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1.
Clin Gastroenterol Hepatol ; 18(2): 368-374.e1, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31220642

RESUMO

BACKGROUND & AIMS: Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. METHODS: We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. RESULTS: We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. CONCLUSIONS: Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC.

2.
J Am Heart Assoc ; 8(18): e012875, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31510873

RESUMO

Background Mutations in the POT1 gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly understood. Methods and Results Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the POT1 gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the POT1 gene has been studied. Patients with CAS and nonfunctional POT1 did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway (KDR gene). The same observation was made in POT1 mutation carriers with tumors different from CAS and also in CAS patients without mutations in the POT1 gene but with mutations in other genes involved in DNA damage signaling. Conclusions Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations.

3.
Eur J Cancer Care (Engl) ; 28(3): e13005, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30761638

RESUMO

INTRODUCTION: The objective was to analyze the usefulness of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) EF subscale to detect emotional problems in patients with breast (BC) and colorectal cancer (CRC). METHODS: A prospective, observational, cross-sectional study was conducted. Participants completed the Brief Symptom Inventory (BSI) and EORTC-QLQ-C30. The following psychometric properties were calculated: accuracy, sensitivity, positive predictive value, specificity and negative predictive value. RESULTS: The sample analyzed included 445 patients: 202 with BC and 243 with CRC. In total, 129 BC patients (64%) and 104 CRC patients (43%) suffered psychological distress according to the BSI. The accuracy of EORTC-QLQ-C30 EF in detecting psychological distress was 77% and 82% in BC and CRC respectively. Specificity rates for BC and CRC were 81% and 82%, and sensitivity was 75% and 82% respectively. Positive predictive value was 87% and 77%, and negative predictive value was 65% and 86% in BC and CRC respectively. The mean AUC for BC was 0.83 and 0.88 for CRC. CONCLUSIONS: The EORTC-QLQ-C30 EF is useful for rapid screening. The systematic application of this scale would allow patients with cancer and emotional problems to be easily identified in clinical practice.


Assuntos
Neoplasias da Mama/psicologia , Neoplasias Colorretais/psicologia , Estresse Psicológico/diagnóstico , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Neoplasias Colorretais/tratamento farmacológico , Emoções , Feminino , Humanos , Masculino , Programas de Rastreamento , Oncologia , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Estresse Psicológico/psicologia , Procedimentos Cirúrgicos Operatórios
4.
J Pain Symptom Manage ; 57(4): 828-834, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30639730

RESUMO

OBJECTIVES: Decisional regret is an indicator of satisfaction with the treatment decision and can help to identify those patients who need more support and evaluate the efficacy of decision support interventions. The objectives of this study are, 1) to evaluate the psychometric properties of the Decision Regret Scale and 2) to analyze the moderating effect of psychological distress on functional status and regret in patients with cancer following adjuvancy. METHODS: A prospective, multicenter cohort of 403 patients who completed the Decision Regret Scale (DRS), Health-Related Quality of Life (EORTC QLQ-C30), and Brief Symptom Inventory (BSI). The evaluation was conducted six months after receiving adjuvant treatment in patients with resected cancer. RESULTS: After treatment, most participants (51.9%) experienced no decision regret; 33.7% felt mild regret, and 14.4% exhibited high levels of regret. The Spanish version of the DRS demonstrated satisfactory properties: it had a strong, clear unidimensional factorial structure with substantial loadings. Decisional regret was related with lower scores on functional, symptom, and quality of life scales, and higher levels of psychological distress (all P = 0.001). Psychological distress was found to have a moderating effect on the relationship between functional state and decision regret. CONCLUSIONS: The Spanish version of the DRS is a reliable, valid tool to evaluate regret and post-decisional quality in clinical practice and further highlights the potential clinical implications of psychological distress for the relation between physical status and regret.

5.
Mayo Clin Proc ; 93(3): 307-320, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29502561

RESUMO

OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.


Assuntos
Carcinoma Epitelial do Ovário/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Neoplasias Ovarianas/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário/mortalidade , Feminino , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Análise de Sobrevida , Análise Serial de Tecidos/métodos
6.
PLoS One ; 12(10): e0184181, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28985233

RESUMO

PURPOSE: To determine the frequency of breast cancer (BC) patients with hereditary risk features in a wide retrospective cohort of patients in Spain. METHODS: a retrospective analysis was conducted from 10,638 BC patients diagnosed between 1998 and 2001 in the GEICAM registry "El Álamo III", dividing them into four groups according to modified ESMO and SEOM hereditary cancer risk criteria: Sporadic breast cancer group (R0); Individual risk group (IR); Familial risk group (FR); Individual and familial risk group (IFR) with both individual and familial risk criteria. RESULTS: 7,641 patients were evaluable. Of them, 2,252 patients (29.5%) had at least one hereditary risk criteria, being subclassified in: FR 1.105 (14.5%), IR 970 (12.7%), IFR 177 (2.3%). There was a higher frequency of newly diagnosed metastatic patients in the IR group (5.1% vs 3.2%, p = 0.02). In contrast, in RO were lower proportion of big tumors (> T2) (43.8% vs 47.4%, p = 0.023), nodal involvement (43.4% vs 48.1%, p = 0.004) and lower histological grades (20.9% G3 for the R0 vs 29.8%) when compared to patients with any risk criteria. CONCLUSIONS: Almost three out of ten BC patients have at least one hereditary risk cancer feature that would warrant further genetic counseling. Patients with hereditary cancer risk seems to be diagnosed with worse prognosis factors.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Neoplasias da Mama/epidemiologia , Feminino , Aconselhamento Genético , Humanos , Pessoa de Meia-Idade , Prevalência , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Espanha/epidemiologia
7.
Eur J Hum Genet ; 25(11): 1278-1281, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28853721

RESUMO

The POT1 protein binds and protects telomeres. Germline variants in the POT1 gene have recently been shown to be associated with risk of developing tumors in different tissues such as familial chronic lymphocytic leukemia, colorectal, glioma and melanoma tumors. Recently, we uncovered a variant in the POT1 gene (p.R117C) as causative of familial cardiac angiosarcomas (CAS) in Li-Fraumeni-like (LFL) syndrome families. Our in silico studies predicted that this protein had lost the ability to interact with TPP1 and single-stranded DNA. In vitro studies corroborated this prediction and showed that this lack of function leads to abnormally long telomeres. To better understand the POT1 gene and its role with tumorigenesis, we extended the study to LFL (with and without members affected with angiosarcomas (AS)) and sporadic AS and cardiac sarcomas. We found POT1 variants in the 20% of the families with members affected with AS and 10% of sporadic AS and sarcomas. In silico studies predicted that these new variants were damaging in the same manner as previously described for the POT1 p.R117C variants. The wide spectrum of variants in the POT1 gene leading to tumorigenesis in different tissues demonstrates its general importance. Study of the POT1 gene should be considered as routine diagnostic in these cancers.


Assuntos
Neoplasias Cardíacas/genética , Hemangiossarcoma/genética , Síndrome de Li-Fraumeni/genética , Polimorfismo de Nucleotídeo Único , Proteínas de Ligação a Telômeros/genética , Frequência do Gene , Humanos
8.
Radiother Oncol ; 121(3): 431-439, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27443449

RESUMO

PURPOSE: Several small studies have indicated that the ATM rs1801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. MATERIALS AND METHODS: The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. RESULTS: For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. CONCLUSION: This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/radioterapia , Neoplasias da Próstata/radioterapia , Lesões por Radiação/genética , Alelos , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Lesões por Radiação/etiologia , Tolerância a Radiação/genética , Radioterapia/efeitos adversos , Fatores de Risco
9.
J Gynecol Oncol ; 27(1): e7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26463438

RESUMO

OBJECTIVE: We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. METHODS: In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients' survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. RESULTS: Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. CONCLUSION: Low levels of GTF2H5 are associated with enhanced prognosis in high-grade serous ovarian cancer patients and may contribute to cisplatin sensitization.


Assuntos
Cistadenocarcinoma Seroso/genética , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Epitelial do Ovário , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Fatores de Transcrição/biossíntese , Células Tumorais Cultivadas
10.
Breast Cancer Res ; 17: 93, 2015 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-26163143

RESUMO

INTRODUCTION: Mammographic density (MD) is one of the strongest determinants of sporadic breast cancer (BC). In this study, we compared MD in BRCA1/2 mutation carriers and non-carriers from BRCA1/2 mutation-positive families and investigated the association between MD and BC among BRCA1/2 mutation carriers per type of mutation and tumor subtype. METHODS: The study was carried out in 1039 female members of BRCA1 and BRCA2 mutation-positive families followed at 16 Spanish Genetic Counseling Units. Participants' density was scored retrospectively from available mammograms by a single blinded radiologist using a 5-category scale (<10 %, 10-25 %, 25-50 %, 50-75 %, >75 %). In BC cases, we selected mammograms taken prior to diagnosis or from the contralateral breast, whereas, in non-cases, the last screening mammogram was evaluated. MD distribution in carriers and non-carriers was compared using ordinal logistic models, and the association between MD and BC in BRCA1/2 mutation carriers was studied using logistic regression. Huber-White robust estimators of variance were used to take into account correlations between family members. A similar multinomial model was used to explore this association by BC subtype. RESULTS: We identified and scored mammograms from 341 BRCA1, 350 BRCA2 mutation carriers and 229 non-carriers. Compared to non-carriers, MD was significantly lower among BRCA2 mutation carriers (odds ratio (OR) =0.71; P-value=0.04), but not among BRCA1 carriers (OR=0.84; P-value=0.33). MD was associated with subsequent development BC (OR per category of MD=1.45; 95 % confidence interval=1.18-1.78, P-value<0.001), with no significant differences between BRCA1 and BRCA2 mutation carriers (P-value=0.48). Finally, no statistically significant differences were observed in the association of MD with specific BC subtypes. CONCLUSIONS: Our study, the largest to date on this issue, confirms that MD is an independent risk factor for all BC subtypes in either BRCA1 and BRCA2 mutation carriers, and should be considered a phenotype risk marker in this context.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Família , Glândulas Mamárias Humanas/anormalidades , Adulto , Densidade da Mama , Neoplasias da Mama/epidemiologia , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Síndrome Hereditária de Câncer de Mama e Ovário/patologia , Heterozigoto , Humanos , Mamografia , Pessoa de Meia-Idade , Mutação , Razão de Chances , Fatores de Risco
11.
PLoS One ; 10(4): e0120020, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25830658

RESUMO

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.


Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença/genética , Mutação , Aurora Quinase A/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Receptor alfa de Estrogênio/metabolismo , Evolução Molecular , Proteínas da Matriz Extracelular/genética , Feminino , Loci Gênicos/genética , Humanos , Receptores de Hialuronatos/genética , Funções Verossimilhança , Glândulas Mamárias Humanas/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Tubulina (Proteína)/genética
12.
Apoptosis ; 20(3): 371-82, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25398538

RESUMO

We tested apoptosis levels in in vitro irradiated T-lymphocytes from breast cancer (BC) patients with radiotherapy-induced late effects. Previous results reported in the literature were revised. We also examined the effect of TP53 Arg72Pro polymorphism on irradiation-induced apoptosis (IA). Twenty BC patients, ten with fibrosis and/or telangiectasias and ten matched controls with no late reactions, were selected from those receiving radiotherapy between 1993 and 2007. All patients were followed-up at least 6 years after radiotherapy. Using the combination of both CD3 and CD8 antibodies the in vitro IA was measured in CD3, CD8 and CD4 T-lymphocytes, and CD8 natural killer lymphocytes (CD8 NK) by flow cytometry. The TP53 Arg72Pro genotype was determined by sequencing. Patients with late radiotherapy toxicity showed less IA for all T-lymphocytes except for the CD8 NK. CD8 NK showed the highest spontaneous apoptosis and the lowest IA. IA in patients with toxicity appears to be lower than the control patients only in TP53 Arg/Arg patients (P = 0.077). This difference was not present in patients carrying at least one Pro allele (P = 0.8266). Our data indicate that late side effects induced by radiotherapy of BC are associated to low levels of IA. CD8 NK cells have a different response to in vitro irradiation compared to CD8 T-lymphocytes. It would be advisable to distinguish the CD8 NK lymphocytes from the pool of CD8+ lymphocytes in IA assays using CD8+ cells. Our data suggest that the 72Pro TP53 allele may influence the IA of patients with radiotherapy toxicity.


Assuntos
Neoplasias da Mama/radioterapia , Linfócitos T CD4-Positivos/efeitos da radiação , Linfócitos T CD8-Positivos/efeitos da radiação , Raios gama/efeitos adversos , Células Matadoras Naturais/efeitos da radiação , Subpopulações de Linfócitos/efeitos da radiação , Polimorfismo Genético , Proteína Supressora de Tumor p53/genética , Adulto , Apoptose/efeitos da radiação , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Células Cultivadas , Feminino , Fibrose , Expressão Gênica , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/patologia , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Tolerância a Radiação , Telangiectasia/genética , Telangiectasia/metabolismo , Telangiectasia/patologia , Resultado do Tratamento , Proteína Supressora de Tumor p53/metabolismo
13.
Neoplasia ; 16(10): 861-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25379022

RESUMO

Human epidermal growth factor receptor 2 (HER2) and topoisomerase II alpha (TOP2A) genes have been proposed as predictive biomarkers of sensitivity to anthracycline chemotherapy. Recently, chromosome 17 centromere enumeration probe (CEP17) duplication has also been associated with increased responsiveness to anthracyclines. However, reports are conflicting and none of these tumor markers can yet be considered a clinically reliable predictor of response to anthracyclines. We studied the association of TOP2A gene alterations, HER2 gene amplification, and CEP17 duplication with response to anthracycline-based neoadjuvant chemotherapy in 140 patients with operable or locally advanced breast cancer. HER2 was tested by fluorescence in situ hybridization and TOP2A and CEP17 by chromogenic in situ hybridization. Thirteen patients (9.3%) achieved pathologic complete response (pCR). HER2 amplification was present in 24 (17.5%) of the tumors. TOP2A amplification occurred in seven tumors (5.1%). CEP17 duplication was detected in 13 patients (9.5%). CEP17 duplication correlated with a higher rate of pCR [odds ratio (OR) 6.55, 95% confidence interval (95% CI) 1.25-34.29, P = .026], and analysis of TOP2A amplification showed a trend bordering on statistical significance (OR 6.97, 95% CI 0.96-50.12, P = .054). TOP2A amplification and CEP17 duplication combined were strongly associated with pCR (OR 6.71, 95% CI 1.66-27.01, P = .007). HER2 amplification did not correlate with pCR. Our results suggest that CEP17 duplication predicts pCR to primary anthracycline-based chemotherapy. CEP17 duplication, TOP2A amplifications, and HER2 amplifications were not associated with prognosis.


Assuntos
Antraciclinas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Centrômero/efeitos dos fármacos , Cromossomos Humanos Par 17 , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/farmacologia , Antígenos de Neoplasias/genética , Neoplasias da Mama/mortalidade , Duplicação Cromossômica , DNA Topoisomerases Tipo II/genética , Proteínas de Ligação a DNA/genética , Feminino , Amplificação de Genes , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Terapia Neoadjuvante , Proteínas de Ligação a Poli-ADP-Ribose , Prognóstico , Receptor ErbB-2/genética , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
14.
Eur J Cancer ; 50(13): 2241-50, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24953332

RESUMO

BACKGROUND AND AIMS: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. METHODS: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. RESULTS: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001). CONCLUSIONS: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Mutação em Linhagem Germinativa , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
15.
PLoS Genet ; 10(4): e1004256, 2014 04.
Artigo em Inglês | MEDLINE | ID: mdl-24698998

RESUMO

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , DNA Glicosilases/genética , Reparo do DNA/genética , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Risco
16.
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
17.
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
18.
PLoS One ; 8(9): e74079, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24058517

RESUMO

Circulating tumor cells (CTCs) are becoming a scientifically recognized indicator of primary tumors and/or metastasis. These cells can now be accurately detected and characterized as the result of technological advances. We analyzed the presence of CTCs in the peripheral blood of patients with metastatic breast cancer by real-time reverse-transcription PCR (RT-qPCR) using a panel of selected genes. The analysis of a single marker, without an EpCAM based enrichment approach, allowed the positive identification of 35% of the metastatic breast cancer patients. The analysis of five genes (SCGB2, TFF1, TFF3, Muc1, KRT20) performed in all the samples increased the detection to 61%. We describe a sensitive, reproducible and easy to implement approach to characterize CTC in patients with metastasic breast cancer.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Proteínas de Neoplasias/sangue , Células Neoplásicas Circulantes/metabolismo , RNA Mensageiro/sangue , RNA Neoplásico/sangue , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Expressão Gênica , Humanos , Metástase Neoplásica , Proteínas de Neoplasias/genética , Células Neoplásicas Circulantes/patologia , RNA Mensageiro/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade
19.
J Cell Biol ; 200(2): 187-202, 2013 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-23337117

RESUMO

Loss of 53BP1 rescues BRCA1 deficiency and is associated with BRCA1-deficient and triple-negative breast cancers (TNBC) and with resistance to genotoxic drugs. The mechanisms responsible for decreased 53BP1 transcript and protein levels in tumors remain unknown. Here, we demonstrate that BRCA1 loss activates cathepsin L (CTSL)-mediated degradation of 53BP1. Activation of this pathway rescued homologous recombination repair and allowed BRCA1-deficient cells to bypass growth arrest. Importantly, depletion or inhibition of CTSL with vitamin D or specific inhibitors stabilized 53BP1 and increased genomic instability in response to radiation and poly(adenosine diphosphate-ribose) polymerase inhibitors, compromising proliferation. Analysis of human breast tumors identified nuclear CTSL as a positive biomarker for TNBC, which correlated inversely with 53BP1. Importantly, nuclear levels of CTSL, vitamin D receptor, and 53BP1 emerged as a novel triple biomarker signature for stratification of patients with BRCA1-mutated tumors and TNBC, with potential predictive value for drug response. We identify here a novel pathway with prospective relevance for diagnosis and customization of breast cancer therapy.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Catepsina L/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Catepsina L/genética , Linhagem Celular Tumoral , Reparo do DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Mutação em Linhagem Germinativa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteína 1 de Ligação à Proteína Supressora de Tumor p53
20.
Hum Mutat ; 33(11): 1576-88, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22736432

RESUMO

Lynch syndrome is associated with germline mutations in DNA mismatch repair (MMR) genes. Up to 30% of DNA changes found are variants of unknown significance (VUS). Our aim was to assess the pathogenicity of eight MLH1 VUS identified in patients suspected of Lynch syndrome. All of them are novel or not previously characterized. For their classification, we followed a strategy that integrates family history, tumor pathology, and control frequency data with a variety of in silico and in vitro analyses at RNA and protein level, such as MMR assay, MLH1 and PMS2 expression, and subcellular localization. Five MLH1 VUS were classified as pathogenic: c.[248G>T(;)306G>C], c.[780C>G;788A>C], and c.791-7T>A affected mRNA processing, whereas c.218T>C (p.L73P) and c.244A>G [corrected] (p.T82A) impaired MMR activity. Two other VUS were considered likely neutral: the silent c.702G>A variant did not affect mRNA processing or stability, and c.974G>A (p.R325Q) did not influence MMR function. In contrast, variant c.25C>T (p.R9W) could not be classified, as it associated with intermediate levels of MMR activity. Comprehensive functional assessment of MLH1 variants was useful in their classification and became relevant in the diagnosis and genetic counseling of carrier families.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Variação Genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Estudos de Casos e Controles , Biologia Computacional , Reparo de Erro de Pareamento de DNA/genética , Reparo de Erro de Pareamento de DNA/fisiologia , Análise Mutacional de DNA , Feminino , Frequência do Gene , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Anatômicos , Dados de Sequência Molecular , Proteína 1 Homóloga a MutL , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Proteínas Nucleares/química , Linhagem , Multimerização Proteica , Estrutura Terciária de Proteína , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
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