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Comprehensive Analysis of BRCA1, BRCA2 and TP53 Germline Mutation and Tumor Characterization: A Portrait of Early-Onset Breast Cancer in Brazil  [PDF]
Dirce Maria Carraro, Maria Aparecida Azevedo Koike Folgueira, Bianca Cristina Garcia Lisboa, Eloisa Helena Ribeiro Olivieri, Ana Cristina Vitorino Krepischi, Alex Fiorini de Carvalho, Louise Danielle de Carvalho Mota, Renato David Puga, Maria do Socorro Maciel, Rodrigo Augusto Depieri Michelli, Eduardo Carneiro de Lyra, Stana Helena Giorgi Grosso, Fernando Augusto Soares, Maria Isabel Alves de Souza Waddington Achatz, Helena Brentani, Carlos Alberto Moreira-Filho, Maria Mitzi Brentani
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0057581
Abstract: Germline mutations in BRCA1, BRCA2 and TP53 genes have been identified as one of the most important disease-causing issues in young breast cancer patients worldwide. The specific defective biological processes that trigger germline mutation-associated and -negative tumors remain unclear. To delineate an initial portrait of Brazilian early-onset breast cancer, we performed an investigation combining both germline and tumor analysis. Germline screening of the BRCA1, BRCA2, CHEK2 (c.1100delC) and TP53 genes was performed in 54 unrelated patients <35 y; their tumors were investigated with respect to transcriptional and genomic profiles as well as hormonal receptors and HER2 expression/amplification. Germline mutations were detected in 12 out of 54 patients (22%) [7 in BRCA1 (13%), 4 in BRCA2 (7%) and one in TP53 (2%) gene]. A cancer familial history was present in 31.4% of the unrelated patients, from them 43.7% were carriers for germline mutation (37.5% in BRCA1 and in 6.2% in the BRCA2 genes). Fifty percent of the unrelated patients with hormone receptor-negative tumors carried BRCA1 mutations, percentage increasing to 83% in cases with familial history of cancer. Over-representation of DNA damage-, cellular and cell cycle-related processes was detected in the up-regulated genes of BRCA1/2-associated tumors, whereas cell and embryo development-related processes were over-represented in the up-regulated genes of BRCA1/2-negative tumors, suggesting distinct mechanisms driving the tumorigenesis. An initial portrait of the early-onset breast cancer patients in Brazil was generated pointing out that hormone receptor-negative tumors and positive familial history are two major risk factors for detection of a BRCA1 germline mutation. Additionally, the data revealed molecular factors that potentially trigger the tumor development in young patients.
A. San Miguel,I. Gonzalez Blanco,J.A. Minguéz Pargas,L. Martín Rodríguez
Electronic Journal of Biomedicine , 2006,
Abstract: RESUMENEn los últimos a os, se realizaron numerosos estudios para establecer la predisposición hereditaria al cáncer y las alteraciones mutacionales a nivel de genes susceptibles de originar cáncer de mama y ovario. En 1994 se identificaron los genes BRCA1 (Breast Cancer Gene 1) y BRCA2 (Breast Cancer Gene 2) como susceptibles de cáncer de mama y ovario. En la actualidad se sabe que las mutaciones en BRCA1 y BRCA2 están lejos de explicar la totalidad de los casos de cáncer de mama y/o ovario, y a pesar de que se postulan alteraciones mutacionales en otros genes como CHEK2, TP53 y PTEN, el BRCA1 y BRCA2, siguen teniendo su importancia y utilidad en la valoración del riesgo de predisposición hereditaria. Aunque las cifras son variables según los distintos estudios y autores, se trata en cualquier caso de porcentajes importantes. Entre el 15 y el 85% de las mujeres portadoras de mutación BRCA 1 o BRCA 2 tienen riesgo de desarrollar un cáncer de mama y entre un 10 y 60% de desarrollar un cáncer de ovario. ABSTRACT:In the last years, numerous studies were made to establish the hereditary predisposition to the cancer and the mutationals alterations at level of genes susceptible to originate breast and ovarian cancers. In 1994 genes BRCA1 (Breast Cancer Gene 1) and BRCA2 were identified (Breast Cancer Gene 2) as susceptible of both of breast and ovarian cancers. At the present time, it is knows that the mutations in BRCA 1 and BRCA 2 are far from explaining the totality of the cases of breast cancer and/or ovary, and although mutationals alterations in other genes like CHEK2, TP53 and PTEN, the BRCA1 and BRCA2 are postulated, they continue having his importance and utility in the valuation of the risk of hereditary predisposition. Correlations between both BRCA1 and BRCA2 levels with tumour grade metastasis and prognostic accuracy. Between 15 and 85% of the carrying women of mutation BRCA 1 or BRCA 2 have risk of developing a cancer of breast and between 10 and 60% to develop an ovarian cancer.
Contribution of the Defective BRCA1, BRCA2 and CHEK2 Genes to the Familial Aggregation of Breast Cancer: a Simulation Study Based on the Swedish Family-Cancer Database
Justo Bermejo, Alfonso Pérez, Kari Hemminki
Hereditary Cancer in Clinical Practice , 2004, DOI: 10.1186/1897-4287-2-4-185
Abstract: Breast cancer aggregates in families, the disease being about twice as common in mothers and sisters of cases as it is in the general population [2]. The higher risks of breast cancer for monozygotic than for dizygotic twins of cases suggest that the familial aggregation of breast cancer is mainly due to genetic effects, rather than to shared environmental factors [3]. Germline mutations in BRCA1 and BRCA2 are frequently found in families containing multiple individuals affected by breast cancer [4]. However, BRCA1 and BRCA2 mutations are only identified in about 15-20% of multiple-case families affected by breast cancer alone [5]. CHEK2*1100delC, a truncating variant that abrogates the kinase activity of CHEK2 [6], has been also found to contribute significantly to the familial clustering of breast cancer [7]. The variant has shown a frequency of 1.1% in healthy individuals and it has been associated with a breast cancer risk ratio of 1.7 in families without BRCA1/2 mutations. By contrast, the variant conferred no increased cancer risk in carriers of BRCA1/2 mutations. The low proportion of familial breast cancers attributable to known genes, from 20% to 25% [1], reflects major gaps in our knowledge of the genetic background of familial breast cancer.In addition to the age, sex and genotype specific penetrance, the family history of breast cancer is influenced by demographic factors such as family size and mortality [8]. The aim of the present study was to assess the contribution of the BRCA1/2 mutations and CHEK2 variants to the relative risk of breast cancer for women with affected mothers or sisters. We used the Swedish Family-Cancer (SFC) Database to estimate the distribution of life expectancy, the number of daughters per family and the age specific cumulative risk of female breast cancer in Sweden. The penetrances associated with BRCA1/2 and CHEK2 were taken from the literature. This information was used to simulate the familial clustering of breast cancer un
Age and Geographical Distribution in Families with BRCA1/BRCA2 Mutations in the Slovak Republic
Sona Ciernikova, Miroslav Tomka, Michal Kovac, Viola Stevurkova, Vladimir Zajac
Hereditary Cancer in Clinical Practice , 2006, DOI: 10.1186/1897-4287-4-1-7
Abstract: Breast cancer is the most common malignancy affecting women in the Slovak Republic, accounting for 1,858 and 1,827 newly diagnosed breast cancer cases in years 2000 and 2001, respectively (World Standardized Rates 47.0/100,000 and 46.1/100,000). The complete data from NCRS show that it is also the leading cause of cancer-related mortality among Slovak women, the proportion being 15.1% of all cancer cases. NCRS was created as one of the first in Central and Eastern Europe and contains 30-year-old data about newly diagnosed cancer patients of all types. According to NCRS evidence, 414 and 449 newly diagnosed cases of ovarian cancer were reported in years 2000 and 2001 (World Standardized Rates: 10.9/100,000 and 11.4/100,000). They represent 4.3% of all cancer deaths, and ovarian cancer is therefore the most frequent cause of death of all gynaecological malignancies.A family history of breast and/or ovarian cancer is the most significant risk factor for developing the disease. An estimated 5-10% of all breast and ovarian cancer cases are hereditary in nature [1]. The search for genes associated with hereditary susceptibility to breast or ovarian cancer has been facilitated by the study of large kindreds with multiple affected individuals, and has led to the identification of several susceptibility genes, of which BRCA1 (MIM 113705) and BRCA2 (MIM 600185) are the most penetrant. Carriers of germline mutations in these genes have a 50-85% lifetime risk of breast cancer and a 15-45% risk of developing ovarian cancer during their lifetime [2,3]. It was estimated that the combination of BRCA1/BRCA2 mutations was responsible for approximately 80% of all HBOC families [4,5]. More recent estimates put this risk at about 30% and other low penetrance candidate genes involved in breast cancer susceptibility, CHEK2, ATM, TP53 and PTEN, have been identified [6,7].Here we aim to determine the frequency, age and geographical distribution of families carrying BRCA1/BRCA2 mutations wit
Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study
Florence Le Calvez-Kelm, Fabienne Lesueur, Francesca Damiola, Maxime Vallée, Catherine Voegele, Davit Babikyan, Geoffroy Durand, Nathalie Forey, Sandrine McKay-Chopin, Nivonirina Robinot, Tù Nguyen-Dumont, Alun Thomas, Graham B Byrnes, Breast Cancer Family Registry, John L Hopper, Melissa C Southey, Irene L Andrulis, Esther M John, Sean V Tavtigian
Breast Cancer Research , 2011, DOI: 10.1186/bcr2810
Abstract: Previously, we adapted an in silico assessment of missense substitutions used for analysis of unclassified missense substitutions in BRCA1 and BRCA2 to the problem of assessing candidate genes using rare missense substitution data observed in case-control mutation-screening studies. The method involves stratifying rare missense substitutions observed in cases and/or controls into a series of grades ordered a priori from least to most likely to be evolutionarily deleterious, followed by a logistic regression test for trends to compare the frequency distributions of the graded missense substitutions in cases versus controls. Here we used this approach to analyze CHEK2 mutation-screening data from a population-based series of 1,303 female breast cancer patients and 1,109 unaffected female controls.We found evidence of risk associated with rare, evolutionarily unlikely CHEK2 missense substitutions. Additional findings were that (1) the risk estimate for the most severe grade of CHEK2 missense substitutions (denoted C65) is approximately equivalent to that of CHEK2 protein-truncating variants; (2) the population attributable fraction and the familial relative risk explained by the pool of rare missense substitutions were similar to those explained by the pool of protein-truncating variants; and (3) post hoc power calculations implied that scaling up case-control mutation screening to examine entire biochemical pathways would require roughly 2,000 cases and controls to achieve acceptable statistical power.This study shows that CHEK2 harbors many rare sequence variants that confer increased risk of breast cancer and that a substantial proportion of these are missense substitutions. The study validates our analytic approach to rare missense substitutions and provides a method to combine data from protein-truncating variants and rare missense substitutions into a one degree of freedom per gene test.Familial clustering of breast cancer is well recognized, having been describe
Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals
Kirsi M Kuusisto, Aleksandra Bebel, Mauno Vihinen, Johanna Schleutker, Satu-Leena Sallinen
Breast Cancer Research , 2011, DOI: 10.1186/bcr2832
Abstract: Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC) BRCA1/2-founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes, BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1. BRCA1/2 were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing. CHEK2 was analyzed by the high resolution melt (HRM) method and PALB2, RAD50, BRIP1 and CDH1 were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC) BRCA1/2-founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test. In silico prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P).Three previously reported breast cancer-associated variants, BRCA1 c.5095C > T, CHEK2 c.470T > C, and CHEK2 c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had CHEK2 variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants, BRCA2 c.72A > T (Leu24Phe) was predicted to be likely pathogenic in silico. No large genomic rearrangements were detected in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA).In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk BRCA1/2-negative HBOC individuals. CHEK2 mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish BRCA1/2-founder mutations and protein truncation test (PTT) of the
Mutation analysis of the AATF gene in breast cancer families
Maria Haanp??, Mervi Reiman, Jenni Nikkil?, Hannele Erkko, Katri Pylk?s, Robert Winqvist
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-457
Abstract: Here we have screened the entire coding region of AATF in affected index cases from 121 Finnish cancer families for germline defects, using conformation sensitive gel electrophoresis and direct sequencing.Altogether seven different sequence changes were observed, one missense variant and six intronic ones. Based on the in silico analyses of these sequence alterations, as well as their occurrence in cases and controls, none of them, however, were predicted to be pathogenic.To our knowledge, this is the first study reporting the mutation screening of the AATF gene in familial breast cancer cases. No evidence for the association with breast cancer was observed.In most Western populations, about one in ten women develop breast cancer [1]. Approximately 5-10% of these cases are considered to be familial [2]. Mutations in two major high penetrance genes BRCA1 and BRCA2 are well known, but they seem to be responsible for less than 20% of heritable disease predisposition [3,4]. Only a small number of the familial cases are explained by mutations in other known cancer susceptibility genes, such as TP53, PTEN, ATM, CHEK2, NBS1, RAD50, BRIP1 and PALB2 [5,6]. The identification of additional genes involved in breast cancer predisposition is complicated by genetic heterogeneity. The remaining cases could be the result of a few additional, yet unidentified, high penetrance mutations, but the polygenic model may provide a more plausible explanation [7]. Recent genome-wide association studies have identified a few common low penetrance breast cancer susceptibility alleles. Together these loci are, however, estimated to account less than 4% of the familial risk of breast cancer in European populations [1]. As most of the known breast cancer susceptibility genes are involved in DNA damage response pathways, other genes involved in these essential and highly complex and multilayered processes represent excellent candidates for identifying further cancer predisposing alleles.AATF (apop
Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer
Aaron G Lewis, James Flanagan, Anna Marsh, Gulietta M Pupo, Graham Mann, Amanda B Spurdle, Geoffrey J Lindeman, Jane E Visvader, Melissa A Brown, Georgia Chenevix-Trench, the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
Breast Cancer Research , 2005, DOI: 10.1186/bcr1336
Abstract: The families used in this study were ascertained through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Denaturing high performance liquid chromatography (DHPLC) analysis of the coding regions of these four genes was conducted in the youngest affected cases of 30 to 267 non-BRCA1/2 breast cancer families. In addition, a further 399 index cases were also screened for mutations in two functionally significant regions of the FANCD2 gene and 253 index cases were screened for two previously reported mutations in BACH1 (p. P47A and p. M299I).DHPLC analysis of FANCD2 identified six silent exonic variants, and a large number of intronic variants, which tagged two common haplotypes. One protein truncating variant was found in BRIP1/BACH1, as well as four missense variants, a silent change and a variant in the 3' untranslated region. No missense or splice site mutations were found in LMO4 or SFN. Analysis of the missense, silent and frameshift variants of FANCD2 and BACH1 in relatives of the index cases, and in a panel of controls, found no evidence suggestive of pathogenicity.There is no evidence that highly penetrant exonic or splice site mutations in FANCD2, BRIP1/BACH1, LMO4 or SFN contribute to familial breast cancer. Large scale association studies will be necessary to determine whether any of the polymorphisms or haplotypes identified in these genes contributes to breast cancer risk.Pathogenic mutations in BRCA1, BRCA2, TP53, PTEN, ATM and CHEK2 account for approximately a third of high-risk breast cancer families, suggesting that other breast cancer susceptibility genes exist [1-5]. Given the number of candidate breast cancer susceptibility genes, any approach to their identification needs to be focussed. Genes whose products are known to interact with BRCA1 and/or BRCA2, or are down-regulated in breast tumours, are particularly attractive candidates, and can be prioritised for investigation.FANCD2 is one of eight gene
RAD51 and Breast Cancer Susceptibility: No Evidence for Rare Variant Association in the Breast Cancer Family Registry Study  [PDF]
Florence Le Calvez-Kelm, Javier Oliver, Francesca Damiola, Nathalie Forey, Nivonirina Robinot, Geoffroy Durand, Catherine Voegele, Maxime P. Vallée, Graham Byrnes, Breast Cancer Family Registry, John L. Hopper, Melissa C. Southey, Irene L. Andrulis, Esther M. John, Sean V. Tavtigian, Fabienne Lesueur
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052374
Abstract: Background Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-established associations with breast cancer susceptibility, it is likely that additional genes involved in the HRR pathway harbor sequence variants associated with increased risk of breast cancer. RAD51 plays a central biological function in DNA repair and despite the fact that rare, likely dysfunctional variants in three of its five paralogs, RAD51C, RAD51D, and XRCC2, have been associated with breast and/or ovarian cancer risk, no population-based case-control mutation screening data are available for the RAD51 gene. We thus postulated that RAD51 could harbor rare germline mutations that confer increased risk of breast cancer. Methodology/Principal Findings We screened the coding exons and proximal splice junction regions of the gene for germline sequence variation in 1,330 early-onset breast cancer cases and 1,123 controls from the Breast Cancer Family Registry, using the same population-based sampling and analytical strategy that we developed for assessment of rare sequence variants in ATM and CHEK2. In total, 12 distinct very rare or private variants were characterized in RAD51, with 10 cases (0.75%) and 9 controls (0.80%) carrying such a variant. Variants were either likely neutral missense substitutions (3), silent substitutions (4) or non-coding substitutions (5) that were predicted to have little effect on efficiency of the splicing machinery. Conclusion Altogether, our data suggest that RAD51 tolerates so little dysfunctional sequence variation that rare variants in the gene contribute little, if anything, to breast cancer susceptibility.
Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer
Sylvie Desjardins, Joly Beauparlant, Yvan Labrie, Geneviève Ouellette, INHERIT BRCAs, Francine Durocher
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-181
Abstract: In a candidate gene study aiming at identifying genetic determinants of breast cancer susceptibility, we undertook the full sequencing of the NBN gene in our cohort of 97 high-risk non-BRCA1 and -BRCA2 breast cancer families, along with 74 healthy unrelated controls, also from the French Canadian population. In silico programs (ESEfinder, NNSplice, Splice Site Finder and MatInspector) were used to assess the putative impact of the variants identified. The effect of the promoter variant was further studied by luciferase gene reporter assay in MCF-7, HEK293, HeLa and LNCaP cell lines.Twenty-four variants were identified in our case series and their frequency was further evaluated in healthy controls. The potentially deleterious p.Ile171Val variant was observed in one case only. The p.Arg215Trp variant, suggested to impair NBN binding to histone γ-H2AX, was observed in one breast cancer case and one healthy control. A promoter variant c.-242-110delAGTA displayed a significant variation in frequency between both sample sets. Luciferase reporter gene assay of the promoter construct bearing this variant did not suggest a variation of expression in the MCF-7 breast cancer cell line, but indicated a reduction of luciferase expression in both the HEK293 and LNCaP cell lines.Our analysis of NBN sequence variations indicated that potential NBN alterations are present, albeit at a low frequency, in our cohort of high-risk breast cancer cases. Further analyses will be needed to fully ascertain the exact impact of those variants on breast cancer susceptibility, in particular for variants located in NBN promoter region.Pathogenic mutations in BRCA1, BRCA2, TP53, ATM, CHEK2, BRIP1 and PALB2 have been associated with an increased breast cancer risk and, together, are found in less than 25% of breast cancer families showing a clear pattern of inheritance (high-risk families) [1]. It is thus clear that other susceptibility alleles remain to be identified to explain the increased risk
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