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1.
JAMA Oncol ; 6(8): 1218-1230, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32614418

RESUMO

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population. Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers. Design, Setting, and Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected. Main Outcomes and Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview. Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier. Conclusions and Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

2.
Cancers (Basel) ; 12(2)2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991861

RESUMO

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

3.
Cancer Res ; 80(3): 624-638, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31723001

RESUMO

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Genômica/métodos , Mutação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto Jovem
4.
Hum Mutat ; 40(5): 566-577, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30817846

RESUMO

There is still around 50% of the familial breast cancer (BC) cases with an undefined genetic cause, here we have used next-generation sequencing (NGS) technology to identify new BC susceptibility genes. This approach has led to the identification of RECQL5, a member of RECQL-helicases family, as a new BC susceptibility candidate, which deserves further study. We have used a combination of whole exome sequencing in a family negative for mutations in BRCA1/2 throughout (BRCAX), in which we found a probably deleterious variant in RECQL5, and targeted NGS of the complete coding regions and exon-intron boundaries of the candidate gene in 699 BC Spanish BRCAX families and 665 controls. Functional characterization and in silico inference of pathogenicity were performed to evaluate the deleterious effect of detected variants. We found at least seven deleterious or likely deleterious variants among the cases and only one in controls. These results prompt us to propose RECQL5 as a gene that would be worth to analyze in larger studies to explore its possible implication in BC susceptibility.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Predisposição Genética para Doença , RecQ Helicases/genética , RecQ Helicases/metabolismo , Processamento Alternativo , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Variação Genética , Humanos , Perda de Heterozigosidade , Família Multigênica , Linhagem , Sequenciamento Completo do Exoma
5.
Int J Cancer ; 143(8): 1954-1962, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29761480

RESUMO

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10-23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.


Assuntos
Dineínas do Axonema/genética , Exonucleases/genética , Predisposição Genética para Doença/genética , Plectina/genética , Neoplasias Testiculares/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Exoma/genética , Feminino , Hereditariedade/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de Risco , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
6.
Br J Cancer ; 117(7): 1048-1062, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28829762

RESUMO

BACKGROUND: Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis. METHODS: To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation. To define a functional-analysis prioritisation criteria, we used outputs for the known functionally confirmed deleterious and benign RAD51C missense changes from nine pathogenicity prediction algorithms. RESULTS: The p.Arg312Trp variant failed to correct mitomycin and olaparib hypersensitivity and to complement abnormal RAD51C foci formation according to functional assays, which altogether with LOH and segregation data demonstrated deleteriousness. Prioritisation criteria were based on the number of predictors providing a deleterious output, with a minimum of 5 to qualify for testing and a PredictProtein score greater than 33 to assign high-priority indication. CONCLUSIONS: Our study points to a non-negligible number of RAD51C missense variants likely to impair protein function, provides a guideline to prioritise and encourage their selection for functional analysis and anticipates that reference laboratories should have available resources to conduct such assays.


Assuntos
Neoplasias da Mama/genética , Carcinoma/genética , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Neoplasias Ovarianas/genética , Neoplasias Gástricas/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Estudos de Casos e Controles , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Instabilidade Cromossômica , Análise Mutacional de DNA , Exoma , Feminino , Predisposição Genética para Doença , Genótipo , Histonas/metabolismo , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mitomicina/farmacologia , Mutação de Sentido Incorreto , Linhagem , Medição de Risco/métodos , Homologia de Sequência
7.
Hum Mol Genet ; 25(24): 5287-5299, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27742776

RESUMO

BRCA1-deficient cells show defects in DNA repair and rely on other members of the DNA repair machinery, which makes them sensitive to PARP inhibitors (PARPi). Although carrying a germline pathogenic variant in BRCA1/2 is the best determinant of response to PARPi, a significant percentage of the patients do not show sensitivity and/or display increased toxicity to the agent. Considering previously suggested mutation-specific BRCA1 haploinsufficiency, we aimed to investigate whether there are any differences in cellular response to PARPi olaparib depending on the BRCA1 mutation type. Lymphoblastoid cell lines derived from carriers of missense pathogenic variants in the BRCA1 BRCT domain (c.5117G > A, p.Gly1706Glu and c.5123C > A, p.Ala1708Glu) showed higher sensitivity to olaparib than cells with truncating variants or wild types (WT). Response to olaparib depended on a basal PARP enzymatic activity, but did not correlate with PARP1 expression. Interestingly, cellular sensitivity to the agent was associated with the level of BRCA1 recruitment into γH2AX foci, being the lowest in cells with missense variants. Since these variants lead to partially stable protein mutants, we propose a model in which the mutant protein acts in a dominant negative manner on the WT BRCA1, impairing the recruitment of BRCA1 into DNA damage sites and, consequently, increasing cellular sensitivity to PARPi. Taken together, our results indicate that carriers of different BRCA1 mutations could benefit from olaparib in a distinct way and show different toxicities to the agent, which could be especially relevant for a potential future use of PARPi as prophylactic agents in BRCA1 mutation carriers.


Assuntos
Proteína BRCA1/genética , Neoplasias Ovarianas/tratamento farmacológico , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Poli(ADP-Ribose) Polimerases/genética , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem
8.
Dis Model Mech ; 9(9): 975-84, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27491072

RESUMO

By whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4a gene, which encodes the proton pump responsible for gastric acidification. This mutation causes an aggressive familial type I gastric neuroendocrine tumor in homozygous individuals. Affected individuals show an early onset of the disease, characterized by gastric hypoacidity, hypergastrinemia, iron-deficiency anemia, gastric intestinal metaplasia and, in one case, an associated gastric adenocarcinoma. Total gastrectomy was performed as the definitive treatment in all affected individuals. We now describe the generation and characterization of a knockin mouse model for the ATP4a(R703C) mutation to better understand the tumorigenesis process. Homozygous mice recapitulated most of the phenotypical alterations that were observed in human individuals, strongly suggesting that this mutation is the primary alteration responsible for disease development. Homozygous mice developed premalignant condition with severe hyperplasia, dysplasia and glandular metaplasia in the stomach. Interestingly, gastric acidification in homozygous mice, induced by treatment with 3% HCl acid in the drinking water, prevented (if treated from birth) or partially reverted (if treated during adulthood) the development of glandular metaplasia and dysplasia in the stomach and partially rescued the abnormal biochemical parameters. We therefore suggest that, in this model, achlorhydria contributes to tumorigenesis to a greater extent than hypergastrinemia. Furthermore, our mouse model represents a unique and novel tool for studying the pathologies associated with disturbances in gastric acid secretion.


Assuntos
Técnicas de Introdução de Genes , ATPase Trocadora de Hidrogênio-Potássio/genética , Mutação/genética , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/terapia , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Anemia/sangue , Anemia/complicações , Anemia/patologia , Animais , Modelos Animais de Doenças , Ácido Gástrico/metabolismo , Gastrinas/sangue , Homozigoto , Humanos , Ácido Clorídrico/farmacologia , Hiperplasia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/prevenção & controle , Fenótipo , Estômago/patologia , Neoplasias Gástricas/sangue , Neoplasias Gástricas/prevenção & controle
9.
Breast Cancer Res Treat ; 152(2): 271-82, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26071757

RESUMO

BRCA1 germline mutations increase the lifetime risk of developing breast and ovarian cancers. However, taking into account the differences in disease manifestation among mutation carriers, it is probable that different BRCA1 mutations have distinct haploinsufficiency effects and lead to the formation of different phenotypes. Using lymphoblastoid cell lines derived from heterozygous BRCA1 mutation carriers and non-carriers, we investigated the haploinsufficiency effects of various mutation types using qPCR, immunofluorescence, and microarray technology. Lymphoblastoid cell lines carrying a truncating mutation showed significantly lower BRCA1 mRNA and protein levels and higher levels of gamma-H2AX than control cells or those harboring a missense mutation, indicating greater spontaneous DNA damage. Cells carrying either BRCA1 mutation type showed impaired RAD51 foci formation, suggesting defective repair in mutated cells. Moreover, compared to controls, cell lines carrying missense mutations displayed a more distinct expression profile than cells with truncating mutations, which is consistent with different mutations giving rise to distinct phenotypes. Alterations in the immune response pathway in cells harboring missense mutations point to possible mechanisms of breast cancer initiation in carriers of these mutations. Our findings offer insight into how various heterozygous mutations in BRCA1 could lead to impairment of BRCA1 function and provide strong evidence of haploinsufficiency in BRCA1 mutation carriers.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Reparo do DNA , Heterozigoto , Mutação , Alelos , Proteína BRCA1/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Análise por Conglomerados , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Haploinsuficiência , Histonas/metabolismo , Humanos , Rad51 Recombinase/metabolismo , Transcriptoma
10.
Fam Cancer ; 14(4): 505-13, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26026974

RESUMO

Male breast cancer (MBC) is a rare disease that represents <1% of all breast cancers (BCs). We analyze the results of a multicenter study performed in Spanish familial MBC including family history of hereditary breast and ovarian cancer syndrome (HBOCS) and clinicopathological features. We also study the relationship between BRCA1/BRCA2 mutational status in male relatives affected with cancer (MAC) and, family history and tumor types. The study included 312 men index cases with family history of HBOCS and 61 MAC BRCA1/2 mutation-carriers. Family history, histological grade (HG), clinicopathological and immunohistochemistry data were collected. BRCA1/2 mutation analyses were performed by direct sequencing or screening methods and the large rearrangements by multiplex ligation dependent probe amplification. We found 49 mutation-carriers (15.7%), 95.9% with BRCA2 mutations. BRCA2 mutation-carriers were associated with families with at least one MBC and one BC in female (type II; p = 0.05). Strong association were found between the presence of pathogenic mutations in MBCs and the advanced HG (p = 0.003). c.658_659delTG, c.2808_2811delACAA, c.6275_6276delTT and c.9026_9030delATCAT were the most prevalent mutations. In 61 MAC we found 20 mutations in BRCA1 and 41 in BRCA2. For MAC we show that mutational status was differentially associated with family history (p = 0.018) and tumor type, being BRCA2 mutations linked with BC and prostatic cancer (p = 0.018). MBC caused by BRCA1/2 mutations define two types of MBCs. The most frequent caused by BRCA2 mutation linked to type II families and the rarest one attributed to BRCA1 mutation. Tumor associated with MAC suggest that only BRCA2 mutations have to do with a specific type of cancer (BC and prostatic cancer); but the linkage to tumors is questionable for BRCA1 mutations .


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Feminino , Seguimentos , Testes Genéticos/métodos , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Prognóstico , Espanha/epidemiologia , Síndrome , Adulto Jovem
11.
Int J Cancer ; 134(9): 2088-97, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24130102

RESUMO

RAD51D mutations have been recently identified in breast (BC) and ovarian cancer (OC) families. Although an etiological role in OC appears to be present, the association of RAD51D mutations and BC risk is more unclear. We aimed to determine the prevalence of germline RAD51D mutations in Spanish BC/OC families negative for BRCA1/BRCA2 mutations. We analyzed 842 index patients: 491 from BC/OC families, 171 BC families, 51 OC families and 129 patients without family history but with early-onset BC or OC or metachronous BC and OC. Mutation detection was performed with high-resolution melting, denaturing high-performance liquid chromatography or Sanger sequencing. Three mutations were found in four families with BC and OC cases (0.82%). Two were novel: c.1A>T (p.Met1?) and c.667+2_667+23del, leading to the exon 7 skipping and one previously described: c.674C>T (p.Arg232*). All were present in BC/OC families with only one OC. The c.667+2_667+23del cosegregated in the family with one early-onset BC and two bilateral BC cases. We also identified the c.629C>T (p.Ala210Val) variant, which was predicted in silico to be potentially pathogenic. About 1% of the BC and OC Spanish families negative for BRCA1/BRCA2 are carriers of RAD51D mutations. The presence of several BC mutation carriers, albeit in the context of familial OC, suggests an increased risk for BC, which should be taken into account in the follow-up and early detection measures. RAD51D testing should be considered in clinical setting for families with BC and OC, irrespective of the number of OC cases in the family.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Neoplasias Ovarianas/genética , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA , Feminino , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Espanha
12.
Hum Mutat ; 34(12): 1615-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24027083

RESUMO

Recently, it has been reported that biallelic mutations in the ERCC4 (FANCQ) gene cause Fanconi anemia (FA) subtype FA-Q. To investigate the possible role of ERCC4 in breast and ovarian cancer susceptibility, as occurs with other FA genes, we screened the 11 coding exons and exon-intron boundaries of ERCC4 in 1573 index cases from high-risk Spanish familial breast and ovarian cancer pedigrees that had been tested negative for BRCA1 and BRCA2 mutations and 854 controls. The frequency of ERCC4 mutation carriers does not differ between cases and controls, suggesting that ERCC4 is not a cancer susceptibility gene. Interestingly, the prevalence of ERCC4 mutation carriers (one in 288) is similar to that reported for FANCA, whereas there are approximately 100-fold more FA-A than FA-Q patients, indicating that most biallelic combinations of ERCC4 mutations are embryo lethal. Finally, we identified additional bone-fide FA ERCC4 mutations specifically disrupting interstrand cross-link repair.


Assuntos
Alelos , Neoplasias da Mama/congênito , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Variação Genética , Neoplasias Ovarianas/genética , Substituição de Aminoácidos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Proteínas de Ligação a DNA/metabolismo , Éxons , Feminino , Síndrome Hereditária de Câncer de Mama e Ovário , Heterozigoto , Humanos , Mutação , Neoplasias Ovarianas/metabolismo , Fenótipo , Espanha
13.
Breast Cancer Res Treat ; 141(2): 231-42, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24036693

RESUMO

Telomere shortening is a common event involved in malignant transformation. Critically short telomeres may trigger chromosomal aberrations and produce genomic instability leading to cancer development. Therefore, telomere shortening is a frequent molecular alteration in early stages of many epithelial tumors and in breast cancer correlates with stage and prognosis. A better understanding of the involvement of short telomeres in tumors may have a significant impact on patient management and the design of more specific treatments. To understand the role of telomere length (TL) in breast cancer etiology we measured the length of individual telomere signals in single cells by using quantitative telomere in situ hybridization in paraffin-embedded tissue from hereditary and sporadic breast cancers. A total of 104 tumor tissue samples from 75 familial breast tumors (BRCA1, n = 14; BRCA2, n = 13; non-BRCA1/2, n = 48) and 29 sporadic tumors were analyzed. Assessment of telomere signal intensity allowed estimation of the mean TL and related variables, such as percentage of critically short telomeres and percentage of cells with short telomeres. These data were correlated with the immunohistochemical expression of molecular breast cancer markers. Hereditary BRCA1, BRCA2, and non-BRCA1/2 tumors were characterized by shorter TL comparing to sporadic tumors. Considering all tumors, tumor grade was a strong risk factor determining the proportion of short telomeres or short telomere cells. Moreover, some histopathological features appeared to be differentially associated to hereditary or sporadic subgroups. Short telomeres correlated with ER-negative tumors in sporadic cases but not in familial cases, whereas a high level of apoptosis was associated with shorter telomeres in hereditary BRCA1 and BRCA2 tumors. In addition, TL helped to define a subset of non-BRCA1/2 tumors with short telomeres associated with increased expression of antiapoptotic proteins. These findings highlight the potential interest of TL measurements as markers of aggressiveness in breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Encurtamento do Telômero , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Gradação de Tumores
14.
Carcinogenesis ; 34(11): 2505-11, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23929434

RESUMO

BRCA2-c.2808_2811del (3036delACAA) is one of the most reported germ line mutations in non-Ashkenazi breast cancer patients. We investigated its genetic origin in 51 Spanish carrier families that were genotyped with 11 13q polymorphic markers. Three independent associated haplotypes were clearly distinguished accounting for 23 [west Castilla y León (WCL)], 20 [east Castilla y León (ECL)] and 6 (South of Spain) families. Mutation age was estimated with the Disequilibrium Mapping using Likelihood Estimation software in a range of 45-68 and 45-71 generations for WCL and ECL haplotypes, respectively. The most prevalent variants, c.2808_2811del and c.2803G > A, were located in a double-hairpin loop structure (c.2794-c.2825) predicted by Quikfold that was proposed as a mutational hotspot. To check this hypothesis, random mutagenesis was performed over a 923 bp fragment of BRCA2, and 86 DNA variants were characterized. Interestingly, three mutations reported in the mutation databases (c.2680G > A, c.2944del and c.2957dup) were replicated and 20 affected the same position with different nucleotide changes. Moreover, five variants were placed in the same hairpin loop of c.2808_2811del, and one affected the same position (c.2808A > G). In conclusion, our results support that at least three different mutational events occurred to generate c.2808_2811del. Other highly prevalent DNA variants, such as BRCA1-c.68_69delAG, BRCA2-c.5946delT and c.8537delAG, are concentrated in hairpin loops, suggesting that these structures may represent mutational hotspots.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Haplótipos/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Pareamento de Bases , Sequência de Bases , Família , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutagênese , Polimorfismo Genético , Prognóstico , Espanha
15.
Breast Cancer Res Treat ; 134(3): 1337-43, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22752289

RESUMO

A majority of the familial breast cancer cases are not explained by mutations in the best-known high susceptibility genes BRCA1 and BRCA2. Since there is a link between DNA repair and telomere maintenance mechanisms, we have investigated for the first time the role of telomere genes in breast cancer predisposition. By a combination of DHPLC and direct sequencing, we screened for sequence variation in 14 telomere-related genes which included telomerase and shelterin complexes in index cases from 50 BRCA1/2-negative families previously characterized to have very short telomere length in peripheral blood leukocytes. Clear pathogenic changes were not detected in any of the genes analyzed. Most of the changes were non-coding variants and only nine corresponded to coding variants located in TPP1, TINF2, NHP2, TNKS, and RAD54B genes; although only two corresponded to coding missense changes leading to aminoacid changes in genes NHP2 and RAD54B. However, functional prediction analysis and control population studies of both variants ruled out its possible pathogenic role. Our results discard a major contribution of telomere-specific genes in hereditary breast cancer.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Mutação , Encurtamento do Telômero , Telômero/genética , Adulto , Idoso , Análise Mutacional de DNA , Família , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética
16.
Carcinogenesis ; 30(11): 1898-902, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19737859

RESUMO

Fanconi Anemia (FA) is a rare recessive syndrome characterized by cellular hypersensitivity to DNA-cross-linking agents. To date, 13 FA complementation groups have been described and all 13 genes associated to each of these groups have been currently identified. Three of the known FA genes are also high-risk (FANCD1/BRCA2) or moderate-risk (FANCN/PALB2 and FANCJ/BRIP1) breast cancer susceptibility genes, which makes all members of the FA pathway particularly attractive breast cancer candidate genes. Most FA genes have been screened for mutations in breast cancer families negative for BRCA1/2 mutations but the role of FANCL, FANCM and the recently identified FANCI has not been evaluated to date. This fact and novel data sustaining greater functional relevance of the three genes within the FA pathway prompted us to scrutinize all coding sequences and splicing sites of FANCI, FANCL and FANCM in 95 BRCA1/2-negative index cases from Spanish high-risk breast cancer families. We identified 68 sequence variants of which 24 were coding and 44 non-coding. Six exonic and 26 non-coding variants had not been described previously. None of the coding changes caused clearly pathogenic changes and computational analysis of all non-described intronic variants did not revealed major impact in splicing. With the present study, all known FA genes have been evaluated within the context of breast cancer high-risk predisposition. Our results rule out a major role of FANCI, FANCL and FANCM in familial breast cancer susceptibility, suggesting that among the 13 known FA genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , DNA Helicases/genética , Análise Mutacional de DNA , Éxons , Anemia de Fanconi/genética , Proteína do Grupo de Complementação L da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Feminino , Humanos , Íntrons , Mutação
17.
Breast Cancer Res Treat ; 113(3): 545-51, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18302019

RESUMO

Recent reports have shown that mutations in the FANCJ/BRIP1 and FANCN/PALB2 Fanconi Anemia (FA) genes confer a moderate breast cancer risk. Discussion has been raised on the phenotypic characteristics of the PALB2-associated families and tumors. The role of FANCB in breast cancer susceptibility has not been tested to date. Likewise PALB2 mutation frequency has not been studied in Spanish population. We analyzed the complete coding sequence and splicing sites of FANCB and PALB2 in 95 index cases of BRCA1/2-negative Spanish breast cancer families. We also performed an exhaustive screening of three previously described rare but recurrent PALB2 mutations in 725 additional probands. Pathogenic changes were not detected in FANCB. We found a novel PALB2 truncating mutation c.1056_1057delGA (p.K353IfsX7) in one of the 95 screened patients, accounting for a mutation frequency of 1% in our series. Further comprehensive screening of the novel mutation and of previously reported rare but recurrent PALB2 mutations did not reveal any carrier patient. We report the first example of LOH occurring in a PALB2-associated tumor. Our results rule out a major contribution of FANCB to hereditary breast cancer. Our data are consistent with the notion of individually rare PALB2 mutations, lack of mutational hot-spots in the gene and existence of between-population disease-allele heterogeneity. We show evidence that PALB2 loss of function might also conform to the inactivation model of a classic tumor-suppressor gene and present data that adds to the clinically relevant discussion about the existence of a PALB2-breast cancer phenotype.


Assuntos
Neoplasias da Mama/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Idoso , Neoplasias da Mama Masculina/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Testes Genéticos , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/genética , Linhagem , Espanha
18.
Breast Cancer Res Treat ; 113(2): 371-6, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18270812

RESUMO

RAP80 and CCDC98 have arisen as new candidate breast cancer susceptibility genes, since they encode for two very recently identified BRCA1 interacting proteins. In this study we have performed the first mutational analysis of both genes in 168 multiple-case breast/ovarian cancer families, negative for mutations in BRCA1 or BRCA2. We have not found truncating mutations in any of the genes and only two missense variants, p.Tyr564His in RAP80, and p.Met299Ile in CCDC98 were found that could be suspected to have a pathogenic effect, although further analyses suggested that they were probably non deleterious. Our analysis suggests that RAP80 and CCDC98 do not play an important role as high penetrance breast cancer susceptibility genes.


Assuntos
Neoplasias da Mama/genética , Proteínas de Transporte/fisiologia , Genes Neoplásicos , Proteínas de Neoplasias/fisiologia , Síndromes Neoplásicas Hereditárias/genética , Proteínas Nucleares/fisiologia , Adulto , Idoso , Proteína BRCA1/fisiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama Masculina/genética , Proteínas de Transporte/genética , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Proteínas de Ligação a DNA , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Chaperonas de Histonas , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Síndromes Neoplásicas Hereditárias/epidemiologia , Proteínas Nucleares/genética , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Linhagem , Penetrância , Polimorfismo de Nucleotídeo Único , Adulto Jovem
19.
Ann Hematol ; 85(3): 185-7, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16341862

RESUMO

Several approved therapies for multicentric Castleman disease (MCD) cannot be uniformly applied due to intolerable side effects. There is also a high percentage of recurrence of this disease despite treatment. Rituximab may be effective in controlling MCD in a subset of patients. This paper includes a brief case report and an extensive review of previously published cases. We observed an aggravation of concomitant cutaneous Kaposi sarcoma, and hypothesize that rituximab could have exacerbated it.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Terapia de Salvação , Sarcoma de Kaposi/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Antineoplásicos/efeitos adversos , Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/patologia , Infecções por HIV/complicações , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Rituximab , Terapia de Salvação/métodos , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/patologia
20.
Clin Cancer Res ; 11(24 Pt 1): 8577-84, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16361540

RESUMO

PURPOSE AND METHODS: High-level DNA amplifications are recurrently found in breast cancer, and some of them are associated with poor patient prognosis. To determine their frequency and co-occurrence in familial breast cancer, we have analyzed 80 tumors previously characterized for BRCA1 and BRCA2 germ-line mutations (26 BRCA1, 18 BRCA2, and 36 non-BRCA1/2) using high-resolution comparative genomic hybridization. RESULTS: Twenty-one regions were identified as recurrently amplified, such as 8q21-23 (26.25%), 17q22-25 (13.75%), 13q21-31 (12.50%), and 8q24 (11.25%), many of which were altered in each familial breast cancer group. These amplifications defined an amplifier phenotype that is correlated with a higher genomic instability. Based on these amplifications, two different genomic pathways have been established in association with 8q21-23 and/or 17q22-25 and with 13q21-31 amplification. These pathways are associated with specific genomic regions of amplification, carry specific immunohistochemical characteristics coincident with high and low aggressiveness, and have a trend to be associated with BRCA1 and BRCA2/X, respectively. CONCLUSION: In summary, our data suggest the existence of two different patterns of evolution, probably common to familial and sporadic breast tumors.


Assuntos
Neoplasias da Mama/genética , Evolução Molecular , Amplificação de Genes , Genes BRCA1 , Genes BRCA2 , Cromossomos Humanos , Feminino , Genoma Humano , Mutação em Linhagem Germinativa , Humanos
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