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1.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

3.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1731-1738, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581112

RESUMO

BACKGROUND: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening. METHODS: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups. RESULTS: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age. CONCLUSIONS: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. IMPACT: Personalized genetic risk assessments could inform prostate cancer screening decisions.

4.
Eur Urol ; 78(3): 316-320, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32409115

RESUMO

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

5.
J Biomed Inform ; 105: 103408, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173502

RESUMO

Limited sample sizes can lead to spurious modeling findings in biomedical research. The objective of this work is to present a new method to generate synthetic populations (SPs) from limited samples using matched case-control data (n = 180 pairs), considered as two separate limited samples. SPs were generated with multivariate kernel density estimations (KDEs) with unconstrained bandwidth matrices. We included four continuous variables and one categorical variable for each individual. Bandwidth matrices were determined with Differential Evolution (DE) optimization by covariance comparisons. Four synthetic samples (n = 180) were derived from their respective SPs. Similarity between observed samples with synthetic samples was compared assuming their empirical probability density functions (EPDFs) were similar. EPDFs were compared with the maximum mean discrepancy (MMD) test statistic based on the Kernel Two-Sample Test. To evaluate similarity within a modeling context, EPDFs derived from the Principal Component Analysis (PCA) scores and residuals were summarized with the distance to the model in X-space (DModX) as additional comparisons. Four SPs were generated from each sample. The probability of selecting a replicate when randomly constructing synthetic samples (n = 180) was infinitesimally small. MMD tests indicated that the observed sample EPDFs were similar to the respective synthetic EPDFs. For the samples, PCA scores and residuals did not deviate significantly when compared with their respective synthetic samples. The feasibility of this approach was demonstrated by producing synthetic data at the individual level, statistically similar to the observed samples. The methodology coupled KDE with DE optimization and deployed novel similarity metrics derived from PCA. This approach could be used to generate larger-sized synthetic samples. To develop this approach into a research tool for data exploration purposes, additional evaluation with increased dimensionality is required. Moreover, given a fully specified population, the degree to which individuals can be discarded while synthesizing the respective population accurately will be investigated. When these objectives are addressed, comparisons with other techniques such as bootstrapping will be required for a complete evaluation.

6.
Int J Cancer ; 146(11): 2987-2998, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469419

RESUMO

Women of African ancestry have lower incidence of epithelial ovarian cancer (EOC) yet worse survival compared to women of European ancestry. We conducted a genome-wide association study in African ancestry women with 755 EOC cases, including 537 high-grade serous ovarian carcinomas (HGSOC) and 1,235 controls. We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10-6 ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1). For HGSOC, we identified six loci with suggestive evidence of association including rs37792 (132 kb 5' of follistatin [FST]), rs57403204 (81 kb 3' of MAGEC1), rs79079890 (LOC105376360 intronic), rs66459581 (5 kb 5' of PRPSAP1), rs116046250 (GABRG3 intronic) and rs192876988 (32 kb 3' of GK2). Among the identified variants, two are near genes known to regulate hormones and diseases of the ovary (AKR1C3 and FST), and two are linked to cancer (AKR1C3 and MAGEC1). In follow-up studies of the 10 identified variants, the GK2 region SNP, rs192876988, showed an inverse association with EOC in European ancestry women (p = 0.002), increased risk of ER positive breast cancer in African ancestry women (p = 0.027) and decreased expression of GK2 in HGSOC tissue from African ancestry women (p = 0.004). A European ancestry-derived polygenic risk score showed positive associations with EOC and HGSOC in women of African ancestry suggesting shared genetic architecture. Our investigation presents evidence of variants for EOC shared among European and African ancestry women and identifies novel EOC risk loci in women of African ancestry.

7.
iScience ; 17: 242-255, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31307004

RESUMO

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of tumorigenesis, and yet their mechanistic roles remain challenging to characterize. Here, we integrate functional proteomics with lncRNA-interactome profiling to characterize Urothelial Cancer Associated 1 (UCA1), a candidate driver of ovarian cancer development. Reverse phase protein array (RPPA) analysis indicates that UCA1 activates transcription coactivator YAP and its target genes. In vivo RNA antisense purification (iRAP) of UCA1 interacting proteins identified angiomotin (AMOT), a known YAP regulator, as a direct binding partner. Loss-of-function experiments show that AMOT mediates YAP activation by UCA1, as UCA1 enhances the AMOT-YAP interaction to promote YAP dephosphorylation and nuclear translocation. Together, we characterize UCA1 as a lncRNA regulator of Hippo-YAP signaling and highlight the UCA1-AMOT-YAP signaling axis in ovarian cancer development.

8.
Cancer Med ; 8(5): 2503-2513, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31001917

RESUMO

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.


Assuntos
Afro-Americanos/genética , Carcinoma Epitelial do Ovário/genética , Glucuronosiltransferase/genética , Neoplasias Ovarianas/genética , Receptores de Calcitriol/genética , Teorema de Bayes , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Receptores ErbB/genética , Feminino , Estudos de Associação Genética , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Vitamina D/biossíntese
9.
Cancer Epidemiol Biomarkers Prev ; 28(7): 1117-1126, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30948450

RESUMO

BACKGROUND: Germline DNA copy number variation (CNV) is a ubiquitous source of genetic variation and remains largely unexplored in association with epithelial ovarian cancer (EOC) risk. METHODS: CNV was quantified in the DNA of approximately 3,500 cases and controls genotyped with the Illumina 610k and HumanOmni2.5M arrays. We performed a genome-wide association study of common (>1%) CNV regions (CNVRs) with EOC and high-grade serous (HGSOC) risk and, using The Cancer Genome Atlas (TCGA), performed in silico analyses of tumor-gene expression. RESULTS: Three CNVRs were associated (P < 0.01) with EOC risk: two large (∼100 kb) regions within the 610k set and one small (<5 kb) region with the higher resolution 2.5M data. Large CNVRs included a duplication at LILRA6 (OR = 2.57; P = 0.001) and a deletion at CYP2A7 (OR = 1.90; P = 0.007) that were strongly associated with HGSOC risk (OR = 3.02; P = 8.98 × 10-5). Somatic CYP2A7 alterations correlated with EGLN2 expression in tumors (P = 2.94 × 10-47). An intronic ERBB4/HER4 deletion was associated with reduced EOC risk (OR = 0.33; P = 9.5 × 10-2), and somatic deletions correlated with ERBB4 downregulation (P = 7.05 × 10-5). Five CNVRs were associated with HGSOC, including two reduced-risk deletions: one at 1p36.33 (OR = 0.28; P = 0.001) that correlated with lower CDKIIA expression in TCGA tumors (P = 2.7 × 10-7), and another at 8p21.2 (OR = 0.52; P = 0.002) that was present somatically where it correlated with lower GNRH1 expression (P = 5.9 × 10-5). CONCLUSIONS: Though CNV appears to not contribute largely to EOC susceptibility, a number of low-to-common frequency variants may influence the risk of EOC and tumor-gene expression. IMPACT: Further research on CNV and EOC susceptibility is warranted, particularly with CNVs estimated from high-density arrays.


Assuntos
Carcinoma Epitelial do Ovário/genética , Variações do Número de Cópias de DNA/genética , Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Feminino , Humanos
10.
Gynecol Oncol ; 153(2): 343-355, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30898391

RESUMO

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.


Assuntos
Carcinoma Epitelial do Ovário/genética , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
11.
Artigo em Inglês | MEDLINE | ID: mdl-33304615

RESUMO

We present a novel method for evaluating local spatial correlation structure in two-dimensional (2D) mammograms and evaluate its capability for risk prediction as one possible application. Two matched case-control studies were analyzed. Study 1 included women (N = 588 pairs) with mammograms acquired with either Hologic Selenia full field digital mammography (FFDM) units or Hologic Dimensions digital breast tomosynthesis units. Study 2 included women (N =180 pairs) with mammograms acquired with a General Electric Senographe 2000D FFDM unit. Matching variables included age, HRT usage/duration, screening history, and mammography unit. Local autocorrelation functions were determined with Fourier analysis and compared with a template defined as a 2D double-sided exponential function with one spatial extent parameter: n = 4, 12, 24, 50, 74, 100, and 124, where (n+1)×(n+1) is the area of the local spatial extent measured in pixels. The difference between the local correlation and template was gauged within an adjustable parameter kernel and summarized, producing two measures: the mean (mn+1), and standard deviation (sn+1). Both adjustable parameters were varied in Study 1. Select measures that produced significant associations with breast cancer were translated to Study 2. Breast cancer associations were evaluated with conditional logistic regression, adjusted for body mass index and ethnicity. Odds ratios (ORs) were estimated as per standard deviation increment with 95% confidence intervals (CIs). Two measures were selected for breast cancer association analysis in Study 1: m75 and s25. Both measures revealed significant associations with breast cancer: OR = 1.45 (1.23, 1.66) for m75 and OR = 1.30 (1.14, 1.49) for s25. When translating to Study 2, these measures also revealed significant associations: OR = 1.49 (1.12, 1.96) for m75 and OR = 1.34 (1.06, 1.69) for s25. Novel correlation metrics presented in this work produced significant associations with breast cancer risk. This approach is general and may have applications beyond mammography.

12.
Med Phys ; 46(2): 679-688, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30525207

RESUMO

PURPOSE: We are developing a calibration methodology for full-field digital mammography (FFDM). Calibration compensates for image acquisition technique influences on the pixel representation, ideally producing improved inter-image breast density estimates. This approach relies on establishing references with rigid breast tissue-equivalent phantoms (BTEs) and requires an accurate estimate of the compressed breast thickness because the system readout is nominal. There is also an attenuation mismatch between adipose breast tissue and the adipose BTE that was noted in our previous work. It is referred to as the "attenuation anomaly" and addressed in this report. The objectives are to evaluate methods to correct for the compressed breast thickness and compensate for the attenuation anomaly. METHODS: Thickness correction surfaces were established with a deformable phantom (DP) using both image and physical measurements for three direct x-ray conversion FFDM units. The Cumulative Sum serial quality control procedure was established to ensure the thickness correction measurements were stable over time by imaging and calibrating DPs biweekly in lieu of physical measurements. The attenuation anomaly was addressed by evaluating adipose image regions coupled with an optimization technique to adjust the adipose calibration data. We compared calibration consistency across matched left and right cranial caudal (CC) mammographic views (n = 199) with and without corrections using Bland-Altman plots. These plots were complemented by comparing the right and left breast calibrated average (µa ) and population distribution mean (ma ) with 95% confidence intervals and difference distribution variances with the F-test for uncorrected and corrected data. RESULTS: Thickness correction surfaces were well approximated as tilted planes and were dependent upon compression force. A correction was developed for the attenuation anomaly. All paddles (large and small paddles for all units) exhibited similar tilt as a function of force. Without correction, ma  = 0.92 (-1.77, 3.62) was not significantly different from zero with many negative µa samples. The thickness correction produced a significant shift in the µa distribution in the positive direction with ma  = 13.99 (11.17, 16.80) and reduced the difference distribution variance significantly (P < 0.0001). Applying both corrections in tandem gave ma  = 22.83 (20.32, 25.34), representing another significant positive shift in comparison with the thickness correction in isolation. Thickness corrections were stable over approximately a 2-year timeframe for all units. CONCLUSION: These correction techniques are valid approaches for addressing technical problems with calibration that relies on reference phantoms. The efficacy of the calibration methodology will require validation with clinical endpoints in future studies.


Assuntos
Densidade da Mama , Mamografia/métodos , Calibragem , Humanos , Processamento de Imagem Assistida por Computador , Mamografia/instrumentação
13.
Acad Radiol ; 26(9): 1181-1190, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30545682

RESUMO

RATIONALE AND OBJECTIVES: Mammographic density is an important risk factor for breast cancer, but translation to the clinic requires assurance that prior work based on mammography is applicable to current technologies. The purpose of this work is to evaluate whether a calibration methodology developed previously produces breast density metrics predictive of breast cancer risk when applied to a case-control study. MATERIALS AND METHODS: A matched case control study (n = 319 pairs) was used to evaluate two calibrated measures of breast density. Two-dimensional mammograms were acquired from six Hologic mammography units: three conventional Selenia two-dimensional full-field digital mammography systems and three Dimensions digital breast tomosynthesis systems. We evaluated the capability of two calibrated breast density measures to quantify breast cancer risk: the mean (PGm) and standard deviation (PGsd) of the calibrated pixels. Matching variables included age, hormone replacement therapy usage/duration, screening history, and mammography unit. Calibrated measures were compared to the percentage of breast density (PD) determined with the operator-assisted Cumulus method. Conditional logistic regression was used to generate odds ratios (ORs) from continuous and quartile (Q) models with 95% confidence intervals. The area under the receiver operating characteristic curve (Az) was also used as a comparison metric. Both univariate models and models adjusted for body mass index and ethnicity were evaluated. RESULTS: In adjusted models, both PGsd and PD were statistically significantly associated with breast cancer with similar Az of 0.61-0.62. The corresponding ORs and confidence intervals were also similar. For PGsd, the OR was 1.34 (1.09, 1.66) for the continuous measure and 1.83 (1.11, 3.02), 2.19 (1.28, 3.73), and 2.20 (1.26, 3.85) for Q2-Q4. For PD, the OR was 1.43 (1.16, 1.76) for the continuous measure and 0.84 (0.52, 1.38), 1.96 (1.19, 3.23), and 2.27 (1.29, 4.00) for Q2-Q4. The results for PGm were slightly attenuated and not statistically significant. The OR was 1.22 (0.99, 1.51) with Az = 0.60 for the continuous measure and 1.24 (0.78, 1.97), 0.98 (0.60, 1.61), and 1.26, (0.77, 2.07) for Q2-Q4 with Az = 0.60. CONCLUSION: The calibrated PGsd measure provided significant associations with breast cancer comparable to those given by PD. The calibrated PGm performed slightly worse. These findings indicate that the calibration approach developed previously replicates under more general conditions.


Assuntos
Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Mamografia , Idoso , Área Sob a Curva , Calibragem , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Curva ROC , Medição de Risco
14.
Cancer Epidemiol Biomarkers Prev ; 28(2): 239-247, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30377205

RESUMO

BACKGROUND: Research reproducibility is vital for translation of epidemiologic findings. However, repeated studies of the same question may be undertaken without enhancing existing knowledge. To identify settings in which additional research is or is not warranted, we adapted research synthesis metrics to determine number of additional observational studies needed to change the inference from an existing meta-analysis. METHODS: The fail-safe number (FSN) estimates number of additional studies of average weight and null effect needed to drive a statistically significant meta-analysis to null (P ≥ 0.05). We used conditional power to determine number of additional studies of average weight and equivalent heterogeneity to achieve 80% power in an updated meta-analysis to detect the observed summary estimate as statistically significant. We applied these metrics to a curated set of 98 meta-analyses on biomarkers and cancer risk. RESULTS: Both metrics were influenced by number of studies, heterogeneity, and summary estimate size in the existing meta-analysis. For the meta-analysis on Helicobacter pylori and gastric cancer with 15 studies [OR = 2.29; 95% confidence interval (CI), 1.71-3.05], FSN was 805 studies, supporting futility of further study. For the meta-analysis on dehydroepiandrosterone sulfate and prostate cancer with 7 studies (OR = 1.29; 95% CI, 0.99-1.69), 5 more studies would be needed for 80% power, suggesting further study could change inferences. CONCLUSIONS: Along with traditional assessments, these metrics could be used by stakeholders to decide whether additional studies addressing the same question are needed. IMPACT: Systematic application of these metrics could lead to more judicious use of resources and acceleration from discovery to population-health impact.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias/sangue , Neoplasias/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias Colorretais/epidemiologia , Sulfato de Desidroepiandrosterona/análise , Neoplasias do Endométrio/epidemiologia , Feminino , Infecções por Helicobacter/complicações , Helicobacter pylori , Humanos , Masculino , Metanálise como Assunto , Estudos Observacionais como Assunto , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/etiologia
15.
Cancer Res ; 79(3): 467-481, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30487138

RESUMO

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.


Assuntos
Carcinoma Epitelial do Ovário/genética , Cromossomos Humanos Par 9 , Neoplasias Ovarianas/genética , Sequência de Bases , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico , Cistadenocarcinoma Seroso/genética , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único
16.
Phys Med Biol ; 64(1): 015006, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30523909

RESUMO

Mammograms represent data that can inform future risk of breast cancer. Data from two case-control study populations were analyzed. Population 1 included women (N = 180 age matched case-control pairs) with mammograms acquired with one indirect x-ray conversion mammography unit. Population 2 included women (N = 319 age matched case-control pairs) with mammograms acquired from 6 direct x-ray conversion units. The Fourier domain was decomposed into n concentric rings (radial spatial frequency bands). The power in each ring was summarized giving a set of measures. We investigated images in raw, for presentation (processed) and calibrated representations and made comparison with the percentage of breast density (BD) determined with the operator assisted Cumulus method. Breast cancer associations were evaluated with conditional logistic regression, adjusted for body mass index and ethnicity. Odds ratios (ORs), per standard deviation increase derived from the respective breast density distributions and 95% confidence intervals (CIs) were estimated. A measure from a lower radial frequency ring, corresponding 0.083-0.166 cycles mm-1 and BD had significant associations with risk in both populations. In Population 1, the Fourier measure produced significant associations in each representation: OR = 1.76 (1.33, 2.32) for raw; OR = 1.43 (1.09, 1.87) for processed; and OR = 1.68 (1.26, 2.25) for calibrated. BD also provided significant associations in Population 1: OR = 1.72 (1.27, 2.33). In Population 2, the Fourier measure produced significant associations for each representation as well: OR = 1.47 (1.19, 1.80) for raw; OR = 1.38 (1.15, 1.67) for processed; and OR = 1.42 (1.15, 1.75) for calibrated. BD provided significant associations in Population 2: OR = 1.43 (1.17, 1.76). Other coincident spectral regions were also predictive of case-control status. In sum, generalized breast density measures were significantly associated with breast cancer in both FFDM technologies.


Assuntos
Densidade da Mama , Mamografia , Índice de Massa Corporal , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Calibragem , Estudos de Casos e Controles , Feminino , Análise de Fourier , Humanos , Modelos Logísticos
17.
Transl Res ; 200: 1-17, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30053382

RESUMO

Adjuvant chemotherapy for solid tumors based on platinum-derived compounds such as cisplatin is the treatment of choice in most cases. Cisplatin triggers signaling pathways that lead to cell death, but it also induces changes in tumor cells that modify the therapeutic response, thereby leading to cisplatin resistance. We have recently reported that microRNA-7 is silenced by DNA methylation and is involved in the resistance to platinum in cancer cells through the action of the musculoaponeurotic fibrosarcoma oncogene family, protein G (MAFG). In the present study, we first confirm the miR-7 epigenetic regulation of MAFG in 44 normal- and/or tumor-paired samples in non-small-cell lung cancer (NSCLC). We also provide translational evidence of the role of MAFG and the clinical outcome in NSCLC by the interrogation of two extensive in silico databases of 2019 patients. Moreover, we propose that MAFG-mediated resistance could be conferred due to lower reactive oxygen species production after cisplatin exposure. We developed specifically selected aptamers against MAFG, with high sensitivity to detect the protein at a nuclear level probed by aptacytochemistry and histochemistry analyses. The inhibition of MAFG activity through the action of the specific aptamer apMAFG6F increased the levels of reactive oxygen species production and the sensitivity to cisplatin. We report first the specific nuclear identification of MAFG as a novel detection method for diagnosis in NSCLC, and then we report that MAFG modulates the redox response and confers cell protection against free radicals generated after platinum administration, thus also being a promising therapeutic target.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Fator de Transcrição MafG/antagonistas & inibidores , Proteínas Repressoras/antagonistas & inibidores , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Aptâmeros de Nucleotídeos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Clonagem Molecular , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Epigênese Genética/genética , Expressão Gênica , Inativação Gênica , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Fator de Transcrição MafG/genética , Fator de Transcrição MafG/fisiologia , MicroRNAs/genética , MicroRNAs/fisiologia , Oxirredução , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/fisiologia , Análise de Sequência de DNA , Transfecção
18.
Bioinformatics ; 34(24): 4141-4150, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29878078

RESUMO

Motivation: The use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistically powerful but suffers from a large computation burden. For large-scale studies, it is necessary to use a powerful and computation-efficient method. The objective of this study is to develop an evidence-based mini-version of SIPI as the screening tool or solitary use and to evaluate the impact of inheritance mode and model structure on detecting SNP-SNP interactions. Results: We tested two candidate approaches: the 'Five-Full' and 'AA9int' method. The Five-Full approach is composed of the five full interaction models considering three inheritance modes (additive, dominant and recessive). The AA9int approach is composed of nine interaction models by considering non-hierarchical model structure and the additive mode. Our simulation results show that AA9int has similar statistical power compared to SIPI and is superior to the Five-Full approach, and the impact of the non-hierarchical model structure is greater than that of the inheritance mode in detecting SNP-SNP interactions. In summary, it is recommended that AA9int is a powerful tool to be used either alone or as the screening stage of a two-stage approach (AA9int+SIPI) for detecting SNP-SNP interactions in large-scale studies. Availability and implementation: The 'AA9int' and 'parAA9int' functions (standard and parallel computing version) are added in the SIPI R package, which is freely available at https://linhuiyi.github.io/LinHY_Software/. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Polimorfismo de Nucleotídeo Único , Software , Algoritmos , Biologia Computacional , Simulação por Computador , Estatística como Assunto
20.
Epigenetics ; 13(3): 251-263, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29436261

RESUMO

Long noncoding RNAs (lncRNAs) are critical regulators of cell biology whose alteration can lead to the development of diseases such as cancer. The potential role of lncRNAs and their epigenetic regulation in response to platinum treatment are largely unknown. We analyzed four paired cisplatin-sensitive/resistant non-small cell lung cancer and ovarian cancer cell lines. The epigenetic landscape of overlapping and cis-acting lncRNAs was determined by combining human microarray data on 30,586 lncRNAs and 20,109 protein coding mRNAs with whole-genome bisulfite sequencing. Selected candidate lncRNAs were further characterized by PCR, gene-ontology analysis, and targeted bisulfite sequencing. Differential expression in response to therapy was observed more frequently in cis-acting than in overlapping lncRNAs (78% vs. 22%, fold change ≥1.5), while significantly altered methylation profiles were more commonly associated with overlapping lncRNAs (29% vs. 8%; P value <0.001). Moreover, overlapping lncRNAs contain more CpG islands (CGIs) (25% vs. 17%) and the majority of CGI-containing overlapping lncRNAs share these CGIs with their associated coding genes (84%). The differences in expression between sensitive and resistant cell lines were replicated in 87% of the selected candidates (P<0.05), while our bioinformatics approach identifying differential methylation was confirmed in all of the selected lncRNAs (100%). Five lncRNAs under epigenetic regulation appear to be involved in cisplatin resistance (AC091814.2, AC141928.1, RP11-65J3.1-002, BX641110, and AF198444). These novel findings provide new insights into epigenetic mechanisms and acquired resistance to cisplatin that highlight specific lncRNAs, some with unknown function, that may signal strategies in epigenetic therapies.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Epigênese Genética , Neoplasias Ovarianas/tratamento farmacológico , RNA Longo não Codificante/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Cisplatino/farmacologia , Biologia Computacional , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Humanos , Análise em Microsséries , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , RNA Mensageiro/genética , Sequenciamento Completo do Genoma
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