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1.
Oncologist ; 24(7): e475-e479, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30541753

RESUMO

BACKGROUND: Inherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) confer high risks of breast and ovarian cancer. In Colombian Hispanic families, four common BRCA1/2 founder mutations have previously been identified. Because nothing is known about the contribution of BRCA1/2 germline mutations to early-onset and hereditary breast and/or ovarian cancer in Afro-Colombians, we conducted the first study on 60 patients with early-onset and familial breast cancer in this population. MATERIALS AND METHODS: Screening for the four Colombian founder mutations BRCA1/c.3331_3334delCAAG, BRCA1/c.5123C>A, BRCA2/c.2806_2809delAAAC, and BRCA2/c.1763_1766delATAA was performed using mismatch polymerase chain reaction (PCR) analysis, PCR-based restriction fragment length polymorphism analysis, and qualitative real-time PCR. Mutations were confirmed by direct DNA sequencing. RESULTS: The BRCA1 founder mutation c.5123C>A was identified in one family with breast and ovarian cancer (1/60, 1.7%). Three women were diagnosed with breast cancer, including one with bilateral disease, at the ages of 30, 30/33, and 52 years, and one woman was diagnosed with ovarian cancer at the age of 60 years. CONCLUSION: Our data showed a low prevalence of the BRCA1/2 founder mutations in Colombians of African descent, implying that these mutations should not be recommended for genetic screening programs in the Afro-Colombian population. IMPLICATIONS FOR PRACTICE: Risk reduction intervention programs are needed for women who are found to carry a BRCA1/2 mutation, as is the implementation of prevention programs for patients with inherited breast cancer, to reduce the burden of inherited diseases. With the aim of reducing racial disparities in breast cancer prevention, this study focused on genetic testing and treatment for patients in a minority population with BRCA1/2 mutations.

2.
Int J Mol Sci ; 19(12)2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30518158

RESUMO

Gastric cancer (GC) is the fifth most common cancer and the third most frequent cause of cancer deaths worldwide. The high death rate associated with GC, and lack of appropriate biomarkers for diagnosis, prognosis, and treatment emphasize the need for identification of novel molecules. Given the emerging roles for long non-coding RNAs (lncRNAs) in cancer development, we studied novel lncRNA candidates involved in gastric carcinogenesis. LncRNA candidate discovery was performed using analyses of available datasets and literature. Validation was done using an internal sample set of GC/normal tissues, and external independent datasets. Network analysis and functional annotation of co-expressed protein coding genes were performed using the weighted gene correlation network analysis (WGCNA) and ingenuity pathway analysis. Two novel lncRNAs, PCAT18 and LINC01133, associated with GC development were identified by analysis of the discovery Gene Expression Omnibus (GEO) datasets. The down-regulation of these genes in GC tissues was successfully validated internally and externally. The results showed a tissue-specific down-regulation of PCAT18 and LINC01133 in gastrointestinal tissues. WGCNA and ingenuity pathway analyses revealed that the genes co-expressed with the two lncRNAs were mostly involved in metabolic pathways and networks of gastrointestinal disease and function. Our findings of a tissue-specific down-regulation of PCAT18 and LINC01133 in gastric and other gastrointestinal cancers imply that these lncRNAs may have a tumor suppressive function in the development of these tumor entities. The two lncRNA biomarkers may contribute to a better understanding of the complex mechanisms of gastric carcinogenesis.

3.
Int J Cancer ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30485434

RESUMO

Latino women show lower incidences of breast cancer (BC) than non-Hispanic whites. Large-scale genetic association studies have identified variants robustly associated with BC risk in European women. We examine here the relevance of these variants to Colombian BC and possible interactions with genetic ancestry. Native American, European and African proportions were estimated for 1,022 Colombian BC cases and 1,023 controls. Logistic regression was applied to assess the association between 78 variants and BC risk and interactions between the variants and ancestry proportions. We constructed a multifactorial risk score combining established BC risk factors, associated risk variants and individual ancestry proportions. Each 1% increase in the Native American proportion translated into a 2.2% lower BC risk (95% CI: 1.4-2.9). Thirteen variants were associated with BC in Colombian women, with allele frequencies and risk effects partially different from European women. Ancestry proportions moderated the risk effects of two variants. The ability of Native American proportions to separate Colombian cases and controls (area-under-the-curve (AUC)=0.61) was similar to the discriminative ability of family history of BC in first-degree female relatives (AUC=0.58) or the combined effect of all 13 associated risk variants (AUC=0.57). Our findings demonstrate ample potential for individualized BC prevention in Hispanic women taking advantage of individual Native American proportions, information on established susceptibility factors and recently identified common risk variants. This article is protected by copyright. All rights reserved.

4.
Cancer Res Treat ; 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30309218

RESUMO

Purpose: Partner and localizer of BRCA2 (PALB2) is a breast cancer susceptibility gene that plays an important role in DNA repair. This is the first study assessing the prevalence of PALB2 mutations in early-onset and familial breast/ovarian cancer patients from Pakistan. Materials and Methods: PALB2 mutation screening was performed in 370 Pakistani patients with early-onset and familial breast/ovarian cancer, who were negative for BRCA1, BRCA2, TP53, CHEK2, and RAD51C mutations, using denaturing high-performance liquid chromatography analysis. Mutations were confirmed by DNA sequencing. Novel PALB2 alterations were analyzed for their potential effect on protein function or splicing using various in silico prediction tools. Three-hundred and seventy-two healthy controls were screened for the presence of the identified (potentially) functional mutations. Results: A novel nonsense mutation, p.Y743*, was identified in one familial breast cancer patient (1/127; 0.8%). Besides, four in silico-predicted potentially functional mutations including three missense mutations and one 5´ untranslated region mutation were identified: p.D498Y, novel p.G644R, novel p.E744K, and novel c.-134_-133delTCinsGGGT. The mutations p.Y743* and p.D498Y were identified in two familial patients diagnosed with unilateral or synchronous bilateral breast cancer at the ages of 29 and 39, respectively. The other mutations were identified in an early-onset (<30 years of age) breast cancer patient each. All five mutations were absent in 372 healthy controls suggesting that they are disease associated. Conclusion: Our findings show that PALB2 mutations account for a small proportion of early-onset and hereditary breast/ovarian cancer cases in Pakistan.

5.
Epigenomics ; 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30208740

RESUMO

AIM: To identify DNA methylation biomarkers in peripheral blood samples from triple-negative breast cancer (TNBC) patients. MATERIALS & METHODS: We conducted an epigenome-wide association study (EWAS): the most promising markers were identified in 233 TNBC case-control pairs (discovery set) and subsequently validated in an independent validation set (57 TNBC patients and 124 controls). RESULTS: cg06588802 (LINC00299/ID2) showed a higher methylation in TNBC patients compared with controls (discovery set: 3% increase, p-value = 0.0009; validation set: 2% increase, p-value = 0.01). Consistent results at four neighboring methylation probes and the strong negative correlation (rho = -0.93) with LINC00299 expression add plausibility to this result. CONCLUSION: Hypermethylation of LINC00299 in peripheral blood may constitute a useful circulating biomarker for TNBC.

6.
Cancer Res ; 78(18): 5419-5430, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30054336

RESUMO

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

7.
Hum Mutat ; 39(5): 593-620, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29446198

RESUMO

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

8.
BMC Genomics ; 18(1): 798, 2017 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-29041903

RESUMO

BACKGROUND: Genotypes not directly measured in genetic studies are often imputed to improve statistical power and to increase mapping resolution. The accuracy of standard imputation techniques strongly depends on the similarity of linkage disequilibrium (LD) patterns in the study and reference populations. Here we develop a novel approach for genotype imputation in low-recombination regions that relies on the coalescent and permits to explicitly account for population demographic factors. To test the new method, study and reference haplotypes were simulated and gene trees were inferred under the basic coalescent and also considering population growth and structure. The reference haplotypes that first coalesced with study haplotypes were used as templates for genotype imputation. Computer simulations were complemented with the analysis of real data. Genotype concordance rates were used to compare the accuracies of coalescent-based and standard (IMPUTE2) imputation. RESULTS: Simulations revealed that, in LD-blocks, imputation accuracy relying on the basic coalescent was higher and less variable than with IMPUTE2. Explicit consideration of population growth and structure, even if present, did not practically improve accuracy. The advantage of coalescent-based over standard imputation increased with the minor allele frequency and it decreased with population stratification. Results based on real data indicated that, even in low-recombination regions, further research is needed to incorporate recombination in coalescence inference, in particular for studies with genetically diverse and admixed individuals. CONCLUSIONS: To exploit the full potential of coalescent-based methods for the imputation of missing genotypes in genetic studies, further methodological research is needed to reduce computer time, to take into account recombination, and to implement these methods in user-friendly computer programs. Here we provide reproducible code which takes advantage of publicly available software to facilitate further developments in the field.


Assuntos
Genótipo , Desequilíbrio de Ligação/genética , Crescimento Demográfico , Genômica , Haplótipos , Humanos , Modelos Genéticos
9.
Int J Cancer ; 141(9): 1830-1840, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28670784

RESUMO

Investigating the most likely causal variants identified by fine-mapping analyses may improve the power to detect gene-environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine-scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER-) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene-environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between CFLAR-rs7558475 and current smoking (ORint = 0.77, 95% CI: 0.67-0.88, pint = 1.8 × 10-4 ). The interaction with the strongest statistical evidence was found between 5q14-rs7707921 and alcohol consumption (ORint =1.36, 95% CI: 1.16-1.59, pint = 1.9 × 10-5 ) in relation to ER- disease risk. The remaining two gene-environment interactions were also identified in relation to ER- breast cancer risk and were found between 3p21-rs6796502 and age at menarche (ORint = 1.26, 95% CI: 1.12-1.43, pint =1.8 × 10-4 ) and between 8q23-rs13267382 and age at first full-term pregnancy (ORint = 0.89, 95% CI: 0.83-0.95, pint = 5.2 × 10-4 ). While these results do not suggest any strong gene-environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed.


Assuntos
Neoplasias da Mama/genética , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Interação Gene-Ambiente , Estudos de Associação Genética , Consumo de Bebidas Alcoólicas/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fumar/genética
10.
J Clin Oncol ; 35(20): 2240-2250, 2017 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-28448241

RESUMO

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.


Assuntos
Neoplasias da Mama Masculina/genética , Genes BRCA1 , Genes BRCA2 , Herança Multifatorial , Mutação , Neoplasias da Próstata/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Predisposição Genética para Doença , Testes Genéticos , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos
11.
Oncotarget ; 8(11): 18381-18398, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28179588

RESUMO

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.


Assuntos
Antraciclinas/uso terapêutico , Neoplasias da Mama/genética , Locos de Características Quantitativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/patologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Ligases SKP Culina F-Box/genética , Análise de Sobrevida , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Adulto Jovem
12.
Genet Med ; 19(5): 599-603, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27711073

RESUMO

PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. RESULTS: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. CONCLUSION: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.


Assuntos
Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Deleção de Sequência , Feminino , Genes Modificadores , Predisposição Genética para Doença , Humanos , Razão de Chances , Penetrância
13.
Breast Cancer Res Treat ; 161(2): 191-201, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27826754

RESUMO

BACKGROUND: Germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers. Pakistan has one of the highest rates of breast cancer incidence in Asia, where BRCA1/2 small-range mutations account for 17% of early-onset and familial breast/ovarian cancer patients. We report the first study from Pakistan evaluating the prevalence of BRCA1/2 large genomic rearrangements (LGRs) in breast and/or ovarian cancer patients who do not harbor small-range BRCA1/2 mutations. MATERIALS AND METHODS: Both BRCA1/2 genes were comprehensively screened for LGRs using multiplex ligation-dependent probe amplification in 120 BRCA1/2 small-range mutations negative early-onset or familial breast/ovarian cancer patients from Pakistan (Group 1). The breakpoints were characterized by long-range PCR- and DNA-sequencing analyses. An additional cohort of 445 BRCA1/2 negative high-risk patients (Group 2) was analyzed for the presence of LGRs identified in Group 1. RESULTS: Three different BRCA1 LGRs were identified in Group 1 (4/120; 3.3%), two of these were novel. Exon 1-2 deletion was observed in two unrelated patients: an early-onset breast cancer patient and another bilateral breast cancer patient from a hereditary breast cancer (HBC) family. Novel exon 20-21 deletion was detected in a 29-year-old breast cancer patient from a HBC family. Another novel exon 21-24 deletion was identified in a breast-ovarian cancer patient from a hereditary breast and ovarian cancer family. The breakpoints of all deletions were characterized. Screening of the 445 patients in Group 2 for the three LGRs revealed ten additional patients harboring exon 1-2 deletion or exon 21-24 deletion (10/445; 2.2%). No BRCA2 LGRs were identified. CONCLUSIONS: LGRs in BRCA1 are found with a considerable frequency in Pakistani breast/ovarian cancer cases. Our findings suggest that BRCA1 exons 1-2 deletion and exons 21-24 deletion should be included in the recurrent BRCA1/2 mutations panel for genetic testing of high-risk Pakistani breast/ovarian cancer patients.


Assuntos
Rearranjo Gênico , Genes BRCA1 , Mutação em Linhagem Germinativa , Síndrome Hereditária de Câncer de Mama e Ovário/epidemiologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Idade de Início , Idoso , Sequência de Bases , Pontos de Quebra do Cromossomo , Éxons , Feminino , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Fenótipo , Vigilância da População , Deleção de Sequência , Adulto Jovem
14.
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
15.
Breast Cancer Res ; 18(1): 112, 2016 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-27836010

RESUMO

BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. CONCLUSIONS: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Vigilância da População , Alelos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Éxons , Feminino , Heterozigoto , Humanos , Perda de Heterozigosidade , Fenótipo , Regiões Promotoras Genéticas
16.
Oncotarget ; 7(49): 80140-80163, 2016 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-27792995

RESUMO

There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Cromossomos Humanos Par 4 , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/patologia , Canadá , Proteínas de Transporte/genética , Estudos de Casos e Controles , DNA Helicases/genética , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Proteínas Mitocondriais/genética , Razão de Chances , Fenótipo , Locos de Características Quantitativas , Medição de Risco , Fatores de Risco
17.
Am J Hum Genet ; 99(4): 903-911, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27640304

RESUMO

Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10-30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER-) breast cancer (lead SNP rs6864776: per-a allele OR ER- = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10-12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10-05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Cromossomos Humanos Par 5/genética , Fator 10 de Crescimento de Fibroblastos/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Estrogênicos/metabolismo , Alelos , Estudos de Casos e Controles , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos/genética , Fator 10 de Crescimento de Fibroblastos/metabolismo , Haplótipos/genética , Humanos , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo
18.
Sci Rep ; 6: 32512, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27600471

RESUMO

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90-0.94; P = 8.96 × 10(-15))) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10(-09), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Locos de Características Quantitativas/genética , Proteínas de Transporte Vesicular/genética , Neoplasias da Mama/patologia , Mapeamento Cromossômico , Cromossomos Humanos Par 17/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
19.
BMC Cancer ; 16(1): 673, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27553291

RESUMO

BACKGROUND: Women harboring BRCA1/2 germline mutations have high lifetime risk of developing breast/ovarian cancer. The recommendation to pursue BRCA1/2 testing is based on patient's family history of breast/ovarian cancer, age of disease-onset and/or pathologic parameters of breast tumors. Here, we investigated if diagnosis of triple-negative breast cancer (TNBC) independently increases risk of carrying a BRCA1/2 mutation in Pakistan. METHODS: Five hundred and twenty-three breast cancer patients including 237 diagnosed ≤ 30 years of age and 286 with a family history of breast/ovarian cancer were screened for BRCA1/2 small-range mutations and large genomic rearrangements. Immunohistochemical analyses were performed at one center. Univariate and multiple logistic regression models were used to investigate possible differences in prevalence of BRCA1/2 mutations according to patient and tumor characteristics. RESULTS: Thirty-seven percent of patients presented with TNBC. The prevalence of BRCA1 mutations was higher in patients with TNBC than non-TNBC (37 % vs. 10 %, P < 0.0001). 1 % of TNBC patients were observed to have BRCA2 mutations. Subgroup analyses revealed a larger proportion of BRCA1 mutations in TNBC than non-TNBC among patients 1) diagnosed at early-age with no family history of breast/ovarian cancer (14 % vs. 5 %, P = 0.03), 2) diagnosed at early-age irrespective of family history (28 % vs. 11 %, P = 0.0003), 3) had a family history of breast cancer (49 % vs. 12 %, P < 0.0001), and 4) those with family history of breast and ovarian cancer (81 % vs. 28 %, P = 0.0005). TNBC patients harboring BRCA1 mutations were diagnosed at a later age than non-carriers (median age at diagnosis: 30 years (range 22-53) vs. 28 years (range 18-67), P = 0.002). The association between TNBC status and presence of BRCA1 mutations was independent of the simultaneous consideration of family phenotype, tumor histology and grade in a multiple logistic regression model (Ratio of the probability of carrying BRCA1/2 mutations for TNBC vs. non-TNBC 4.23; 95 % CI 2.50-7.14; P < 0.0001). CONCLUSION: Genetic BRCA1 testing should be considered for Pakistani women diagnosed with TNBC.


Assuntos
Proteína BRCA1/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Mutação em Linhagem Germinativa/genética , Neoplasias de Mama Triplo Negativas/genética , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paquistão/epidemiologia , Prevalência , Prognóstico , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto Jovem
20.
PLoS Med ; 13(8): e1002105, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27551723

RESUMO

BACKGROUND: Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. METHODS: We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. RESULTS: In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk. CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/genética , Grupo com Ancestrais do Continente Europeu/genética , Neoplasias da Mama/etiologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Predisposição Genética para Doença/genética , Humanos , Análise da Randomização Mendeliana , Menopausa , Pessoa de Meia-Idade , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
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