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1.
Circulation ; 140(18): 1506-1518, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31657957

RESUMO

Reports highlighting the problems with the standard practice of using bar graphs to show continuous data have prompted many journals to adopt new visualization policies. These policies encourage authors to avoid bar graphs and use graphics that show the data distribution; however, they provide little guidance on how to effectively display data. We conducted a systematic review of studies published in top peripheral vascular disease journals to determine what types of figures are used, and to assess the prevalence of suboptimal data visualization practices. Among papers with data figures, 47.7% of papers used bar graphs to present continuous data. This primer provides a detailed overview of strategies for addressing this issue by (1) outlining strategies for selecting the correct type of figure depending on the study design, sample size, and the type of variable; (2) examining techniques for making effective dot plots, box plots, and violin plots; and (3) illustrating how to avoid sending mixed messages by aligning the figure structure with the study design and statistical analysis. We also present solutions to other common problems identified in the systematic review. Resources include a list of free tools and templates that authors can use to create more informative figures and an online simulator that illustrates why summary statistics are meaningful only when there are enough data to summarize. Last, we consider steps that investigators can take to improve figures in the scientific literature.

2.
Breast Cancer Res ; 21(1): 118, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660981

RESUMO

BACKGROUND: Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls. METHODS: Eligible cases (n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1-5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time. RESULTS: Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (- 0.26% and - 2.10 cm3) than the normal breast (- 0.39% and - 2.74 cm3) for a difference of 0.13% (p value < 0.001) and 0.63 cm3 (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (- 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54 (95% CI 0.52, 0.56) for VPD and 0.56 (95% CI, 0.54, 0.58) for DV. CONCLUSION: There is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer.

3.
BMC Genomics ; 20(1): 689, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477010

RESUMO

BACKGROUND: Archived formalin fixed paraffin embedded (FFPE) samples are valuable clinical resources to examine clinically relevant morphology features and also to study genetic changes. However, DNA quality and quantity of FFPE samples are often sub-optimal, and resulting NGS-based genetics variant detections are prone to false positives. Evaluations of wet-lab and bioinformatics approaches are needed to optimize variant detection from FFPE samples. RESULTS: As a pilot study, we designed within-subject triplicate samples of DNA derived from paired FFPE and fresh frozen breast tissues to highlight FFPE-specific artifacts. For FFPE samples, we tested two FFPE DNA extraction methods to determine impact of wet-lab procedures on variant calling: QIAGEN QIAamp DNA Mini Kit ("QA"), and QIAGEN GeneRead DNA FFPE Kit ("QGR"). We also used negative-control (NA12891) and positive control samples (Horizon Discovery Reference Standard FFPE). All DNA sample libraries were prepared for NGS according to the QIAseq Human Breast Cancer Targeted DNA Panel protocol and sequenced on the HiSeq 4000. Variant calling and filtering were performed using QIAGEN Gene Globe Data Portal. Detailed variant concordance comparisons and mutational signature analysis were performed to investigate effects of FFPE samples compared to paired fresh frozen samples, along with different DNA extraction methods. In this study, we found that five times or more variants were called with FFPE samples, compared to their paired fresh-frozen tissue samples even after applying molecular barcoding error-correction and default bioinformatics filtering recommended by the vendor. We also found that QGR as an optimized FFPE-DNA extraction approach leads to much fewer discordant variants between paired fresh frozen and FFPE samples. Approximately 92% of the uniquely called FFPE variants were of low allelic frequency range (< 5%), and collectively shared a "C > T|G > A" mutational signature known to be representative of FFPE artifacts resulting from cytosine deamination. Based on control samples and FFPE-frozen replicates, we derived an effective filtering strategy with associated empirical false-discovery estimates. CONCLUSIONS: Through this study, we demonstrated feasibility of calling and filtering genetic variants from FFPE tissue samples using a combined strategy with molecular barcodes, optimized DNA extraction, and bioinformatics methods incorporating genomics context such as mutational signature and variant allelic frequency.

4.
J Psychiatr Res ; 117: 45-54, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279243

RESUMO

Dorsolateral prefrontal cortex (DLPFC) and temporal pole (TP) are brain regions that display abnormalities in bipolar disorder (BD) patients. DNA methylation - an epigenetic mechanism both heritable and sensitive to the environment - may be involved in the pathophysiology of BD. To study BD-associated DNA methylomic differences in these brain regions, we extracted genomic DNA from the postmortem tissues of Brodmann Area (BA) 9 (DLPFC) and BA38 (TP) gray matter from 20 BD, ten major depression (MDD), and ten control age-and-sex-matched subjects. Genome-wide methylation levels were measured using the 850 K Illumina MethylationEPIC BeadChip. We detected striking differences between cortical regions, with greater numbers of between-brain-region differentially methylated positions (DMPs; i.e., CpG sites) in all groups, most pronounced in the BD group, and with substantial overlap across groups. The genes of DMPs common to both BD and MDD (hypothetically associated with their common features such as depression) and those distinct to BD (hypothetically associated with BD-specific features such as mania) were enriched in pathways involved in neurodevelopment including axon guidance. Pathways enriched only in the BD-MDD shared list pointed to GABAergic dysregulation, while those enriched in the BD-only list suggested glutamatergic dysregulation and greater impact on synaptogenesis and synaptic plasticity. We further detected group-specific between-brain-region gene expression differences in ODC1, CALY, GALNT2, and GABRD, which contained significant between-brain-region DMPs. In each brain region, no significant DMPs or differentially methylated regions (DMRs) were found between diagnostic groups. In summary, the methylation differences between DLPFC and TP may provide molecular targets for further investigations of genetic and environmental vulnerabilities associated with both unique and common features of various mood disorders and suggest directions of future development of individualized treatment strategies.

5.
Expert Rev Neurother ; 19(9): 867-879, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31269819

RESUMO

Introduction: Clinical and genetic study of psychiatric conditions has underscored the co-occurrence of complex phenotypes and the need to refine them. Bipolar Disorder (BD) and Binge Eating (BE) behavior are common psychiatric conditions that have high heritability and high co-occurrence, such that at least one quarter of BD patients have BE (BD + BE). Genetic studies of BD alone and of BE alone suggest complex polygenic risk models, with many genetic risk loci yet to be identified. Areas covered: We review studies of the epidemiology of BD+BE, its clinical features (cognitive traits, psychiatric comorbidity, and role of obesity), genomic studies (of BD, eating disorders (ED) defined by BE, and BD + BE), and therapeutic implications of BD + BE. Expert opinion: Subphenotyping of complex psychiatric disorders reduces heterogeneity and increases statistical power and effect size; thus, it enhances our capacity to find missing genetic (and other) risk factors. BD + BE has a severe clinical picture and genetic studies suggests a distinct genetic architecture. Differential therapeutic interventions may be needed for patients with BD + BE compared with BD patients without BE. Recognizing the BD + BE subphenotype is an example of moving towards more precise clinical and genetic entities.

6.
Cancer Epidemiol Biomarkers Prev ; 28(8): 1324-1330, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31186265

RESUMO

BACKGROUND: Mammographic breast density declines during menopause. We assessed changes in volumetric breast density across the menopausal transition and factors that influence these changes. METHODS: Women without a history of breast cancer, who had full field digital mammograms during both pre- and postmenopausal periods, at least 2 years apart, were sampled from four facilities within the San Francisco Mammography Registry from 2007 to 2013. Dense breast volume (DV) was assessed using Volpara on mammograms across the time period. Annualized change in DV from pre- to postmenopause was estimated using linear mixed models adjusted for covariates and per-woman random effects. Multiplicative interactions were evaluated between premenopausal risk factors and time to determine whether these covariates modified the annualized changes. RESULTS: Among the 2,586 eligible women, 1,802 had one premenopausal and one postmenopausal mammogram, 628 had an additional perimenopausal mammogram, and 156 had two perimenopausal mammograms. Women experienced an annualized decrease in DV [-2.2 cm3 (95% confidence interval, -2.7 to -1.7)] over the menopausal transition. Declines were greater among women with a premenopausal DV above the median (54 cm3) versus below (DV, -3.5 cm3 vs. -1.0 cm3; P < 0.0001). Other breast cancer risk factors, including race, body mass index, family history, alcohol, and postmenopausal hormone therapy, had no effect on change in DV over the menopausal transition. CONCLUSIONS: High premenopausal DV was a strong predictor of greater reductions in DV across the menopausal transition. IMPACT: We found that few factors other than premenopausal density influence changes in DV across the menopausal transition, limiting targeted prevention efforts.

7.
Mod Pathol ; 32(12): 1834-1846, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31239549

RESUMO

Primary ovarian mucinous tumors can be difficult to distinguish from metastatic gastrointestinal neoplasms by histology alone. The expected immunoprofile of a suspected metastatic lower gastrointestinal tumor is CK7-/CK20+/CDX2+/PAX8-. This study assesses the addition of a novel marker SATB2, to improve the diagnostic algorithm. A test cohort included 155 ovarian mucinous tumors (105 carcinomas and 50 borderline tumors) and 230 primary lower gastrointestinal neoplasms (123 colorectal adenocarcinomas and 107 appendiceal neoplasms). All cases were assessed for SATB2, PAX8 CK7, CK20, and CDX2 expression on tissue microarrays. Expression was scored in a 3-tier system as absent, focal (1-50% of tumor cells) and diffuse ( >50% of tumor cells) and then categorized into either absent/present or nondiffuse/diffuse. SATB2 and PAX8 expression was further evaluated in ovarian tumors from an international cohort of 2876 patients (expansion cohort, including 159 mucinous carcinomas and 46 borderline mucinous tumors). The highest accuracy of an individual marker in distinguishing lower gastrointestinal from ovarian mucinous tumors was CK7 (91.7%, nondiffuse/diffuse cut-off) followed by SATB2 (88.8%, present/absent cut-off). The most effective combination was CK7 and SATB2 with accuracy of 95.3% using the 3-tier interpretation, absent/focal/diffuse. This combination outperformed the standard clinical set of CK7, CK20 and CDX2 (87.5%). Re-evaluation of outlier cases confirmed ovarian origin for all but one case. The accuracy of SATB2 was confirmed in the expansion cohort (91.5%). SATB2 expression was also detected in 15% of ovarian endometrioid carcinoma but less than 5% of other ovarian histotypes. A simple two marker combination of CK7 and SATB2 can distinguish lower gastrointestinal from ovarian primary mucinous tumors with greater than 95% accuracy. PAX8 and CDX2 have value as second-line markers. The utility of CK20 in this setting is low and this warrants replacement of this marker with SATB2 in clinical practice.

8.
Mod Pathol ; 32(9): 1263-1270, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30996252

RESUMO

We describe the histology and the frequency of a histologic entity that we term "hyaline fibrous involution", which is characterized by symmetric and regular deposition of basal lamina-like periacinar hyaline material in association with atrophic epithelium, in breast samples from patients with either benign breast disease or germline BRCA mutation. Women with germline BRCA mutation (n = 93) who underwent prophylactic mastectomy (BRCA group) were compared to an age-matched sample of women who underwent biopsy for benign breast disease (n = 93). Median age was 45 years (range, 25-72 years). A single H&E section of each subject's benign breast tissue was reviewed. The total number of terminal duct lobular units and the number of terminal duct lobular units with hyaline fibrous involution were recorded for each case. The presence of any hyaline fibrous involution lobules and the within-sample proportion of hyaline fibrous involution lobules relative to total lobules were compared between groups. Presence of any hyaline fibrous involution was significantly more frequent in the BRCA group compared to the benign breast disease group, 47% vs. 15% (p < 0.0001, adjusted for total lobules). In women with any hyaline fibrous involution lobules, these unusual lobules were similarly rare in both groups, with median proportion of hyaline fibrous involution-positive lobules relative to all lobules of 0.03 in BRCA specimens (n = 44) and 0.03 in the benign breast disease group (n = 14). Within the BRCA group, frequency of any hyaline fibrous involution present was significantly higher in the perimenopausal age group (45-55 years: 63%) compared to other age groups (<45 years, 44%; >55 years, 15%; p = 0.05 and p = 0.02, respectively). Increased presence of hyaline fibrous involution in the setting of BRCA mutation suggests that it may represent a pathologic entity, possibly reflecting abnormal involution or an abnormal response to DNA damage.

9.
Drug Alcohol Depend ; 197: 183-190, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30840924

RESUMO

BACKGROUND: Sex-related differences in the susceptibility, progression, and treatment response in alcohol-dependent subjects have been repeatedly reported. In this study, we aimed to investigate the associations of the sex-related hormone/protein levels with alcohol dependence (AD) and alcohol craving in male and female subjects. METHODS: Plasma sex-related hormones (estradiol, estrone, total testosterone, progesterone, follicle stimulated hormone [FSH], luteinizing hormone), and sex hormone binding globulin were measured by mass spectrometry or automated immunoassays from 44 recently-abstained subjects (29 males and 15 females; mean age = 45.9 ± 15.6) meeting DSM-IV-TR criteria for AD and 44 age-, sex- and race-matched non-AD controls. Conditional logistic regression was conducted to examine the association of sex-related hormone and protein levels with AD risk, accounting for matching variables. Their associations with alcohol craving scales (Penn Alcohol Craving Scale and Inventory of Drug-Taking Situations) were assessed in AD subjects. RESULTS: Plasma FSH level was significantly higher in AD males (10.3 ± 9.8 IU/L) than control males (8.0 ± 15.9 IU/L; p = 0.005, pcorrected = 0.035). We also found a significant inverse correlation of FSH level with propensity to drink in negative emotional situations (Spearman's rho=-.540; p = 0.021) and positive correlations between progesterone level and craving intensity (Spearman's rho=.464; p = 0.020) and between total testosterone level and propensity to drink under temptations (adjusted for no-drinking days; ß=6.496; p = 0.041) in AD males. CONCLUSIONS: These results suggest that FSH, progesterone, and testosterone levels may be associated with AD and alcohol craving in AD males. Future research is needed to replicate these findings and investigate the underlying biological mechanisms.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/sangue , Alcoolismo/psicologia , Fissura/fisiologia , Hormônios Esteroides Gonadais/sangue , Adulto , Alcoolismo/epidemiologia , Biomarcadores/sangue , Emoções/fisiologia , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Progesterona/sangue , Autorrelato , Testosterona/sangue
10.
Hum Mol Genet ; 28(8): 1331-1342, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30576442

RESUMO

X chromosome inactivation (XCI) is a key epigenetic gene expression regulatory process, which may play a role in women's cancer. In particular tissues, some genes are known to escape XCI, yet patterns of XCI in ovarian cancer (OC) and their clinical associations are largely unknown. To examine XCI in OC, we integrated germline genotype with tumor copy number, gene expression and DNA methylation information from 99 OC patients. Approximately 10% of genes showed different XCI status (either escaping or being subject to XCI) compared with the studies of other tissues. Many of these genes are known oncogenes or tumor suppressors (e.g. DDX3X, TRAPPC2 and TCEANC). We also observed strong association between cis promoter DNA methylation and allele-specific expression imbalance (P = 2.0 × 10-10). Cluster analyses of the integrated data identified two molecular subgroups of OC patients representing those with regulated (N = 47) and dysregulated (N = 52) XCI. This XCI cluster membership was associated with expression of X inactive specific transcript (P = 0.002), a known driver of XCI, as well as age, grade, stage, tumor histology and extent of residual disease following surgical debulking. Patients with dysregulated XCI (N = 52) had shorter time to recurrence (HR = 2.34, P = 0.001) and overall survival time (HR = 1.87, P = 0.02) than those with regulated XCI, although results were attenuated after covariate adjustment. Similar findings were observed when restricted to high-grade serous tumors. We found evidence of a unique OC XCI profile, suggesting that XCI may play an important role in OC biology. Additional studies to examine somatic changes with paired tumor-normal tissue are needed.


Assuntos
Carcinoma Epitelial do Ovário/genética , Genes Ligados ao Cromossomo X/genética , Inativação do Cromossomo X/fisiologia , Idoso , Alelos , Carcinoma Epitelial do Ovário/metabolismo , Cromossomos Humanos X/genética , Análise por Conglomerados , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Regulação da Expressão Gênica/genética , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante , Fatores de Transcrição/genética , Inativação do Cromossomo X/genética
11.
Int J Cancer ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30499236

RESUMO

As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), this study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9,971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs never) and rs13255292 (P-value = 3.48 x 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI=0.46-0.60) compared to 0.71 (95%CI=0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer. This article is protected by copyright. All rights reserved.

12.
Elife ; 72018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30574870

RESUMO

Transparent reporting is essential for the critical evaluation of studies. However, the reporting of statistical methods for studies in the biomedical sciences is often limited. This systematic review examines the quality of reporting for two statistical tests, t-tests and ANOVA, for papers published in a selection of physiology journals in June 2017. Of the 328 original research articles examined, 277 (84.5%) included an ANOVA or t-test or both. However, papers in our sample were routinely missing essential information about both types of tests: 213 papers (95% of the papers that used ANOVA) did not contain the information needed to determine what type of ANOVA was performed, and 26.7% of papers did not specify what post-hoc test was performed. Most papers also omitted the information needed to verify ANOVA results. Essential information about t-tests was also missing in many papers. We conclude by discussing measures that could be taken to improve the quality of reporting.


Assuntos
Projetos de Pesquisa/normas , Relatório de Pesquisa/normas , Pesquisa/estatística & dados numéricos , Pesquisa/normas , Análise de Variância , Humanos , Estatística como Assunto/métodos
13.
J Affect Disord ; 245: 597-601, 2018 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-30445384

RESUMO

BACKGROUND: Patients with bipolar disorder demonstrate sex differences in clinical presentation, particularly in the sub-phenotypes related to periodicity of mood episodes, such as rapid cycling. Additionally, recent studies have linked P2RX7 gene variants with the risk of rapid cycling in clinical cohorts of patients with bipolar disorder, as well as other mood disorders. However, little is known about potential sex differences in the relationship between variants in P2RX7 and bipolar disorder. METHODS: We investigated sex-specific genetic associations between variants of P2RX7 (rs1621388 and rs2230912) in 756 patients with bipolar disorder and 787 control patients matched on age, sex, and ancestry. We examined sex-specific genetic associations with bipolar disorder by comparing cases and controls, as well as rapid cycling of mood episodes in cases. Findings were replicated in an independent dataset. RESULTS: P2RX7 variants implying an increased pore activity were more common in bipolar disorder, in females but not in males. Neither P2RX7 variants associated with rapid cycling among bipolar patients. LIMITATIONS: Low sample size limited power for tests of SNP by sex interaction, and data about the onset of rapid cycling and the timing of medication use were not available. CONCLUSION: The effects of P2RX7 variants on bipolar disorder may be sex-specific, with increased P2X7 activity potentially elevating risk for bipolar disorder in females. Future research to examine the effect of P2RX7 on bipolar disorder should consider sex-specific effects.

14.
Radiology ; : 180179, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375931

RESUMO

Purpose To identify phenotypes of mammographic parenchymal complexity by using radiomic features and to evaluate their associations with breast density and other breast cancer risk factors. Materials and Methods Computerized image analysis was used to quantify breast density and extract parenchymal texture features in a cross-sectional sample of women screened with digital mammography from September 1, 2012, to February 28, 2013 (n = 2029; age range, 35-75 years; mean age, 55.9 years). Unsupervised clustering was applied to identify and reproduce phenotypes of parenchymal complexity in separate training (n = 1339) and test sets (n = 690). Differences across phenotypes by age, body mass index, breast density, and estimated breast cancer risk were assessed by using Fisher exact, χ2, and Kruskal-Wallis tests. Conditional logistic regression was used to evaluate preliminary associations between the detected phenotypes and breast cancer in an independent case-control sample (76 women diagnosed with breast cancer and 158 control participants) matched on age. Results Unsupervised clustering in the screening sample identified four phenotypes with increasing parenchymal complexity that were reproducible between training and test sets (P = .001). Breast density was not strongly correlated with phenotype category (R2 = 0.24 for linear trend). The low- to intermediate-complexity phenotype (prevalence, 390 of 2029 [19%]) had the lowest proportion of dense breasts (eight of 390 [2.1%]), whereas similar proportions were observed across other phenotypes (from 140 of 291 [48.1%] in the high-complexity phenotype to 275 of 511 [53.8%] in the low-complexity phenotype). In the independent case-control sample, phenotypes showed a significant association with breast cancer (P = .001), resulting in higher discriminatory capacity when added to a model with breast density and body mass index (area under the curve, 0.84 vs 0.80; P = .03 for comparison). Conclusion Radiomic phenotypes capture mammographic parenchymal complexity beyond conventional breast density measures and established breast cancer risk factors. © RSNA, 2018 Online supplemental material is available for this article.

15.
PLoS One ; 13(7): e0197561, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29979793

RESUMO

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.

16.
Cancer Epidemiol Biomarkers Prev ; 27(9): 1101-1109, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29967001

RESUMO

Background: Endometrioid carcinoma (EC) and clear cell carcinoma (CC) histotypes of epithelial ovarian cancer are understudied compared with the more common high-grade serous carcinomas (HGSC). We therefore sought to characterize EC and CC transcriptomes in relation to HGSC.Methods: Following bioinformatics processing and gene abundance normalization, differential expression analysis of RNA sequence data collected on fresh-frozen tumors was completed with nonparametric statistical analysis methods (55 ECs, 19 CCs, 112 HGSCs). Association of gene expression with progression-free survival (PFS) was completed with Cox proportional hazards models. Eight additional multi-histotype expression array datasets (N = 852 patients) were used for replication.Results: In the discovery set, tumors generally clustered together by histotype. Thirty-two protein-coding genes were differentially expressed across histotype (P < 1 × 10-10) and showed similar associations in replication datasets, including MAP2K6, KIAA1324, CDH1, ENTPD5, LAMB1, and DRAM1 Nine genes associated with PFS (P < 0.0001) showed similar associations in replication datasets. In particular, we observed shorter PFS time for CC and EC patients with high gene expression for CCNB2, CORO2A, CSNK1G1, FRMD8, LIN54, LINC00664, PDK1, and PEX6, whereas, the converse was observed for HGSC patients.Conclusions: The results suggest important histotype differences that may aid in the development of treatment options, particularly those for patients with EC or CC.Impact: We present replicated findings on transcriptomic differences and how they relate to clinical outcome for two of the rarer ovarian cancer histotypes of EC and CC, along with comparison with the common histotype of HGSC. Cancer Epidemiol Biomarkers Prev; 27(9); 1101-9. ©2018 AACR.

17.
Cancer ; 124(16): 3319-3328, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29932456

RESUMO

BACKGROUND: More than 1.5 million women per year have a benign breast biopsy resulting in concern about their future breast cancer (BC) risk. This study examined the performance of 2 BC risk models that integrate clinical and histologic findings in this population. METHODS: The BC risk at 5 and 10 years was estimated with the Breast Cancer Surveillance Consortium (BCSC) and Benign Breast Disease to Breast Cancer (BBD-BC) models for women diagnosed with benign breast disease (BBD) at the Mayo Clinic from 1997 to 2001. Women with BBD were eligible for the BBD-BC model, but the BCSC model also required a screening mammogram. Calibration and discrimination were assessed. RESULTS: Fifty-six cases of BC were diagnosed among the 2142 women with BBD (median age, 50 years) within 5 years (118 were diagnosed within 10 years). The BBD-BC model had slightly better calibration at 5 years (0.89; 95% confidence interval [CI], 0.71-1.21) versus 10 years (0.81; 95% CI, 0.70-1.00) but similar discrimination in the 2 time periods: 0.68 (95% CI, 0.60-0.75) and 0.66 (95% CI, 0.60-0.71), respectively. In contrast, among the 1089 women with screening mammograms (98 cases of BC within 10 years), the BCSC model had better calibration (0.94; 95% CI, 0.85-1.43) and discrimination (0.63; 95% CI, 0.56-0.71) at 10 years versus 5 years (calibration, 1.31; 95% CI, 0.94-2.25; discrimination, 0.59; 95% CI, 0.46-0.71) where discrimination was not different from chance. CONCLUSIONS: The BCSC and BBD-BC models were validated in the Mayo BBD cohort, although their performance differed by 5-year risk versus 10-year risk. Further enhancement of these models is needed to provide accurate BC risk estimates for women with BBD.

18.
J Clin Oncol ; 36(18): 1840-1846, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29676945

RESUMO

Purpose Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but existing risk prediction models do not provide accurate individualized estimates of risk in this subset of high-risk women. Here, we used the Mayo benign breast disease cohort to develop and validate a model of BC risk prediction that is specifically for women with AH, which we have designated as AH-BC. Patients and Methods Retrospective cohorts of women age 18 to 85 years with pathologically confirmed benign AH from Rochester, MN, and Nashville, TN, were used for model development and external validation, respectively. Clinical risk factors and histologic features of the tissue biopsy were selected using L1-penalized Cox proportional hazards regression. Identified features were included in a Fine and Gray regression model to estimate BC risk, with death as a competing risk. Model discrimination and calibration were assessed in the model-building set and an external validation set. Results The model-building set consisted of 699 women with AH, 142 of whom developed BC (median follow-up, 8.1 years), and the external validation set consisted of 461 women with 114 later BC events (median follow-up, 11.4 years). The final AH-BC model included three covariates: age at biopsy, age at biopsy squared, and number of foci of AH. At 10 years, the AH-BC model demonstrated good discrimination (0.63 [95% CI, 0.57 to 0.70]) and calibration (0.87 [95% CI, 0.66 to 1.24]). In the external validation set, the model showed acceptable discrimination (0.59 [95% CI, 0.51 to 0.67]) and calibration (0.91 [95% CI, 0.65 to 1.42]). Conclusion We have created a new model with which to refine BC risk prediction for women with AH. The AH-BC model demonstrates good discrimination and calibration, and it validates in an external data set.

19.
Cancer Med ; 7(5): 1978-1987, 2018 May.
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.

20.
Mayo Clin Proc ; 93(3): 307-320, 2018 Mar.
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.

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