RESUMO
BACKGROUND: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. PATIENTS AND METHODS: This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. RESULTS: From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS: In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.
Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/metabolismo , Estudos Retrospectivos , Proteína BRCA1/genética , Proteína BRCA2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Prognóstico , Intervalo Livre de Doença , Adulto Jovem , Mutação em Linhagem Germinativa , Heterozigoto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high-risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene-panel sequencing including also copy number variants (CNV) analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18 of 95 patients (19%). BRCA1/2 mutations were observed in 8 patients (8.4%) and CHEK2 protein-truncating mutations in 7 patients (7.4%). In addition, we identified a novel duplication encompassing most of the RAD51C gene. We further genotyped the duplication in breast or ovarian cancer families (n = 1149), in unselected breast (n = 1729) and ovarian cancer cohorts (n = 553), and in population controls (n = 1273). Seven additional duplication carries were observed among cases but none among controls. The duplication associated with ovarian cancer risk (3/590 of all ovarian cancer patients, 0.5%, P = .032 compared with controls) and was found to represent a large fraction of all identified RAD51C mutations in the Finnish population. Our data emphasizes the importance of comprehensive mutation analysis including CNV detection in all the relevant genes.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Duplicação Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Adulto , Idoso , Alelos , Biomarcadores Tumorais , Éxons , Feminino , Finlândia , Frequência do Gene , Estudos de Associação Genética/métodos , Testes Genéticos , Mutação em Linhagem Germinativa , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Increasing use of BRCA1/2 testing for tailoring cancer treatment and extension of testing to tumour tissue for somatic mutation is moving BRCA1/2 mutation screening from a primarily prevention arena delivered by specialist genetic services into mainstream oncology practice. A considerable number of gene tests will identify rare variants where clinical significance cannot be inferred from sequence information alone. The proportion of variants of uncertain clinical significance (VUS) is likely to grow with lower thresholds for testing and laboratory providers with less experience of BRCA. Most VUS will not be associated with a high risk of cancer but a misinterpreted VUS has the potential to lead to mismanagement of both the patient and their relatives. DESIGN: Members of the Clinical Working Group of ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) global consortium (www.enigmaconsortium.org) observed wide variation in practices in reporting, disclosure and clinical management of patients with a VUS. Examples from current clinical practice are presented and discussed to illustrate potential pitfalls, explore factors contributing to misinterpretation, and propose approaches to improving clarity. RESULTS AND CONCLUSION: Clinicians, patients and their relatives would all benefit from an improved level of genetic literacy. Genetic laboratories working with clinical geneticists need to agree on a clinically clear and uniform format for reporting BRCA test results to non-geneticists. An international consortium of experts, collecting and integrating all available lines of evidence and classifying variants according to an internationally recognized system, will facilitate reclassification of variants for clinical use.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Testes Genéticos/normas , Variação Genética/genética , Mutação/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias da Mama/genética , Interpretação Estatística de Dados , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/genética , Guias de Prática Clínica como Assunto , Prognóstico , Fatores de RiscoRESUMO
Studies indicate variant of uncertain significance (VUS) results are challenging for genetic counselors and patients, often resulting in negative patient outcomes. Genetic counselors' current practices regarding VUS are unknown. This study utilized a national survey of genetic counselors (n = 932) to examine current practices and confidence related to disclosing BRCA VUS results and reclassification information. For participants (n = 398), descriptive statistics were calculated regarding patient demographic characteristics, practices and confidence, and cross tabulation was used to identify participant's actions when receiving a reclassified VUS. Upon receiving a BRCA VUS report, the majority reported providing patients with information about the frequency with which their VUS was seen and patient ancestry, but a minority discussed DNA banking. Most were confident in their understanding of, and ability to explain, VUS results to patients, but felt less confident about achieving high levels of patient understanding. Upon reclassification, the majority reported calling the patient and mailing the results, but when the reclassification was deleterious, the majority also met with the patient face-to-face. Given the lack of standard professional guidelines about informing patients of initial and reclassified VUS results, this overview provides important insight into genetic counselors' current practices and confidence.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Aconselhamento Genético/métodos , Testes Genéticos/métodos , Variação Genética , Adulto , Idoso , Feminino , Aconselhamento Genético/psicologia , Predisposição Genética para Doença/genética , Inquéritos Epidemiológicos/métodos , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Relações Profissional-Paciente , Revelação da Verdade , Incerteza , Adulto JovemRESUMO
BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Modelos Estatísticos , Receptor ErbB-2/biossíntese , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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.
Assuntos
Neoplasias da Mama/genética , Carcinoma/genética , Proteínas de Ligação a DNA/fisiologia , Epistasia Genética/fisiologia , Genes BRCA1 , Genes BRCA2 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Carcinoma/epidemiologia , Proteínas de Ligação a DNA/genética , Feminino , Grupos Focais , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Predisposição Genética para Doença , Heterozigoto , Humanos , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteína 1 Complementadora Cruzada de Reparo de Raio-X , Adulto JovemRESUMO
Glycogen synthase kinase-3 beta (GSK-3ß) is overexpressed in a number of human malignancies and has been shown to contribute to tumor cell proliferation and survival. Although regulation of GSK-3ß activity has been extensively studied, the mechanisms governing GSK-3ß gene expression are still unknown. Using pancreatic cancer as a model, we find that constitutively active Ras signaling increases GSK-3ß gene expression via the canonical mitogen-activated protein kinase signaling pathway. Analysis of the mechanism revealed that K-Ras regulates the expression of this kinase through two highly conserved E-twenty six (ETS) binding elements within the proximal region. Furthermore, we demonstrate that mutant K-Ras enhances ETS2 loading onto the promoter, and ETS requires its transcriptional activity to increase GSK-3ß gene transcription in pancreatic cancer cells. Lastly, we show that ETS2 cooperates with p300 histone acetyltransferase to remodel chromatin and promote GSK-3ß expression. Taken together, these results provide a general mechanism for increased expression of GSK-3ß in pancreatic cancer and perhaps other cancers, where Ras signaling is deregulated.
Assuntos
Genes ras , Quinase 3 da Glicogênio Sintase/genética , Mutação , Neoplasias Pancreáticas/genética , Proteína EWS de Ligação a RNA/genética , Fatores de Transcrição de p300-CBP/genética , Animais , Montagem e Desmontagem da Cromatina , Imunoprecipitação da Cromatina , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/patologia , Regiões Promotoras Genéticas , Transcrição GênicaRESUMO
Centrosome amplification has been detected in premalignant lesions and in situ tumors in the breast and in over 70% of invasive breast tumors, and has been associated with aneuploidy and tumor development. Based on these observations, the contribution of commonly inherited genetic variation in candidate genes related to centrosome structure and function to breast cancer risk was evaluated in an association study. Seven-hundred and 82 single nucleotide polymorphisms (SNPs) from 101 centrosomal genes were analyzed in 798 breast cancer cases and 843 controls from the Mayo Clinic Breast Cancer Study to assess the association between these SNPs (both individually and combined) and risk of breast cancer in this population. Eleven SNPs out of 782 from six genes displayed associations with breast cancer risk (P < 0.01). Haplotypes in five genes also displayed significant associations with risk. A two SNP combination of rs10145182 in NIN and rs2134808 in the TUBG1 locus (P-interaction = 0.00001), suggested SNPs in mediators of microtubule nucleation from the centrosome contribute to breast cancer. Evaluation of the simultaneous significance of all SNPs in the centrosome pathway suggested that the centrosome pathway is highly enriched (P = 4.76 × 10(-50)) for SNPs that are associated with breast cancer risk. Collections of weakly associated genetic variants in the centrosome pathway, rather than individual highly significantly associated SNPs, may account for a putative role for the centrosome pathway in predisposition to breast cancer.
Assuntos
Neoplasias da Mama/genética , Centrossomo/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Minnesota , Razão de Chances , Medição de Risco , Fatores de RiscoRESUMO
The down-regulation of genes involved in normal cell division can cause aberrant mitoses and increased cell death. Surviving cells exhibit aneuploidy and/or polyploidy. Since mitotic disruption has been linked with tumor development and progression, alterations in the expression or activity of these mitotic regulators may contribute to breast tumor formation. We evaluated associations between common inherited variation in these genes and breast cancer risk. Two hundred and five tagging and candidate functional single nucleotide polymorphisms in 30 genes required for normal cell division were genotyped in 798 breast cancer cases and 843 controls from the Mayo Clinic breast cancer study. Two variants in EIF3A (rs10787899 and rs3824830; P < 0.01) and four variants in SART1 (rs660118, rs679581, rs754532, and rs735942; P(trend) < or = 0.02) were significantly associated with an altered risk of breast cancer along with single variants in RRM2, PSCD3, C11orf51, CDC16, SNW1, MFAP1, and CDC2 (P < 0.05). Variation in both SART1 (P = 0.009) and EIF3A (P = 0.02) was also significant at the gene level. Analyses suggested that SART1 SNPs rs660118 and rs679581 accounted for the majority of the association of that gene with breast cancer. The observed associations between breast cancer risk and genetic variation in the SART1 and EIF3A genes that are required for maintenance of normal mitosis suggest a direct role for these genes in the development of breast cancer.
Assuntos
Antígenos de Neoplasias/genética , Neoplasias da Mama/genética , Fator de Iniciação 3 em Eucariotos/genética , Regulação Neoplásica da Expressão Gênica , Mitose/genética , Polimorfismo de Nucleotídeo Único , Ribonucleoproteínas Nucleares Pequenas/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Meio-Oeste dos Estados Unidos/epidemiologia , Invasividade Neoplásica , Razão de Chances , Linhagem , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
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. METHODS: 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. RESULTS: 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. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.
Assuntos
Proteínas de Ligação a DNA/genética , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Mutação , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Feminino , Humanos , Estudos RetrospectivosRESUMO
BACKGROUND: Dysregulation of the cell cycle is a hallmark of many cancers including ovarian cancer, a leading cause of gynaecologic cancer mortality worldwide. METHODS: We examined single nucleotide polymorphisms (SNPs) (n=288) from 39 cell cycle regulation genes, including cyclins, cyclin-dependent kinases (CDKs) and CDK inhibitors, in a two-stage study. White, non-Hispanic cases (n=829) and ovarian cancer-free controls (n=941) were genotyped using an Illumina assay. RESULTS: Eleven variants in nine genes (ABL1, CCNB2, CDKN1A, CCND3, E2F2, CDK2, E2F3, CDC2, and CDK7) were associated with risk of ovarian cancer in at least one genetic model. Seven SNPs were then assessed in four additional studies with 1689 cases and 3398 controls. Association between risk of ovarian cancer and ABL1 rs2855192 found in the original population [odds ratio, OR(BB vs AA) 2.81 (1.29-6.09), P=0.01] was also observed in a replication population, and the association remained suggestive in the combined analysis [OR(BB vs AA) 1.59 (1.08-2.34), P=0.02]. No other SNP associations remained suggestive in the replication populations. CONCLUSION: ABL1 has been implicated in multiple processes including cell division, cell adhesion and cellular stress response. These results suggest that characterization of the function of genetic variation in this gene in other ovarian cancer populations is warranted.
Assuntos
Ciclo Celular/genética , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Quinases Ciclina-Dependentes/genética , Feminino , Humanos , Neoplasias Ovarianas/etiologiaRESUMO
Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P<0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation.
Assuntos
Genes BRCA2 , Mutação , Neoplasias da Próstata/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Genes BRCA1 , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/patologiaRESUMO
Early-life exposures may influence the development of breast cancer. The authors examined the association of childhood and adolescent anthropometric factors, physical activity levels, and diet with adult mammographic breast density, a strong risk factor for breast cancer. Women in the Minnesota Breast Cancer Family Study cohort who had undergone mammograms but had not had breast cancer (n=1,893) formed the sample. Information on adolescent exposures, including relative height, weight, and physical activity at ages 7, 12, and 18 years and diet at age 12-13 years, was self-reported during two follow-up studies (1990-2003). Mammographic percent density was estimated using a computer-assisted thresholding program. Statistical analyses were performed using linear mixed-effects models with two-sided tests. Positive associations with height at ages 7 (p<0.001), 12 (p<0.001), and 18 (p<0.001) years and percent density were evident overall and within menopausal status categories. The minimum difference in percent density between the tallest and shortest girls was 3 percent, with a maximum of 7 percent. Weight at age 12 years (p=0.005) and adiposity at age 12 years (p=0.005) were both inversely associated with adult percent density. Adolescent physical activity and diet were unrelated to percent density. These results suggest that adolescent height, a known risk factor for breast cancer, is also associated with mammographic percent density.
Assuntos
Pesos e Medidas Corporais , Mama/anatomia & histologia , Dieta , Aptidão Física , Adolescente , Fatores Etários , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Criança , Fatores de Confusão Epidemiológicos , Feminino , Humanos , Mamografia , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: The vast majority of BRCA1 missense sequence variants remain uncharacterized for their possible effect on protein expression and function, and therefore are unclassified in terms of their pathogenicity. BRCA1 plays diverse cellular roles and it is unlikely that any single functional assay will accurately reflect the total cellular implications of missense mutations in this gene. OBJECTIVE: To elucidate the effect of two BRCA1 variants, 5236G>C (G1706A) and 5242C>A (A1708E) on BRCA1 function, and to survey the relative usefulness of several assays to direct the characterisation of other unclassified variants in BRCA genes. METHODS AND RESULTS: Data from a range of bioinformatic, genetic, and histopathological analyses, and in vitro functional assays indicated that the 1708E variant was associated with the disruption of different cellular functions of BRCA1. In transient transfection experiments in T47D and 293T cells, the 1708E product was mislocalised to the cytoplasm and induced centrosome amplification in 293T cells. The 1708E variant also failed to transactivate transcription of reporter constructs in mammalian transcriptional transactivation assays. In contrast, the 1706A variant displayed a phenotype comparable to wildtype BRCA1 in these assays. Consistent with functional data, tumours from 1708E carriers showed typical BRCA1 pathology, while tumour material from 1706A carriers displayed few histopathological features associated with BRCA1 related tumours. CONCLUSIONS: A comprehensive range of genetic, bioinformatic, and functional analyses have been combined for the characterisation of BRCA1 unclassified sequence variants. Consistent with the functional analyses, the combined odds of causality calculated for the 1706A variant after multifactorial likelihood analysis (1:142) indicates a definitive classification of this variant as "benign". In contrast, functional assays of the 1708E variant indicate that it is pathogenic, possibly through subcellular mislocalisation. However, the combined odds of 262:1 in favour of causality of this variant does not meet the minimal ratio of 1000:1 for classification as pathogenic, and A1708E remains formally designated as unclassified. Our findings highlight the importance of comprehensive genetic information, together with detailed functional analysis for the definitive categorisation of unclassified sequence variants. This combination of analyses may have direct application to the characterisation of other unclassified variants in BRCA1 and BRCA2.
Assuntos
Proteína BRCA1/química , Proteína BRCA1/genética , Mutação de Sentido Incorreto/genética , Adulto , Idoso , Austrália , Neoplasias da Mama/patologia , Centrossomo/metabolismo , Feminino , Genes Reporter/genética , Humanos , Perda de Heterozigosidade/genética , Pessoa de Meia-Idade , Modelos Moleculares , Processamento de Proteína Pós-Traducional , Transporte Proteico , Splicing de RNA/genética , Estabilidade de RNA/genética , Transcrição Gênica , Ativação Transcricional/genéticaAssuntos
Proteína de Ligação a CREB/genética , Mutação da Fase de Leitura , Neoplasias Ovarianas/genética , Neoplasias da Mama/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Análise Mutacional de DNA , Éxons , Feminino , Genes p53 , Predisposição Genética para Doença , Humanos , Íntrons , Perda de Heterozigosidade , Mutação de Sentido IncorretoAssuntos
Proteínas de Ligação a DNA/genética , Mutação , Neoplasias Pancreáticas/genética , Idoso , Análise Mutacional de DNA , DNA de Neoplasias , Proteína do Grupo de Complementação A da Anemia de Fanconi , Feminino , Predisposição Genética para Doença , Análise Heteroduplex , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNARESUMO
BACKGROUND: In women with a family history of breast cancer, bilateral prophylactic mastectomy is associated with a decreased risk of subsequent breast cancer of approximately 90%. We examined the association between bilateral prophylactic mastectomy and breast cancer risk in women at high risk for breast cancer who also had mutations in BRCA1 and BRCA2 genes. METHODS: We obtained blood samples from 176 of the 214 high-risk women who participated in our previous retrospective cohort study of bilateral prophylactic mastectomy. We used conformation-sensitive gel electrophoresis and direct sequence analysis of the blood specimens to identify women with mutations in BRCA1 and BRCA2. The carriers' probabilities of developing breast cancer were estimated from two different penetrance models. RESULTS: We identified 26 women with an alteration in BRCA1 or BRCA2. Eighteen of the mutations were considered to be deleterious and eight to be of uncertain clinical significance. None of the 26 women has developed breast cancer after a median of 13.4 years of follow-up (range, 5.8-28.5 years). Three of the 214 women are known to have developed a breast cancer after prophylactic mastectomy. For two of these women, BRCA1 and BRCA2 screening was negative, and no blood specimen was available for the third. Estimations of the effectiveness of prophylactic mastectomy were performed, considering this woman as both a mutation carrier and a noncarrier. These calculations predicted that six to nine breast cancers should have developed among the mutation carriers, which translates into a risk reduction, after bilateral prophylactic mastectomy, of 89.5%-100% (95% confidence interval = 41.4% to 100%). CONCLUSIONS: Prophylactic mastectomy is associated with a substantial reduction in the incidence of subsequent breast cancer not only in women identified as being at high risk on the basis of a family history of breast cancer but also in known BRCA1 or BRCA2 mutation carriers.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Genes BRCA1 , Heterozigoto , Mastectomia , Mutação , Neoplasias da Mama/epidemiologia , Feminino , Genes BRCA2 , Humanos , IncidênciaRESUMO
In the United States, ovarian cancer is the fourth most common cause of cancer-related deaths among women. The most important prognostic factor for this cancer is tumor stage, or extent of disease at diagnosis. Although women with low-stage tumors have a relatively good prognosis, most women diagnosed with late-stage disease eventually succumb to their cancer. In an attempt to understand early events in ovarian carcinogenesis, and to explore steps in its progression, we have applied multiple molecular genetic techniques to the analysis of 21 early-stage (stage I/II) and 17 advanced-stage (stage III/IV) ovarian tumors. These techniques included expression profiling with cDNA microarrays containing approximately 18,000 expressed sequences, and comparative genomic hybridization to address the chromosomal locations of copy number gains as well as losses. Results from the analysis indicate that early-stage ovarian cancers exhibit profound alterations in gene expression, many of which are similar to those identified in late-stage tumors. However, differences observed at the genomic level suggest differences between the early- and late-stage tumors and provide support for a progression model for ovarian cancer development.
Assuntos
Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Estadiamento de Neoplasias , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
A novel region of amplification in breast tumors has recently been identified on chromosome 17q22-23. In an effort to identify the oncogenes in the region that are targeted by the amplification process, we determined the structure of the amplicon in breast cancer cell lines and tumors. Physical and transcription maps of the approximately 3.5-Mb region were established and used as the basis for copy number analysis within the region by Southern blot and fluorescence in situ hybridization. Seven specific and independent amplification maxima were identified in breast cancer cell lines and breast tumors. We present correlative amplification and overexpression studies for the FLJ21316 and Hs.6649 genes suggesting a role for these candidates as amplification-dependent oncogenes.
Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Cromossomos Humanos Par 17/genética , Amplificação de Genes , Sequência de Aminoácidos , Regulação Neoplásica da Expressão Gênica , Humanos , Dados de Sequência Molecular , Oncogenes , Mapeamento Físico do Cromossomo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Most epidemiological studies of cigarette smoking and breast cancer have failed to demonstrate a strong association. Only one study has been performed on women at high genetic risk, and smoking was reported to be a protective factor. To further explore this observation, we examined the association of cigarette smoking with the risk of breast cancer in a historical cohort study of high-risk breast cancer families. A total of 426 families ascertained through a consecutive series of breast cancer patients (probands) between 1944 and 1952 were followed through 1996. Occurrence of breast cancer and detailed smoking histories for sisters, daughters, granddaughters, nieces, and marry-ins were obtained through telephone interviews between 1991 and 1996. Cox proportional hazards regression, accounting for age, birth cohort, and other risk factors, was used to calculate relative risks and 95% confidence intervals (CIs) of breast cancer. All of the models were constructed within strata defined by relationship to the index case (proband), with nonsmokers designated as the referent group. Of the 426 families in the cohort, 132 had at least three incident breast and/or ovarian cancers in the biological relatives at the end of the follow-up period. Among sisters and daughters in these 132 high-risk families, those who ever smoked were at 2.4-fold increased risk of breast cancer (95% CI, 1.2-5.1) relative to never-smokers. No association between breast cancer and smoking was observed among nieces and granddaughters of probands or among marry-ins. When the analysis was restricted to 35 families at highest genetic risk (each containing five breast and/or ovarian cancers), smoking became an even stronger risk factor. Among sisters and daughters, ever-smokers were at 5.8-fold greater risk than nonsmokers (95% CI, 1.4-23.9). Among nieces and granddaughters, the risk of breast cancer associated with smoking was increased 60% (95% CI, 0.8-3.2). These results suggest that smoking may increase risk for breast cancer in families with multiple cases of breast or ovarian cancer, especially those with the strongest apparent familial predisposition.