Common BRCA2 Variants and Modification of Breast and Ovarian Cancer Risk in BRCA1 Mutation Carriers

Unit of Genetic Epidemiology, IARC, 150, cours Albert-Thomas, 69372 Lyon cedex 08, France.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 02/2005; 14(1):265-7.
Source: PubMed


The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.

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    • "The -26 G>A polymorphism in the 5' UTR of BRCA2 has been analyzed in some cancer types. In one study, the -26A allele was reported to show a borderline association with ovarian cancer, but similar results in breast cancer with BRCA1 mutation carriers were not found [49]. Another study showed a monotonic increase in the frequency of the heterozygous G/A genotype from the lowest to highest risk groups of esophageal squamous cell carcinoma from northern China [50]. "
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    ABSTRACT: The absence of mutation or promoter hypermethylation in the BRCA2 gene in the majority of breast cancer cases has indicated alternative ways of its involvement, deregulated expression being one possibility. We show how a polymorphism in the 5' untranslated region (UTR) of BRCA2 can serve as one such factor. Based on the hypothesis that variants of genes involved in the same pathway can influence the risk provided for breast cancer, the status of p53 codon 72 polymorphism was also investigated and a possible interaction between the polymorphisms was examined. The luciferase reporter assay followed by RNA secondary structure analysis was used for the functional characterization of -26 5' UTR G>A polymorphism in BRCA2. The genotype and the allele frequency for the polymorphisms were determined and relative risk adjusted for age was calculated in a case-control study of 576 individuals (243 patients and 333 controls) from north India. -26 G>A polymorphism in the 5' UTR of BRCA2 was found to be functional whereby the A allele increased the reporter gene expression by twice that of the G allele in MCF-7 (P = 0.003) and HeLa (P = 0.013) cells. RNA secondary structure analysis by two different programs predicted the A allele to alter the stability of a loop in the vicinity of the translation start site. Its direct implication in breast cancer became evident by a case-control study in which the heterozygous genotype was found to be protective in nature (P heterozygote advantage model = 0.0005, odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.4 to 0.8), which was further supported by trends observed in a genomic instability study. The p53 codon 72 Arg homozygous genotype was found to be over-represented in patients (P = 0.0005, OR = 2.3, 95% CI = 1.4 to 3.6). The interaction study indicated an increased protection under simultaneous presence of protector genotypes of both the polymorphic loci (P = 0.0001, OR = 0.2, 95% CI = 0.1 to 0.4). Our study shows that -26 5' UTR polymorphism in BRCA2 can modulate the fine-tuned regulation of the multifunctional gene BRCA2 and renders risk or protection according to the genotype status in the sporadic form of breast cancer, which is further influenced by the germline genetic backgrounds of codon 72 polymorphism of p53.
    Breast cancer research: BCR 02/2007; 9(5):R71. DOI:10.1186/bcr1780 · 5.49 Impact Factor
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    • "However, this method requires post-PCR manipulations and the availability of specialized equipment. On the other hand, allelic discrimination assays have been widely used in the study of associations between single nucleotide polymorphisms and diseases such as cancers [15] and rheumatoid arthritis [16]. The validity of the approach for single nucleotide polymorphism genotyping has been previously demonstrated [17-19]. "
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    ABSTRACT: The Severe Acute Respiratory Syndrome (SARS) was a newly emerged infectious disease which caused a global epidemic in 2002-2003. Sequence analysis of SARS-coronavirus isolates revealed that specific genotypes predominated at different periods of the epidemic. This information can be used as a footprint for tracing the epidemiology of infections and monitor viral evolution. However, direct sequencing analysis of a large number of clinical samples is cumbersome and time consuming. We present here a simple and rapid assay for the screening of SARS-coronavirus genotypes based on the use of fluorogenic oligonucleotide probes for allelic discrimination. Thirty SARS patients were recruited. Allelic discrimination assays were developed based on the use of fluorogenic oligonucleotide probes (TaqMan). Genotyping of the SARS-coronavirus isolates obtained from these patients were carried out by the allelic discrimination assays and confirmed by direct sequencing. Genotyping based on the allelic discrimination assays were fully concordant with direct sequencing. All of the 30 SARS-coronavirus genotypes studied were characteristic of genotypes previously documented to be associated with the latter part of the epidemic. Seven of the isolates contained a previously reported major deletion but in patients not epidemiologically related to the previously studied cohort. We have developed a simple and accurate method for the characterization and screening of SARS-coronavirus genotypes. It is a promising tool for the study of epidemiological relationships between documented cases during an outbreak.
    BMC Infectious Diseases 02/2005; 5(1):87. DOI:10.1186/1471-2334-5-87 · 2.61 Impact Factor
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    ABSTRACT: About 90% of all breast cancers can be considered as sporadic, without inherited gene alteration. The rest of breast cancers (about 5 to 10%) are considered hereditary, most commonly caused by alterations of BRCA1/2 tumor suppressor genes. Lifetime risks for breast and ovarian cancers are increased among BRCA1/2 mutation carriers - 4 to 8 and 10 to 20 fold higher respectively. Due to the small proportion of hereditary form of disease, as well as to the high cost, BRCA testing is not screening test for general population. It is addressed to selected part of population that fit to recommended criteria. Full coding region sequencing of both genes is "gold standard" for detection of BRCA mutation. Concerning BRCA testing in Serbia, complete or partial sequencing of BRCA1/2 coding region was performed in 60 samples. The presence of 4 BRCA1 known mutations, previously detected elsewhere, has been shown: 185delAG, C61G, 3447del4 and 5382insC (detected twice). In BRCA1 gene, exon 16, an unclassified variant M1652I was found. Polymorphic variants in BRCA1 (8 polymorphisms) and BRCA2 (5 polymorphisms) genes were also detected. The majority of found BRCA1 and BRCA2 polymorphic variants are the missense ones and their influence on breast/ovarian cancer risk in our population has to be proved. Identification of BRCA mutations carriers and establishment of spectra and frequency of BRCA mutations should enable introduction of BRCA1/2 testing into the clinical practice of Serbia. .
    Archive of oncology 12/2006; 14(3). DOI:10.2298/AOO0604131B
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