kb, encompassing exon 15 and exons 8-13, respectively. These alterations both lead to a frameshift in the mutant mRNA and to premature stop codon-mediated mRNA decay. The other two deletions encompass exons 1 and 2. On the basis of previous and present analyses, rearrangements represent 8% (3/37) of all mutations in our set of BRCA1 American families. Consequently, the search for rearrangements appears mandatory in BRCA1 mutation screening studies.
Cancer Research 02/1999; 59(2):455-61. · 7.86 Impact Factor
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G. Martrat,
C. A. Maxwell,
E. Tominaga,
M. Porta,
N. Bonifaci,
L. Gomez-Baldo,
M. Bogliolo,
C. Lazaro,
I. Blanco,
J. Brunet, [......],
M. A. Collonge-Rame,
I. Mortemousque,
L. McGuffog,
G. Chenevix-Trench,
O. M. Pereira-Smith,
A. C. Antoniou,
J. Ceron,
K. Tominaga,
J. Surralles,
M. A. Pujana
Breast Cancer Research. 13(2):40.
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D. Campa,
A. Husing,
J.D. McKay, O M Sinilnikova,
U. vogel,
A. Tjonneland,
K. Overvad,
N.C. Onland-Moret,
C.H. van Gils,
H.B. Bueno-de-Mesquita,
X et al,
F Canzian
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M.M. Gaudet,
T Kirchhoff,
T. Green,
J Vijai,
J.M. Korn,
S. Guiducci,
A.V. Segrè,
K. McGee,
L McGuffog,
C. Kartsonaki, [......],
M Gauthier-Villars,
H Sobol,
M Longy,
M Frenay,
F B Hogervorst,
M A Rookus,
J.M. Collée,
N Hoogerbrugge,
M.G.E.M. Ausems,
R.B. van der Luijt
