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1.
J Pharm Bioallied Sci ; 12(Suppl 1): S564-S568, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33149522

RESUMO

Introduction: Among all teeth, mandibular canine shows greatest variation in dimensions between the sexes, a phenomenon known as sexual dimorphism. This can be immensely beneficial to the forensic investigator for the purposes of both investigation and identification, as it significantly narrows down the possibilities, as the probable perpetrators and/or victims are concerned. Sex identification is an absolute necessity in cases of suicide, homicide, mass, casualties (both manmade or natural), and a tooth, which shows obvious sexual dimorphism can be a useful means of personal identification, especially where there has been extensive decomposition or destruction of facial soft tissue features. Another facet of forensic investigation is identification of racial origin. So, any odontometric parameter showing significant racial divergence can be used as a means of identification. Aim and Objective: The aim of this study was to determine and compare cervico-incisal heights and mesiodistal widths of both mandibular canines of the Gujarati and non-Gujarati subjects under study. Materials and Methods: The study sample involved 100 participants, divided into four groups, each of the four groups included 25 participants, representing Gujarati males, Gujarati females, non-Gujarati males, and non-Gujarati females, respectively. Results: When we compared the mesiodistal and cervico-incisal dimensions of the mandibular canine, both right and left, Gujarati males were found to possess significantly larger sized teeth in comparison to their female counterparts, and the same results were replicated for non-Gujarati males vis-a-vis their female counterparts. Non-Gujarati males and non-Gujarati females were found to have significantly higher odontometric values in comparison with their Gujarati counterparts. Conclusion: Gujaratis have smaller sized mandibular canine in comparison with non-Gujaratis. However, studies comparing specific groups are required, as non-Gujaratis are a diverse racial group.

2.
J Clin Exp Hepatol ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33052182

RESUMO

Accidental or suicidal poisoning with yellow phosphorus or metal phosphides (YPMP) such as aluminum (AlP) zinc phosphide (Zn3P2) commonly cause acute liver failure (ALF) and cardiotoxicity. These are used as household, agricultural and industrial rodenticides and in production of ammunitions, firecrackers and fertilizers. In absence of a clinically available laboratory test for diagnosis or toxin measurement or an antidote, managing their poisoning is challenging even at a tertiary care center with a dedicated liver intensive care unit (LICU) and liver transplant facility. Patients and methods: Patients with YPMP related ALF were monitored using standardized clinical, hemodynamic, biochemical, metabolic, neurological, electrocardiography (ECG) and SOFA score and managed using uniform intensive care, treatment and transplant protocols in LICU. Socio-demographic characteristics, clinical and biochemical parameters and scores were summarized and compared between 3 groups i.e. spontaneous survivors, transplanted patients and non-survivors. Predictors of spontaneous survival and the need for liver transplant are also evaluated. Results: Nineteen patients with YPMP related ALF were about 32 years old (63.2% females) and presented to us at a median of 3 (0 - 10) days after poisoning. YPMP related cardiotoxicity was rapidly progressive and fatal whereas liver transplant was therapeutic for ALF. Spontaneous survivors had lower dose ingestion (<17.5 grams), absence of cardiotoxicity, < grade 3 HE, lactate < 5.8, SOFA score < 14.5, and increase in SOFA score by < 5.5. Patients with renal failure need for CVVHDF and KCC positivity on account of PT-INR > 6.5 had higher mortality risk. Patients undergoing liver transplant and with spontaneous recovery required longer ICU and hospital stay. At median follow-up of 3.4 (2.6 - 5.5) years, all spontaneous survivors and transplanted patients are well with normal liver function. Conclusions: Early transfer to a specialized center, pre-emptive close monitoring, and intensive care and organ support with ventilation, CVVHDF, plasmapheresis and others may maximize their chances of spontaneous recovery, allow accurate prognostication and a timely liver transplant.

3.
Breast Cancer Res Treat ; 181(2): 423-434, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32279280

RESUMO

BACKGROUND: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). METHODS: We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. RESULTS: The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. CONCLUSIONS: Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making.


Assuntos
Neoplasias da Mama/patologia , Tomada de Decisão Clínica , Segunda Neoplasia Primária/patologia , Medição de Risco/métodos , Adulto , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Agências Internacionais , Mastectomia , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/cirurgia , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Fatores de Risco
4.
J Clin Oncol ; 38(7): 674-685, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841383

RESUMO

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

5.
Breast Cancer Res ; 21(1): 144, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847907

RESUMO

BACKGROUND: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. METHODS: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. RESULTS: In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Área Sob a Curva , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Mutação em Linhagem Germinativa , Humanos , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/prevenção & controle , Países Baixos/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco
6.
Cancer Epidemiol Biomarkers Prev ; 28(4): 822-825, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30642840

RESUMO

BACKGROUND: Genes regulated by breast cancer risk alleles identified through genome-wide association studies (GWAS) may harbor rare coding risk alleles. METHODS: We sequenced the coding regions for 38 genes within 500 kb of 38 lead GWAS SNPs in 13,538 breast cancer cases and 5,518 controls. RESULTS: Truncating variants in these genes were rare, and were not associated with breast cancer risk. Burden testing of rare missense variants highlighted 5 genes with some suggestion of an association with breast cancer, although none met the multiple testing thresholds: MKL1, FTO, NEK10, MDM4, and COX11. Six common alleles in COX11, MAP3K1 (two), and NEK10 (three) were associated at the P < 0.0001 significance level, but these likely reflect linkage disequilibrium with causal regulatory variants. CONCLUSIONS: There was no evidence that rare coding variants in these genes confer substantial breast cancer risks. However, more modest effect sizes could not be ruled out. IMPACT: We tested the hypothesis that rare variants in 38 genes near breast cancer GWAS loci may mediate risk. These variants do not appear to play a major role in breast cancer heritability.


Assuntos
Neoplasias da Mama/genética , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos
7.
Cancer Med ; 7(5): 1978-1987, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29608257

RESUMO

Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg  = 0.23, P = 9.3 × 10-3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 × 10-3 ) and concordance in effect direction (P = 2.0 × 10-3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P ≤ 10-5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 × 10-8 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.


Assuntos
Neoplasias do Endométrio/genética , Endometriose/genética , Predisposição Genética para Doença/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Austrália/epidemiologia , Neoplasias do Endométrio/epidemiologia , Endometriose/epidemiologia , Endométrio/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fator de Transcrição STAT3/metabolismo
9.
J Med Genet ; 54(11): 732-741, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28779002

RESUMO

BACKGROUND: Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. METHODS: Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms. RESULTS: Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect. CONCLUSIONS: Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Proteínas Mutadas de Ataxia Telangiectasia/química , Quinase do Ponto de Checagem 2/química , Proteínas de Ligação a DNA/química , Proteína do Grupo de Complementação N da Anemia de Fanconi/química , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Análise de Sequência de Proteína
10.
Oncotarget ; 8(11): 18381-18398, 2017 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-28179588

RESUMO

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


Assuntos
Antraciclinas/uso terapêutico , Neoplasias da Mama/genética , Locos de Características Quantitativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose/genética , Neoplasias da Mama/patologia , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteínas Ligases SKP Culina F-Box/genética , Análise de Sobrevida , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Adulto Jovem
11.
Genet Med ; 19(5): 599-603, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27711073

RESUMO

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


Assuntos
Neoplasias da Mama/genética , Quinase do Ponto de Checagem 2/genética , Deleção de Sequência , Feminino , Genes Modificadores , Predisposição Genética para Doença , Humanos , Razão de Chances , Penetrância
12.
Breast Cancer Res ; 18(1): 98, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27716369

RESUMO

BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. RESULTS: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. CONCLUSIONS: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Quinase do Ponto de Checagem 2/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Análise por Conglomerados , Códon , Europa (Continente)/epidemiologia , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Heterozigoto , Humanos , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Transcriptoma
13.
J Minim Invasive Gynecol ; 23(7): 1152-1157, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27568225

RESUMO

STUDY OBJECTIVE: To assess the effectiveness of vestibulectomy in treating vulvodynia for patients with inadequate response to vulvar care guidelines and medical management. DESIGN: Retrospective case series (Canadian Task Force classification II-2). PATIENTS: All patients who underwent a vestibulectomy from 2004 to 2013 for vulvodynia. INTERVENTIONS: All patients in this study underwent a vestibulectomy. MEASUREMENTS AND MAIN RESULTS: In this study we analyzed 31 patients' overall reported pain scores and Q-tip test scores before and after vestibulectomy. The efficacy of vestibulectomy on reduction of pain was then analyzed after surgical management. There was no significant difference in pain scores from initial visit compared with the last visit before vestibulectomy after vulvar care guidelines and medical management were initiated (p = .48-.94). However, mean subjective pain scores before and after vestibulectomy decreased by 67% (p < .001). Q-tip testing showed reductions of pain by 63% (p < .001) and 73% (p < .001) at the right and left Bartholin gland areas, respectively. There was approximately a 60% decrease of pain scored around the bilateral periurethral areas (p < .05). CONCLUSIONS: Vestibulectomy is an effective treatment for vulvodynia. For those with intractable pain, vestibulectomy is an appropriate next step after unsuccessful medical treatment. The surgery leads to a significant decrease in patients' pain scores, nearly eliminating it in most cases.


Assuntos
Vestibulite Vulvar/cirurgia , Vulvodinia/cirurgia , Adulto , Idoso , Feminino , Procedimentos Cirúrgicos em Ginecologia , Humanos , Pessoa de Meia-Idade , Missouri , Medição da Dor , Dor Intratável , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
Cancer Epidemiol Biomarkers Prev ; 25(11): 1503-1510, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27550749

RESUMO

BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.


Assuntos
Índice de Massa Corporal , Neoplasias do Endométrio/etiologia , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Obesidade/complicações , Polimorfismo de Nucleotídeo Único , Neoplasias do Endométrio/genética , Feminino , Humanos , Obesidade/genética , Relação Cintura-Quadril
15.
Nat Genet ; 48(6): 667-674, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27135401

RESUMO

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.


Assuntos
Neoplasias do Endométrio/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cromossomos Humanos Par 8 , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas
16.
J Med Genet ; 53(5): 298-309, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26921362

RESUMO

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação , RNA Helicases/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Risco
17.
BMC Cancer ; 15: 978, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26674097

RESUMO

BACKGROUND: Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment. METHODS: We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p<0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed. RESULTS: rs878156 in PARP2 showed a differential effect by chemotherapy (p=0.093) and was replicated in BCAC studies (p=0.009; combined analysis p=0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency=0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR)=0.75, 95% 0.53-1.07) and poorer survival when not treated with chemotherapy (HR=1.42, 95% 1.08-1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR=0.73, 95% CI 0.40-1.32). None of the SNPs showed significant differential effects by radiotherapy. CONCLUSIONS: Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Poli(ADP-Ribose) Polimerases/genética , Idoso , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia
18.
Endocr Relat Cancer ; 22(5): 851-61, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26330482

RESUMO

Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P=1.86×10(-5)), which was stronger for cancers of endometrioid subtype (P=3.76×10(-6)). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.


Assuntos
Neoplasias da Mama/genética , Neoplasias do Endométrio/genética , Receptor alfa de Estrogênio/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Biologia Computacional , Proteínas do Citoesqueleto , Bases de Dados Genéticas , Feminino , Loci Gênicos , Genótipo , Humanos , Metanálise como Assunto , Prognóstico , Regiões Promotoras Genéticas/genética , Fatores de Risco
19.
J Natl Cancer Inst ; 107(11)2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26296642

RESUMO

BACKGROUND: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. METHODS: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control patients, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control patients. RESULTS: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10(-8). CONCLUSIONS: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.


Assuntos
Estatura , Neoplasias da Mama/epidemiologia , Medicina Baseada em Evidências , Feminino , Humanos , Análise da Randomização Mendeliana , Razão de Chances , Estudos Prospectivos , Fatores de Risco
20.
Clin Obstet Gynecol ; 58(3): 536-45, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26125963

RESUMO

Vulvodynia, a chronic pain disorder, affects women throughout the lifespan. Appropriate evaluation and diagnosis is necessary to enable effective management. The etiology is considered multifactorial. Therapies include self-management, nonpharmacologic, pharmacologic, and surgical. Vulvodynia can have a significant impact upon a patient's quality of life. Emotional and psychological support is invaluable. This article serves to give the primary gynecologist and practitioner a basic framework with which to identify, diagnose, and begin treatment for such patients as well as understanding for referral if necessary. The initial evaluation and physical examination will be discussed in detail.


Assuntos
Neuralgia/diagnóstico , Vulvodinia/diagnóstico , Dor Crônica/epidemiologia , Comorbidade , Feminino , Exame Ginecológico , Humanos , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Neuralgia/epidemiologia , Neuralgia/psicologia , Neuralgia/terapia , Qualidade de Vida , Vulvodinia/epidemiologia , Vulvodinia/psicologia , Vulvodinia/terapia
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