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1.
Endocr Connect ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31336362

RESUMO

Breast cancer in men is a rare and still poorly characterized disease. Inherited mutations in BRCA1, BRCA2 and PALB2 genes, as well as common polymorphisms, play a role in male breast cancer genetic predisposition. Male breast cancer is considered a hormone-dependent tumor specifically related to hyperestrogenism. Polymorphisms in genes involved in estrogen biosynthesis and metabolism pathways, such as CYP17A1 and CYP1B1, have been associated with breast cancer risk. Here, we aimed to investigate the role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk. A series of 597 male breast cancer cases and 1022 male controls, recruited within the Italian Multicenter Study on male breast cancer, was genotyped for CYP17A1 rs743572, CYP1B1 rs1056836 and rs1800440 polymorphisms by allelic discrimination real-time PCR with TaqMan probes. Associations with male breast cancer risk were estimated using logistic regression. No statistically significant associations between male breast cancer risk and the three analyzed polymorphisms emerged. Similar results were obtained also when BRCA1/2 mutational status was considered. No significant differences in the distribution of the genotypes according to estrogen receptor status emerged. In conclusion, our study, based on a large series of male breast cancer cases, is likely to exclude a relevant role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer predisposition. Overall, these results add new data to the increasing evidence that polymorphisms in these genes may not be associated with breast cancer risk.

2.
Int J Cancer ; 145(2): 390-400, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30613976

RESUMO

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.


Assuntos
Neoplasias da Mama Masculina/genética , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Mutação , Análise de Sequência de DNA/métodos , Proteína da Polipose Adenomatosa do Colo/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , DNA Glicosilases/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Adulto Jovem
3.
Ophthalmic Surg Lasers Imaging Retina ; 49(11): e210-e213, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30457658

RESUMO

Torpedo maculopathy is characterized by a congenital, unilateral, and torpedo-shaped chorioretinal lesion with unclear pathogenesis and evolution. Although the optical coherence tomography angiography (OCTA) characteristics have already been defined in literature, the authors describe for the first time the presence of choroidal neovascularization (CNV) on the temporal edge of this lesion in a 36-year-old woman with a history of altered visual field in her left eye. The authors' investigation supports the hypothesis of an aberrant choroidal circulation underlying the pathogenesis of this condition, and proves the advantage conferred by OCTA in CNV detection over the other angiographic techniques. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e210-e213.].

6.
Hum Mutat ; 39(5): 729-741, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29460995

RESUMO

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

7.
Breast ; 38: 92-97, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29287190

RESUMO

INTRODUCTION: Breast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10-15% of all cases. FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility. METHODS: We screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls. RESULTS: Two FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%). CONCLUSION: Rare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations.


Assuntos
Neoplasias da Mama Masculina/genética , DNA Helicases/genética , Predisposição Genética para Doença/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Genótipo , Mutação em Linhagem Germinativa , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Sequenciamento Completo do Genoma , Adulto Jovem
8.
Eur J Ophthalmol ; 28(2): 251-252, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29077180

RESUMO

PURPOSE: To describe a case of rubella retinopathy complicated by bilateral choroidal neovascularization (CNV) and late development of large choroidal excavation (LCE). METHODS: A 19-year-old woman with a diagnosis of rubella retinopathy underwent her annual ophthalmologic examination, including visual acuity testing and slit-lamp biomicroscopy with dilated fundus examination. Color fundus photography, spectral-domain optical coherence tomography (SD-OCT) scans, and optical coherence tomography angiography were acquired to complete the investigation of her ocular condition. The main findings are described in this case report. RESULTS: This woman came to our attention in 2010 with a history of rubella retinopathy, complicated by bilateral CNV and treated with photodynamic therapy (PDT) in 2006. After 6 years of annual follow-up examinations, her visual acuity remained stable in both eyes (20/100), whereas SD-OCT scans uncovered the development of a bilateral LCE in the macular area, associated with a macular hole in the right eye. Optical coherence tomography angiography revealed a vascular network surrounding the choroidal excavation. CONCLUSIONS: Large choroidal excavation is a rare finding that has been described in few chorioretinal diseases, e.g., North Carolina macular dystrophy and toxoplasmosis. We propose to include rubella retinopathy complicated by CNV in the differential diagnosis of LCE, although we recognize the possibility that PDT might have induced or facilitated its formation.


Assuntos
Doenças da Coroide/etiologia , Infecções Oculares Virais/complicações , Doenças Retinianas/complicações , Síndrome da Rubéola Congênita/complicações , Doenças da Coroide/diagnóstico por imagem , Neovascularização de Coroide/diagnóstico por imagem , Neovascularização de Coroide/etiologia , Feminino , Angiofluoresceinografia , Humanos , Fotoquimioterapia , Tomografia de Coerência Óptica , Acuidade Visual/fisiologia , Adulto Jovem
9.
Eur J Hum Genet ; 25(4): 432-438, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28145423

RESUMO

Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Genes Modificadores , Neoplasias Ovarianas/genética , Adulto , Hidrocarboneto de Aril Hidroxilases/genética , Família 2 do Citocromo P450/genética , Proteínas de Ligação a DNA/genética , Feminino , Glutamato Carboxipeptidase II/genética , Heterozigoto , Humanos , Glicoproteínas beta 1 Específicas da Gravidez/genética , Fatores de Transcrição TFII/genética
10.
Cancer ; 123(2): 210-218, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27648926

RESUMO

BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors. BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genetic factors not yet identified. To further explain the genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted gene sequencing were applied to high-risk, BRCA1/2 mutation-negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 female BRCA1/2 mutation-negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzed with WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation-negative MBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation-negative MBC and female breast cancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partner and localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affected with BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband's maternal aunt. Targeted PALB2 sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation-negative MBC cases. NAT1 c.97C>T was not found in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BC risk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation-negative families with multiple MBC and FBC cases. Cancer 2017;123:210-218. © 2016 American Cancer Society.


Assuntos
Neoplasias da Mama Masculina/genética , Exoma/genética , Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Análise Mutacional de DNA/métodos , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Humanos , Itália , Masculino , Mutação/genética , Linhagem
11.
Epidemiol Prev ; 39(4 Suppl 1): 99-101, 2015 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26499424

RESUMO

INTRODUCTION: Today it is well-known that high risk of genetic breast cancer concerns a very limited part of the population: no more than 2-3 women are affected every thousand and this condition as a whole accounts for no more than 3%-5% of all breast cancers. OBJECTIVES AND METHODS: Following the directions contained in the 2014-2018 National Prevention Plan, Veneto's 2014-2018 Regional Program of Prevention (PRP), approved by Regional Council Resolution (DGR) No. 749 of 14.5.2015, consolidation of a pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma is thus proposed. The principal activities of this policy will be the following: creation of a regional working group, survey of currently existing pathways for the identification of women at risk of hereditary breast cancer and adoption of the same, approval and consolidation of a structured regional pathway for women at high risk of hereditary breast and/or ovarian cancer, from paths of oncogenetic consultation and genetic testing to management of disease risk. Subsequent to the recognition of the pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma, the Veneto region undertakes to develop a co-ordinated program of information and training on this pathway directed at the population and healthcare workers. CONCLUSIONS: It is firmly hoped that with the inclusion of a program for the management of women at high risk of hereditary breast cancer within the Veneto PRP this topic may become more defined and structured in terms of sustainability, integration with the existing regional networks (mammography network, Breast Unit), contrasting inequality, monitoring and evaluation, in this way pursuing the objectives of a reduction of cause-specific mortality and improvement of quality of life.


Assuntos
Neoplasias da Mama/prevenção & controle , Promoção da Saúde/organização & administração , Síndromes Neoplásicas Hereditárias/genética , Prevenção Primária/organização & administração , Adulto , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Bases de Dados Factuais , Detecção Precoce de Câncer , Feminino , Genes Neoplásicos , Predisposição Genética para Doença , Testes Genéticos , Humanos , Comunicação Interdisciplinar , Itália , Mamografia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Qualidade de Vida
12.
Eur J Cancer ; 51(16): 2289-95, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26248686

RESUMO

Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC). In the frame of the ongoing Italian Multicenter Study on MBC, we performed a case-control study on 386 MBC cases, including 50 BRCA1/2 mutation carriers, and 1105 healthy male controls, including 197 unaffected BRCA1/2 mutation carriers. All 1491 subjects were genotyped by Sequenom iPLEX technology for a total of 29 susceptibility SNPs. By logistic regression models, we found a significant association with MBC risk for five SNPs: rs1562430 (p=0.002) and rs445114 (p=0.026) both within the 8q24.21 region; rs1011970/9p21.3 (p=0.011), rs614367/11q13.3 (p=0.016) and rs1314913/14q24.1 (p<0.0001). Differences in the distribution of rs614367/11q13.3 genotypes according to oestrogen receptor (ER) status (p=0.006), and of rs1011970/9p21.3 genotypes according to human epidermal growth factor receptor 2 (HER2) status (p=0.002) emerged. Association of rs1011970/9p21.3 risk genotype with HER2+MBC was confirmed by a multivariate analysis. rs1314913/14q24.1 was associated with increased MBC risk in analyses restricted to male BRCA1/2 mutation carriers (p=0.041). In conclusion, we provided the first evidence that the 8q24.21 region is associated with MBC risk. Furthermore, we showed that the SNPs rs1562430/8q24.21 and rs1314913/14q24.1 strongly influence BC risk in men and suggested that the SNP rs1314913/14q24.1 may act as a risk modifier locus in male BRCA1/2 mutation carriers.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama Masculina/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 8 , Cromossomos Humanos Par 9 , Polimorfismo de Nucleotídeo Único , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/patologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Frequência do Gene , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Itália , Modelos Lineares , Modelos Logísticos , Masculino , Análise Multivariada , Mutação , Razão de Chances , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco
13.
Cancer Epidemiol Biomarkers Prev ; 24(1): 308-16, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25336561

RESUMO

BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1/fisiologia , Genes BRCA2/fisiologia , Neoplasias Ovarianas/genética , Adulto , Estudos de Coortes , Feminino , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Adulto Jovem
14.
Clin Cancer Res ; 21(3): 652-7, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25398451

RESUMO

PURPOSE: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. EXPERIMENTAL DESIGN: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. RESULTS: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality. CONCLUSIONS: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.


Assuntos
Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Idoso , Carcinoma Epitelial do Ovário , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Prognóstico , Análise de Sobrevida
15.
Hum Mutat ; 35(7): 828-40, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24659262

RESUMO

CDKN2A codes for two oncosuppressors by alternative splicing of two first exons: p16INK4a and p14ARF. Germline mutations are found in about 40% of melanoma-prone families, and most of them are missense mutations mainly affecting p16INK4a. A growing number of p16INK4a variants of uncertain significance (VUS) are being identified but, unless their pathogenic role can be demonstrated, they cannot be used for identification of carriers at risk. Predicting the effect of these VUS by either a "standard" in silico approach, or functional tests alone, is rather difficult. Here, we report a protocol for the assessment of any p16INK4a VUS, which combines experimental and computational tools in an integrated approach. We analyzed p16INK4a VUS from melanoma patients as well as variants derived through permutation of conserved p16INK4a amino acids. Variants were expressed in a p16INK4a-null cell line (U2-OS) and tested for their ability to block proliferation. In parallel, these VUS underwent in silico prediction analysis and molecular dynamics simulations. Evaluation of in silico and functional data disclosed a high agreement for 15/16 missense mutations, suggesting that this approach could represent a pilot study for the definition of a protocol applicable to VUS in general, involved in other diseases, as well.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Variação Genética , Melanoma/genética , Motivos de Aminoácidos , Substituição de Aminoácidos , Linhagem Celular Tumoral , Proliferação de Células , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Melanoma/diagnóstico , Modelos Moleculares , Mutação de Sentido Incorreto , Conformação Proteica , Neoplasias Cutâneas
16.
Clin Chem ; 60(2): 341-52, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24212087

RESUMO

BACKGROUND: Accurate evaluation of unclassified sequence variants in cancer predisposition genes is essential for clinical management and depends on a multifactorial analysis of clinical, genetic, pathologic, and bioinformatic variables and assays of transcript length and abundance. The integrity of assay data in turn relies on appropriate assay design, interpretation, and reporting. METHODS: We conducted a multicenter investigation to compare mRNA splicing assay protocols used by members of the ENIGMA (Evidence-Based Network for the Interpretation of Germline Mutant Alleles) consortium. We compared similarities and differences in results derived from analysis of a panel of breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2) gene variants known to alter splicing (BRCA1: c.135-1G>T, c.591C>T, c.594-2A>C, c.671-2A>G, and c.5467+5G>C and BRCA2: c.426-12_8delGTTTT, c.7988A>T, c.8632+1G>A, and c.9501+3A>T). Differences in protocols were then assessed to determine which elements were critical in reliable assay design. RESULTS: PCR primer design strategies, PCR conditions, and product detection methods, combined with a prior knowledge of expected alternative transcripts, were the key factors for accurate splicing assay results. For example, because of the position of primers and PCR extension times, several isoforms associated with BRCA1, c.594-2A>C and c.671-2A>G, were not detected by many sites. Variation was most evident for the detection of low-abundance transcripts (e.g., BRCA2 c.8632+1G>A Δ19,20 and BRCA1 c.135-1G>T Δ5q and Δ3). Detection of low-abundance transcripts was sometimes addressed by using more analytically sensitive detection methods (e.g., BRCA2 c.426-12_8delGTTTT ins18bp). CONCLUSIONS: We provide recommendations for best practice and raise key issues to consider when designing mRNA assays for evaluation of unclassified sequence variants.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Testes Genéticos/métodos , Testes Genéticos/normas , Laboratórios/normas , Processamento de RNA , Predisposição Genética para Doença , Humanos , Análise Multivariada , Guias de Prática Clínica como Assunto , Sítios de Splice de RNA , Sensibilidade e Especificidade
17.
PLoS Genet ; 9(3): e1003212, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23544013

RESUMO

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco
18.
Breast Cancer Res Treat ; 136(1): 295-302, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23011509

RESUMO

Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.25-1.92, p = 6.0 × 10(-5)]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here, we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers (HR = 1.09, 95 % CI 0.96-1.24, p = 0.18). No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama , Mutação em Linhagem Germinativa , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Cromossomos Humanos Par 6/genética , Feminino , Seguimentos , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
PLoS One ; 7(9): e44460, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22962615

RESUMO

Stromal cell-Derived Factor 1 (SDF1) is the natural ligand of CXCR4, the coreceptor of HIV-1 X4 viruses. This study investigated the role of the single nucleotide polymorphism (SNP) rs1801157 (NM_000609.5:c.*519G>A) of the SDF1 gene in the natural history of mother-to-child transmission of HIV-1 and disease progression of HIV-1-infected children. The study was conducted in 428 children born to HIV-1-seropositive mothers, who had not undergone antiretroviral therapy (ART) during pregnancy, and in 120 HIV-1-infected children for whom the end-point was the onset of AIDS or the initiation of ART; 16 children developed early AIDS (<24 months of life), 13 from 24 to 84 months of age, and 14 had late AIDS (>84 months). The rs1801157 SNP was not associated with risk of perinatal infection in any genetic models tested. By contrast, this SNP influenced disease progression in a time-dependent manner. rs1801157 GA heterozygous children had a higher risk of late AIDS (HR = 6.3, 95%CI 1.9-20.7, p = 0.002) than children with the rs1801157 GG genotype. Children were studied for viral coreceptor usage at birth, after 84 months of age and/or at AIDS onset. While R5 viruses using CCR5 coreceptor were predominant at birth (94%) and at early AIDS (85%), viruses using CXCR4 coreceptor emerged during the course of infection and were detected in 49% of children older than 84 months and in 62% of late AIDS. The rs1801157 SNP did not influence the emergence of R5X4 viruses, but children with the rs1801157 GA genotype and R5X4 viruses were at significantly higher risk of late AIDS than children with rs1801157 GG genotype (OR = 8.0, 95% CI 1.2-52.2, p = 0.029). Our results indicate that the rs1801157 SNP does not influence perinatal infection, but impacts disease progression. This effect is time-dependent and linked to the coreceptor-usage of viral variants that undergo evolution during the course of HIV-1 infection.


Assuntos
Quimiocina CXCL12/genética , Infecções por HIV , HIV-1/fisiologia , Transmissão Vertical de Doença Infecciosa , Receptores CXCR4/genética , Receptores Virais/genética , Idade de Início , Quimiocina CXCL12/metabolismo , Criança , Pré-Escolar , Progressão da Doença , Feminino , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Itália/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único , Gravidez , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Receptores Virais/metabolismo
20.
Breast Cancer Res Treat ; 134(1): 411-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22527108

RESUMO

Recently, the number of studies on male breast cancer (MBC) has been increasing. However, as MBC is a rare disease there are difficulties to undertake studies to identify specific MBC subgroups. At present, it is still largely unknown whether BRCA-related breast cancer (BC) in men may display specific characteristics as it is for BRCA-related BC in women. To investigate the clinical-pathologic features of MBC in association with BRCA mutations we established a collaborative Italian Multicenter Study on MBC with the aim to recruit a large series of MBCs. A total of 382 MBCs, including 50 BRCA carriers, were collected from ten Italian Investigation Centres covering the whole country. In MBC patients, BRCA2 mutations were associated with family history of breast/ovarian cancer (p<0.0001), personal history of other cancers (p=0.044) and contralateral BC (p=0.001). BRCA2-associated MBCs presented with high tumor grade (p=0.001), PR-(p=0.026) and HER2+ (p=0.001) status. In a multivariate logistic model BRCA2 mutations showed positive association with personal history of other cancers (OR 11.42, 95% CI 1.79-73.08) and high tumor grade (OR 4.93, 95% CI 1.02-23.88) and inverse association with PR+ status (OR 0.19, 95% CI 0.04-0.92). Based on immunohistochemical (IHC) profile, four molecular subtypes of MBC were identified. Luminal A was the most common subtype (67.7%), luminal B was observed in 26.5% of the cases and HER2 positive and triple negative were represented by 2.1% and 3.7% of tumors, respectively. Intriguingly, we found that both luminal B and HER2 positive subtypes were associated with high tumor grade (p=0.003 and 0.006, respectively) and with BRCA2 mutations (p=0.016 and 0.001, respectively). In conclusion, our findings indicate that BRCA2-related MBCs represent a subgroup of tumors with a peculiar phenotype characterized by aggressive behavior. The identification of a BRCA2-associated phenotype might define a subset of MBC patients eligible for personalized clinical management.


Assuntos
Neoplasias da Mama Masculina/genética , Carcinoma Ductal de Mama/genética , Genes BRCA1 , Genes BRCA2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/patologia , Análise Mutacional de DNA , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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