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1.
Nat Commun ; 12(1): 1078, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597508

RESUMO

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.

2.
Am J Hum Genet ; 107(5): 837-848, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022221

RESUMO

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

3.
Sci Rep ; 10(1): 9688, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546843

RESUMO

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

4.
Br J Cancer ; 121(2): 180-192, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31213659

RESUMO

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.


Assuntos
Estatura , Índice de Massa Corporal , Genes BRCA1 , Genes BRCA2 , Heterozigoto , Análise da Randomização Mendeliana , Mutação , Neoplasias Ovarianas/etiologia , Adulto , Idoso , Feminino , Humanos , Menopausa , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Modelos de Riscos Proporcionais
5.
Cancer Res ; 77(11): 2789-2799, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28283652

RESUMO

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Idoso , Substituição de Aminoácidos , Animais , Estudos de Casos e Controles , Feminino , Genótipo , Mutação em Linhagem Germinativa , Humanos , Camundongos , Mutação de Sentido Incorreto , Risco
6.
Mod Pathol ; 30(1): 15-25, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27612322

RESUMO

Female BRCA1/2 mutation carriers affected with breast and/or ovarian cancer may develop new tumor deposits over time. It is of utmost importance to know the clonal relationships between multiple tumor localizations, enabling differentiation between multiple primaries or metastatic disease with consequences for therapy and prognosis. We evaluated the value of targeted next generation sequencing in the diagnostic workup of BRCA1/2 mutation carriers with ≥2 tumor localizations and uncertain tumor origins. Forty-two female BRCA1/2 mutation carriers with ≥2 tumor localizations were selected. Patients with inconclusive tumor origin after histopathological revision were 'cases'; patients with certain tumor origin of ≥3 tumors served as 'controls'. Tumors of cases and controls were analyzed by targeted next generation sequencing using a panel including CDKN2A, PTEN and TP53, hotspot mutation sites for 27 different genes and 143 single nucleotide polymorphisms for detection of loss of heterozygosity. Based on prevalence of identical or different mutations and/or loss of heterozygosity patterns, tumors were classified as 'multiple primaries' or 'one entity'. Conventional histopathology yielded a conclusive result in 38/42 (90%) of patients. Four cases and 10 controls were analyzed by next generation sequencing. In 44 tumor samples, 48 mutations were found; 39 (81%) concerned TP53 mutations. In all 4 cases, the intra-patient clonal relationships between the tumor localizations could be unequivocally identified by molecular analysis. In all controls, molecular outcomes matched the conventional histopathological results. In most BRCA1/2 mutation carriers with multiple tumors routine pathology work-up is sufficient to determine tumor origins and relatedness. In case of inconclusive conventional pathology results, molecular analyses using next generation sequencing can reliably determine clonal relationships between tumors, enabling optimal treatment of individual patients.


Assuntos
Neoplasias da Mama/metabolismo , Genes BRCA1 , Genes BRCA2 , Neoplasias Primárias Múltiplas/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
7.
Sci Rep ; 6: 36874, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27845421

RESUMO

NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936-1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969-1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905-1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , MicroRNAs/metabolismo , Proteínas Nucleares/genética , Regiões 3' não Traduzidas , Alelos , Proteína BRCA1/genética , Proteína BRCA2/genética , Sítios de Ligação , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Sci Rep ; 6: 30026, 2016 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-27424772

RESUMO

The HOXB13 p.G84E mutation has been firmly established as a prostate cancer susceptibility allele. Although HOXB13 also plays a role in breast tumor progression, the association of HOXB13 p.G84E with breast cancer risk is less evident. Therefore, we comprehensively interrogated the entire HOXB13 coding sequence for mutations in 1,250 non-BRCA1/2 familial breast cancer cases and 800 controls. We identified two predicted deleterious missense mutations, p.G84E and p.R217C, that were recurrent among breast cancer cases and further evaluated their association with breast cancer risk in a larger study. Taken together, 4,520 familial non-BRCA1/2 breast cancer cases and 3,127 controls were genotyped including the cases and controls of the whole gene screen. The concordance rate for the genotyping assays compared with Sanger sequencing was 100%. The prostate cancer risk allele p.G84E was identified in 18 (0.56%) of 3,187 cases and 16 (0.70%) of 2,300 controls (OR = 0.81, 95% CI = 0.41-1.59, P = 0.54). Additionally, p.R217C was identified in 10 (0.31%) of 3,208 cases and 2 (0.087%) of 2,288 controls (OR = 3.57, 95% CI = 0.76-33.57, P = 0.14). These results imply that none of the recurrent HOXB13 mutations in the Dutch population are associated with breast cancer risk, although it may be worthwhile to evaluate p.R217C in a larger study.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Países Baixos/epidemiologia , Risco
9.
J Cancer Res Clin Oncol ; 141(10): 1879-87, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25958056

RESUMO

PURPOSE: The role of CHEK2 in DNA repair by homologous recombination suggests that CHEK2-associated breast cancer (BC) patients might be more sensitive to chemotherapy inducing double-strand DNA breaks, but results hereon are lacking. We compared the sensitivity to first-line chemotherapy and endocrine therapy between CHEK2 1100delC and non-CHEK2 metastatic breast cancer (MBC) patients. METHODS: Sixty-two CHEK2 1100delC MBC patients were selected from three cohorts genotyped for CHEK2 1100delC (one non-BRCA1/2 cohort and two sporadic cohorts). Controls were 62 non-CHEK2 MBC patients, matched for age at and year of primary BC diagnosis, and year of metastatic disease. Objective response rate (complete and partial response) to, and progression-free survival (PFS) and overall survival (OS) after start of first-line chemotherapy and endocrine therapy were compared between CHEK2 and non-CHEK2 patients. RESULTS: Median age at BC diagnosis was 46 and 51 years at MBC diagnosis. First-line chemotherapy consisted of anthracycline-based chemotherapy (n = 73), taxanes (n = 16), CMF(-like) chemotherapy (n = 33) and taxane/anthracycline regimens (n = 2). CHEK2 and non-CHEK2 patients had a comparable objective response rate (44 vs. 52 %). Also, PFS and OS after start of chemotherapy were comparable between both patient groups (hazard ratio 0.91; 95 % confidence interval 0.63-1.30 and 1.03; 95 % CI 0.71-1.49, respectively). Thirty-six CHEK2 and 32 non-CHEK2 patients received first-line endocrine therapy (mainly tamoxifen) for MBC. No significant differences were observed in objective response rate to, and PFS and OS after start of endocrine therapy. CONCLUSION: No differential efficacy of chemotherapy and endocrine therapy given for MBC was observed in CHEK2 versus non-CHEK2 patients.


Assuntos
Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Mutação/genética , Taxoides/uso terapêutico , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Adulto Jovem
10.
Breast Cancer Res ; 14(1): R33, 2012 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-22348646

RESUMO

INTRODUCTION: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). METHODS: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. RESULTS: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). CONCLUSIONS: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 9/genética , Proteínas de Ligação a DNA/genética , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Heterozigoto , Fatores de Transcrição/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
Hum Mutat ; 33(4): 690-702, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22253144

RESUMO

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Mutação , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Adulto , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos
12.
Cancer ; 118(4): 899-907, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21761396

RESUMO

BACKGROUND: We assessed the efficacy of taxane chemotherapy in BRCA1- and BRCA2-associated patients compared with sporadic metastatic breast cancer patients. METHODS: Response rates (RRs) to and progression-free survival (PFS) after taxane chemotherapy of 35 BRCA1-associated and 13 BRCA2-associated metastatic breast cancer patients were compared with those outcomes in 95 matched (1:2) sporadic patients. Matching was performed for age at and year of diagnosis of primary breast cancer, year of metastatic disease, and line of therapy (first vs second or third). RESULTS: Among BRCA1-associated patients, the RR was worse (objective response [OR], 23% vs 38%; progressive disease [PD], 60% vs 19%; P < 0.001); and the median PFS shorter (2.2 vs 4.9 months; P = 0.04) compared with sporadic patients. In the subgroup of hormone receptor (HRec)-negative patients, BRCA1-associated patients (n = 20) had a worse RR (OR, 20% vs 42%, respectively; PD, 70% vs 26%, respectively; P = 0.03) and a shorter PFS (1.8 vs 3.8 months; P = 0.004) compared with sporadic patients (n = 19). These outcomes in HRec-positive patients were similar in BRCA1-associated (n = 11) and sporadic (n = 61) patients (OR, 36% vs 38%; PD, 28% vs 20%; median PFS, both 5.7 months). In BRCA2-associated patients, who were mainly HRec-positive, the OR was higher than in sporadic patients (89% vs 38%, respectively; P = 0.02), whereas the median PFS was not significantly different (7.1 vs 5.7 months, respectively). CONCLUSIONS: BRCA1-associated, HRec-negative metastatic breast cancer patients were less sensitive to taxane chemotherapy than sporadic HRec-negative patients. HRec-positive BRCA1- and BRCA2-associated patients had a sensitivity to taxane chemotherapy similar to that of sporadic patients.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/secundário , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Mutação/genética , Taxoides/uso terapêutico , Adulto , Antineoplásicos/uso terapêutico , Neoplasias da Mama/genética , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Farmacogenética , Prognóstico , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Estudos Retrospectivos , Resultado do Tratamento
13.
PLoS Biol ; 9(11): e1001199, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22110403

RESUMO

Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.


Assuntos
Proteína BRCA1/metabolismo , Neoplasias da Mama/metabolismo , Polaridade Celular , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Aurora Quinase A , Aurora Quinases , Proteína BRCA1/genética , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Mama/citologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Polaridade Celular/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Variação Genética , Genótipo , Células HeLa , Heterozigoto , Humanos , Microtúbulos/fisiologia , Microtúbulos/ultraestrutura , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Estrogênicos/análise
14.
Genet Med ; 13(9): 800-11, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21885922

RESUMO

PURPOSE: Genetic counseling may help counselees understand their genetic risk of developing breast/ovarian cancer. However, many studies have shown that their perception of their risks is inaccurate. Information-oriented variables often predicted the level of accuracy, focusing on specific processes of receiving and processing risks. We examined counselee-oriented predictors about how counselees embed cancer risks in their lives. These predictors reflect the personal meaning of genetic risks and are expected to explain/mediate the impact of genetic counseling on risk-perception-accuracy. METHOD: We analyzed 248 questionnaires of a prospective study, filled in by probands with breast/ovarian cancer and pathogenic mutations, unclassified variants, or uninformative results (n = 30, 16, and 202, respectively). Mediation regression analyses were performed to examine whether counselee predictors mediated/explained the influence of information predictors on the accuracy. Information-oriented predictors regarded presentation format, communicated information, question format, education, pedigree information, cancer experience, and cognitive processes/heuristics. Counselee-oriented predictors regarded their self/personality, life/existence, and need for certainty about DNA test result, heredity, and cancer. RESULTS: Both information-oriented and counselee-oriented variables significantly predicted the accuracy of the counselees' risk perception, with moderate to large effect sizes. Counselee-oriented variables completely mediated/explained the effects of information-oriented variables on the accuracy. DISCUSSION: Counselees seemed to transform objective cancer risks into personally relevant information. Only through this personal meaning of genetic information, information-oriented processes seemed to cause inaccurate perceptions. Genetic counselors are suggested to focus communication on these personal processes.


Assuntos
Neoplasias da Mama/psicologia , Aconselhamento Genético/psicologia , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Feminino , Humanos , Percepção , Análise de Regressão , Risco , Inquéritos e Questionários
15.
Hum Genet ; 130(5): 685-99, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21597964

RESUMO

Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.


Assuntos
Artrite/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Surdez/genética , Haplótipos/genética , Policondrite Recidivante/genética , Sequência de Bases , Simulação por Computador , Feminino , Efeito Fundador , Genótipo , Heterozigoto , Humanos , Judeus/genética , Deleção de Sequência
16.
Breast Cancer Res Treat ; 128(1): 79-84, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20676756

RESUMO

Recently, a variant allele in the 3'UTR of the KRAS gene (rs61764370 T>G) was shown to be associated with an increased risk for developing non-small cell lung cancer, as well as ovarian cancer, and was most enriched in ovarian cancer patients from hereditary breast and ovarian cancer families. This functional variant has been shown to disrupt a let-7 miRNA binding site leading to increased expression of KRAS in vitro. In the current study, we have genotyped this KRAS-variant in breast cancer index cases from 268 BRCA1 families, 89 BRCA2 families, 685 non-BRCA1/BRCA2 families, and 797 geographically matched controls. The allele frequency of the KRAS-variant was found to be increased among patients with breast cancer from BRCA1, but not BRCA2 or non-BRCA1/BRCA2 families as compared to controls. As BRCA1 carriers mostly develop ER-negative breast cancers, we also examined the variant allele frequency among indexes from non-BRCA1/BRCA2 families with ER-negative breast cancer. The prevalence of the KRAS-variant was, however, not significantly increased as compared to controls, suggesting that the variant allele not just simply associates with ER-negative breast cancer. Subsequent expansion of the number of BRCA1 carriers with breast cancer by including other family members in addition to the index cases resulted in loss of significance for the association between the variant allele and mutant BRCA1 breast cancer. In this same cohort, the KRAS-variant did not appear to modify breast cancer risk for BRCA1 carriers. Importantly, results from the current study suggest that KRAS-variant frequencies might be increased among BRCA1 carriers, but solid proof requires confirmation in a larger cohort of BRCA1 carriers.


Assuntos
Regiões 3' não Traduzidas/genética , Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adulto , Neoplasias da Mama/epidemiologia , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Razão de Chances , Prevalência , Proteínas Proto-Oncogênicas p21(ras)
17.
PLoS Genet ; 6(10): e1001183, 2010 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-21060860

RESUMO

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 20 , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Haplótipos , Heterozigoto , Humanos , Desequilíbrio de Ligação , Pessoa de Meia-Idade , Mutação , Penetrância , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Fatores de Risco , Fatores de Transcrição/genética
18.
Breast Cancer Res Treat ; 120(1): 235-44, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19680614

RESUMO

BRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity is one of the few modifiable risk factors, it may provide a target to add to breast cancer prevention in this high-risk population. We examined the association between self-reported lifetime sports activity and breast cancer risk in a nationwide retrospective cohort study, including 725 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. We found a nonsignificantly decreased risk for ever engaging in sports activity (HR = 0.84, 95%CI = 0.57-1.24). Among women who had participated in sports, a medium versus low level of intensity and duration (i.e., between 11.0 and 22.7 mean MET hours/week averaged over a lifetime) reduced the risk of breast cancer (HR = 0.59, 95%CI = 0.36-0.95); no dose-response trend was observed. For mean hours/week of sports activity, a nonsignificant trend was observed (HR(low versus never) = 0.93, 95%CI = 0.60-1.43; HR(medium versus never) = 0.81, 95%CI = 0.51-1.29; HR(high versus never) = 0.78, 95%CI = 0.48-1.29; p (trend overall) = 0.272; p (trend active women) = 0.487). For number of years of sports activity no significant associations were found. Among women active in sports before age 30, mean MET hours/week showed the strongest inverse association of all activity measures (HR(medium versus low) = 0.60, 95%CI = 0.38-0.96; HR(high versus low) = 0.58, 95%CI = 0.35-0.94; p (trend) = 0.053). Engaging in sports activity after age 30 was also inversely associated with breast cancer risk (HR = 0.63, 95%CI = 0.44-0.91). Our results indicate that sports activity may reduce the risk of breast cancer in BRCA1/2 mutation carriers.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Exercício Físico/fisiologia , Genes BRCA1 , Genes BRCA2 , Adulto , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Fatores de Risco
19.
J Clin Oncol ; 27(23): 3764-71, 2009 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-19564533

RESUMO

PURPOSE: Preclinical as well as a few small retrospective, neoadjuvant studies suggest that breast cancer (cells) without functional BRCA1 or BRCA2 protein have an increased sensitivity to some chemotherapeutic agents causing double-strand DNA breaks. In this study we assessed the sensitivity to standard first-line chemotherapy of metastatic BRCA1/2-associated breast cancer, compared with sporadic breast cancer patients. PATIENTS AND METHODS: From the Family Cancer Clinic database, we selected 93 BRCA1- and 28 BRCA2-associated breast cancer patients treated with chemotherapy for metastatic disease before January 1, 2007. Objective response (OR), progression-free survival (PFS), and overall survival (OS) after start of first-line chemotherapy were compared with those of sporadic patients, matched for year of birth, age at diagnosis of primary breast cancer, and year of detection of metastatic disease. RESULTS: The chemotherapy regimens most frequently used were anthracycline-based (n = 147) and cyclophosphamide, methotrexate, and fluorouracil (CMF)/CMF like (n = 68). As compared to sporadic patients, BRCA2-associated patients had a significantly higher OR (89% v 50%; P = .001), a longer PFS (hazard ratio multivariate [HR(mult)] 0.64; P = .04) and a prolonged OS (HR(mult), 0.53; P = .005) after start of first-line chemotherapy for metastatic breast cancer. For BRCA1-associated patients, a nonsignificant trend for an increased OR (66% v 50%; P = .07), and a longer PFS (HR(mult), 0.79; P = .14) after first-line chemotherapy for metastatic breast cancer was observed, but not for OS. CONCLUSION: BRCA2-associated breast cancer is more sensitive to standard first-line chemotherapy for metastatic breast cancer in comparison with sporadic breast cancer, especially to anthracyclines. For BRCA1-associated breast cancer no statistically significant higher sensitivity was observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Mutação , Adulto , Idoso , Análise de Variância , Proteínas Reguladoras de Apoptose , Neoplasias da Mama/química , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Progressão da Doença , Intervalo Livre de Doença , Feminino , Heterozigoto , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores Estrogênicos/análise , Receptores de Progesterona/análise , Projetos de Pesquisa
20.
Breast Cancer Res Treat ; 111(2): 303-11, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17952592

RESUMO

BACKGROUND: Data on distant disease-free interval (DDFI) and the localization of the first distant metastasis (DM) in BRCA1- and BRCA2-associated breast cancer (BC) patients are as yet scarcely available. PATIENTS AND METHODS: We identified 57 BRCA1-associated and 31 BRCA2-associated BC patients, diagnosed between 1980 and 2001, and developing DM disease before 2004, July 1. DDFI, the site(s) of first DM and post-relapse survival of these patients were compared with those of 192 sporadic BC patients. RESULTS: As compared to sporadic patients, BRCA1 patients developed less often bone DM (30% vs. 51%; P = 0.005), but tended to develop more often lung DM (26% vs. 16%; P = 0.07), and DM at multiple sites (44% vs. 32%; P = 0.11). In BRCA2-associated compared to sporadic patients, first DM more commonly occurred in lymph nodes (23% vs. 7%; P = 0.007) and at multiple sites (48% vs. 32%; P = 0.08). Adjuvant systemic therapy appeared to be most effective in BRCA2 mutation carriers. Post-relapse survival was worse for BRCA1- and better for BRCA2-associated patients as compared to sporadic patients, but differences disappeared after adjustment for ER-status, site of first DM and DDFI. CONCLUSION: The site of first DM is different between BRCA1- and BRCA2-associated and sporadic BC patients. Differences in post-relapse survival could be explained by differences in site of first DM, in ER-status and in DDFI. Treatment efficacy may differ dependent on genetic status.


Assuntos
Neoplasias da Mama/mortalidade , Genes BRCA1 , Genes BRCA2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Receptores Estrogênicos/análise
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