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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]
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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]
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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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[show abstract]
[hide abstract]
ABSTRACT: Knapp 8000 Frauen erkranken jährlich in Deutschland an einem epithelialen Ovarialkarzinom, welches damit den zweithäufigsten
malignen Genitaltumor der Frau darstellt. In der Todesursachenstatistik steht es an 7. Stelle und nimmt demzufolge eine führende
Rolle unter den gynäkologischen Tumoren ein. 95% der Ovarialkarzinome treten sporadisch auf. Bei etwa 5–10% geht man von einer
genetischen Prädisposition aus. Das Ovarialkarzinom zählt zu den Genitalkarzinomen mit der ungünstigsten Prognose. Keimbahnmutationen
der Gene BRCA1 und BRCA2 liegen der erblichen Variante des Ovarialkarzinoms ursächlich zugrunde. Die klinische Bedeutung der betreffenden Syndrome
wächst mit der Möglichkeit der prädiktiven Diagnostik der prädisponierenden Gene. Mutationsträgerinnen besitzen ein bis zu
60%iges Risiko für das Auftreten eines Ovarialkarzinoms. Die klinische Herausforderung besteht in der Identifikation von Hochrisikopatientinnen
mit dem Ziel, diese im Rahmen von interdisziplinären Beratungskonzepten über effektive präventive Maßnahmen zu informieren.
Approximately 8000 women are diagnosed with epithelial ovarian carcinoma in Germany every year, making it the second most
common genital malignancy. It comes seventh in cause-of-death statistics, thus assuming a prominent place among gynaecological
tumours. Of these tumours, 95% occur sporadically. In 5%–10% of cases, a genetic predisposition is assumed. Ovarian carcinoma
belongs to the genital malignancies which carry a poor prognosis. Germline mutations in the BRCA1 and BRCA2 genes are responsible for the inherited variant of ovarian carcinoma. The clinical significance of this syndrome assumes
greater proportions with the potential to predictively diagnose the predisposing gene. Mutation carriers have up to a 60%
risk of developing ovarian carcinoma. The clinical challenge lies in identifying high-risk patients and, in the context of
interdisciplinary counselling, informing them about effective preventive measures.
Der Onkologe 04/2012; 14(11):1120-1129. · 0.17 Impact Factor
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Breast Cancer Research 04/2012; 7:1-2. · 5.33 Impact Factor
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Breast Cancer Research 04/2012; 2:1-1. · 5.33 Impact Factor
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S Seitz,
E Korsching,
J Weimer,
A Jacobsen, N Arnold,
A Meindl,
W Arnold,
D Gustavus,
C Klebig,
I Petersen,
S Scherneck
Breast Cancer Research 04/2012; 7:1-1. · 5.33 Impact Factor
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Annals of Oncology 03/2011; 22(3):500-2. · 6.43 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: BRCA1 is a major gatekeeper of genomic stability. Acting in multiple central processes like double-strand break repair, centrosome replication, and checkpoint control, BRCA1 participates in maintaining genomic integrity and protects the cell against genomic instability. Chromosomal instability (CIN) as part of genomic instability is an inherent characteristic of most solid tumors and is also involved in breast cancer development. In this study, we determined the extent of CIN in 32 breast cancer tumors of women with a BRCA1 germline mutation compared to 62 unselected breast cancers. We applied fluorescence in situ hybridization (FISH) with centromere-specific probes for the chromosomes 1, 7, 8, 10, 17, and X and locus-specific probes for 3q27 (BCL6), 5p15.2 (D5S23), 5q31 (EGR1), 10q23.3 (PTEN), and 14q32 (IGH@) on formalin-fixed paraffin-embedded tissue microarray sections. Our hypothesis of an increased level of CIN in BRCA1-associated breast cancer could not be confirmed by this approach. Surprisingly, we detected no significant difference in the extent of CIN in BRCA1-mutated versus sporadic tumors. The only exception was the CIN value for chromosome 1. Here, the extent of CIN was slightly higher in the group of sporadic tumors.
Cytogenetic and Genome Research 01/2011; 135(2):84-92. · 1.53 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 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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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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[show abstract]
[hide abstract]
ABSTRACT: Unter dem Begriff Ovarialkarzinom wird eine heterogene Gruppe unterschiedlicher Tumoren subsumiert. Die pathogenetischen Mechanismen der Tumorgenese von Ovarialkarzinomen wurden trotz zahlreicher Untersuchungen bislang erst ansatzweise verstanden. Die vollstndige Entschlsselung des humanen Genoms und die Entwicklung der Gen-Chip-Technologie ermglichte die genomweite Erstellung von Genexpressionsprofilen von Zellen und Geweben. Wichtige Anwendungen dieses Expression Profiling im Bereich onkologischer Fragestellungen sind die Identifikation bzw. Klassifizierung eines Tumor-Phnotyps aufgrund seines Expressionsprofils (Signatur), Krankheitsverlufe (prognostische Signaturen) und Ansprechen auf therapeutische Manahmen (prdiktive Signaturen) vorherzusagen und neue molekulare Targets fr medikamentse Therapien zu identifizieren. Die vorliegende Arbeit vermittelt einen berblick ber genetische und molekulargenetische Grundlagen des Ovarialkarzinoms und Anstze zur Prvention der Erkrankung.A number of heterogeneous tumors are combined under the term malignant ovarian tumors. Numerous studies have been performed to improve our knowledge of the morphology and biological behavior of these, however, the underlying mechanisms of tumorigenesis of ovarian cancer are still not fully understood. Novel molecular techniques, such as gene-chip technologies, allow new insights into the genetic basis of ovarian cancer. Expression profiling allows the identification and characterization of morphologically heterogeneous tumor types. Several candidate markers have been identified for the early detection and prediction of such tumors. In addition, novel targets that might have the potential to be exploited therapeutically have been identified. This review provides an overview on the genetic and molecular basis of the disease as well as options for the prevention of hereditary ovarian cancer.
Der Gynäkologe 05/2006; 39(6):420-427.
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[show abstract]
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ABSTRACT: We report on a family in which a daughter is described with mental retardation, as well as malformations of the heart, and of the brain (Dandy-Walker variant). The patient's phenotype suggests a chromosomal rearrangement. However, her karyotype was unremarkable by conventional cytogenetic analysis. In order to detect chromosome rearrangements overseen by this method, the subtelomere regions of suspicious chromosomes were verified by fluorescence in situ hybridization (FISH). A rearranged derivative chromosome 6 was identified. Further examinations by FISH-microdissection (FISH-MD) revealed a maternal complex balanced translocation. The patient inherited the derivative chromosome 6 from her mother and therefore carries a partial monosomy 6q26-->qter and a partial trisomy 11q23.3-->qter.
Cytogenetic and Genome Research 02/2006; 114(3-4):235-9. · 1.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The use of electrical charge for electroporation or electrofusion is widely applied to customize dendritic cells (DC) and their immunological properties as anticancer vaccines. The aim of this study was to evaluate the influence of various electrical field strengths on the recovery, viability and physiology of DC. Immature DC were transferred into low-conductive medium and electrically charged within a range of 0-1500 V/cm. Viability was assessed by Trypan Blue dye exclusion or staining with impermeant nucleic acid stains and fluorescence-activated cell sorter analysis. Additionally, apoptosis was determined by flow cytometry after staining with Annexin-V, endocytosis by uptake of fluorescein isothiocyanate-dextran and metabolic activity by a standardized fluorescent live/dead assay. There was a strong correlation between the electrical field strength and the viability and physiology of DC. Field strengths > or =1000 V/cm significantly impaired viability, metabolism and endocytotic activity. Dual fluorescence with 7-7-amino-actinomycin D and Annexin-V demonstrated that loss of viability was predominantly due to necrosis rather than apoptosis. Field strengths < or =500 V/cm allowed to maintain good cell viability and recovery of DC and did not cause alterations of metabolism and endocytosis. Therefore, the frequently used amplification of field strengths to improve the efficacy of electroporation and electrofusion requires critical re-evaluation.
Scandinavian Journal of Immunology 11/2005; 62(4):399-406. · 2.23 Impact Factor
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[hide abstract]
ABSTRACT: Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10).
For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated.
We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 x 10-8 in favour of neutrality of the variant.
Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.
Breast cancer research: BCR 02/2005; 7(5):R775-9. · 5.24 Impact Factor
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Journal of Investigative Dermatology 04/2001; 116(3):472-4. · 6.31 Impact Factor
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[show abstract]
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ABSTRACT: In the current study the authors attempted to evaluate genetic alterations in a large set of primary ovarian carcinomas and to compare the genetic findings with clinical parameters such as grade of tumor differentiation. This strategy was applied to identify chromosomal regions containing genes associated with tumor progression.
Genetic imbalances were assessed in 106 primary ovarian carcinomas using comparative genomic hybridization (CGH). CGH was applied because it is a powerful tool with which to screen the entire genome of a tumor for genetic changes by highlighting regions of altered DNA sequence copy numbers (deletions and amplifications). Multivariate statistical standard procedures were used to determine an association between tumor grading and genetic alterations.
One hundred three carcinomas showed aberrant CGH profiles. The most frequent alterations were amplifications of 8q, 1q, 20q, 3q, and 19p, which occurred in 69-53% of tumors, and underrepresentations of 13q, 4q, and 18q, which occurred in 54-50% of tumors. Undifferentiated ovarian carcinomas (World Health Organization Grade 3) were found to be correlated significantly with underrepresentation of 11p and 13q as well as with overrepresentation of 8q and 7p (P = 0.001, 0.001, 0.01, and 0.027, respectively). However, 12p underrepresentation and 18p overrepresentation were significantly more frequent in well and moderately differentiated tumors (P = 0.01 and 0.004, respectively). To facilitate the interpretation and clinical application of the results of the current study, the significant aberrations were translated into a score system. This score system can be used easily for the prediction of an undifferentiated phenotype with a specificity and sensitivity of 79% and 86%, respectively.
The current study data show that primary ovarian carcinomas are based on consistent genetic alterations that most likely are important for the development of this tumor entity. The correlation between certain aberrations and undifferentiated carcinomas may help to discriminate between primary and secondary genetic events and may indicate the location of those genes involved in cellular functions associated with tumor progression and the development of anaplastic and aggressive phenotypes.
Cancer 03/2001; 91(3):534-40. · 4.77 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Up to now, ovarian carcinomas represent a major health problem among female cancers because they are the leading cause of death from gynecological malignancy. A high proportion of these tumors selects for mutations in the p53 gene. There is evidence that inactivation of the p53 protein could indicate poor prognosis and chemoresistance of patients. To set up a fast and sensitive test for p53 defects in tumor tissues, we analyzed ovarian cancer cells by denaturing high-performance liquid chromatography (DHPLC). A primer set spanning the whole coding region of p53 with seven fragments was designed and appropriate heteroduplex detection in DHPLC analysis was elaborated. The analysis of 45 ovarian tumor specimens yielded 17 genetic alterations (38%) occurring exclusively in the malignant tissue of the patients. In addition, frequent polymorphisms present in normal compared to tumor tissue could serve as a tool for the rapid identification of loss of heterozygosity (LOH) in the tumor. We observed that LOH in intron 2 or 3 correlated well with a lack of one allele in mutated fragments. In conclusion, DHPLC screening appears to be a sensitive and effective test for genetic alterations in tumors with p53 involvement. Since p53 mutations point to a poor prognosis state in several cancers, a fast screening of tumor material for genetic variations may have implications for further individual treatment of patients.
Journal of Biochemical and Biophysical Methods 02/2001; 47(1-2):73-81. · 2.33 Impact Factor
