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1.
JAMA Netw Open ; 7(6): e2414582, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38833252

RESUMEN

Importance: Prostate-specific antigen (PSA) screening for prostate cancer is controversial but may be associated with benefit for certain high-risk groups. Objectives: To evaluate associations of county-level PSA screening prevalence with prostate cancer outcomes, as well as variation by sociodemographic and clinical factors. Design, Setting, and Participants: This cohort study used data from cancer registries based in 8 US states on Hispanic, non-Hispanic Black, and non-Hispanic White men aged 40 to 99 years who received a diagnosis of prostate cancer between January 1, 2000, and December 31, 2015. Participants were followed up until death or censored after 10 years or December 31, 2018, whichever end point came first. Data were analyzed between September 2023 and January 2024. Exposure: County-level PSA screening prevalence was estimated using the Behavior Risk Factor Surveillance System survey data from 2004, 2006, 2008, 2010, and 2012 and weighted by population characteristics. Main Outcomes and Measures: Multivariable logistic, Cox proportional hazards regression, and competing risks models were fit to estimate adjusted odds ratios (AOR) and adjusted hazard ratios (AHR) for associations of county-level PSA screening prevalence at diagnosis with advanced stage (regional or distant), as well as all-cause and prostate cancer-specific survival. Results: Of 814 987 men with prostate cancer, the mean (SD) age was 67.3 (9.8) years, 7.8% were Hispanic, 12.2% were non-Hispanic Black, and 80.0% were non-Hispanic White; 17.0% had advanced disease. There were 247 570 deaths over 5 716 703 person-years of follow-up. Men in the highest compared with lowest quintile of county-level PSA screening prevalence at diagnosis had lower odds of advanced vs localized stage (AOR, 0.86; 95% CI, 0.85-0.88), lower all-cause mortality (AHR, 0.86; 95% CI, 0.85-0.87), and lower prostate cancer-specific mortality (AHR, 0.83; 95% CI, 0.81-0.85). Inverse associations between PSA screening prevalence and advanced cancer were strongest among men of Hispanic ethnicity vs other ethnicities (AOR, 0.82; 95% CI, 0.78-0.87), older vs younger men (aged ≥70 years: AOR, 0.77; 95% CI, 0.75-0.79), and those in the Northeast vs other US Census regions (AOR, 0.81; 95% CI, 0.79-0.84). Inverse associations with all-cause mortality were strongest among men of Hispanic ethnicity vs other ethnicities (AHR, 0.82; 95% CI, 0.78-0.85), younger vs older men (AHR, 0.81; 95% CI, 0.77-0.85), those with advanced vs localized disease (AHR, 0.80; 95% CI, 0.78-0.82), and those in the West vs other US Census regions (AHR, 0.89; 95% CI, 0.87-0.90). Conclusions and Relevance: This population-based cohort study of men with prostate cancer suggests that higher county-level prevalence of PSA screening was associated with lower odds of advanced disease, all-cause mortality, and prostate cancer-specific mortality. Associations varied by age, race and ethnicity, and US Census region.


Asunto(s)
Detección Precoz del Cáncer , Antígeno Prostático Específico , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/diagnóstico , Antígeno Prostático Específico/sangre , Anciano , Persona de Mediana Edad , Detección Precoz del Cáncer/estadística & datos numéricos , Detección Precoz del Cáncer/métodos , Estados Unidos/epidemiología , Anciano de 80 o más Años , Adulto , Estudios de Cohortes , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos
2.
Eur Urol Oncol ; 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38734542

RESUMEN

BACKGROUND AND OBJECTIVE: Polygenic risk scores (PRSs) have been developed to identify men with the highest risk of prostate cancer. Our aim was to compare the performance of 16 PRSs in identifying men at risk of developing prostate cancer and then to evaluate the performance of the top-performing PRSs in differentiating individuals at risk of aggressive prostate cancer. METHODS: For this case-control study we downloaded 16 published PRSs from the Polygenic Score Catalog on May 28, 2021 and applied them to Michigan Genomics Initiative (MGI) patients. Cases were matched to the Michigan Urological Surgery Improvement Collaborative (MUSIC) registry to obtain granular clinical and pathological data. MGI prospectively enrolls patients undergoing surgery at the University of Michigan, and MUSIC is a multi-institutional registry that prospectively tracks demographic, treatment, and clinical variables. The predictive performance of each PRS was evaluated using the area under the covariate-adjusted receiver operating characteristic curve (aAUC), and the association between PRS and disease aggressiveness according to prostate biopsy data was measured using logistic regression. KEY FINDINGS AND LIMITATIONS: We included 18 050 patients in the analysis, of whom 15 310 were control subjects and 2740 were prostate cancer cases. The median age was 66.1 yr (interquartile range 59.9-71.6) for cases and 56.6 yr (interquartile range 42.6-66.7) for control subjects. The PRS performance in predicting the risk of developing prostate cancer according to aAUC ranged from 0.51 (95% confidence interval 0.51-0.53) to 0.67 (95% confidence interval 0.66-0.68). By contrast, there was no association between PRS and disease aggressiveness. CONCLUSIONS AND CLINICAL IMPLICATIONS: Prostate cancer PRSs have modest real-world performance in identifying patients at higher risk of developing prostate cancer; however, they are limited in distinguishing patients with indolent versus aggressive disease. PATIENT SUMMARY: Risk scores using data for multiple genes (called polygenic risk scores) can identify men at higher risk of developing prostate cancer. However, these scores need to be refined to be able to identify men with the highest risk for clinically significant prostate cancer.

3.
Nat Commun ; 15(1): 3557, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38670944

RESUMEN

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.


Asunto(s)
Pueblo Asiatico , Neoplasias Colorrectales , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Población Blanca , Humanos , Neoplasias Colorrectales/genética , Pueblo Asiatico/genética , Población Blanca/genética , Secuenciación del Exoma , Estudios de Casos y Controles , Transcriptoma , Mapeo Cromosómico , Masculino , Femenino , Pueblos del Este de Asia
4.
Genome Med ; 16(1): 65, 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38685057

RESUMEN

Using computational tools, bulk transcriptomics can be deconvoluted to estimate the abundance of constituent cell types. However, existing deconvolution methods are conditioned on the assumption that the whole study population is served by a single reference panel, ignoring person-to-person heterogeneity. Here, we present imply, a novel algorithm to deconvolute cell type proportions using personalized reference panels. Simulation studies demonstrate reduced bias compared with existing methods. Real data analyses on longitudinal consortia show disparities in cell type proportions are associated with several disease phenotypes in Type 1 diabetes and Parkinson's disease. imply is available through the R/Bioconductor package ISLET at https://bioconductor.org/packages/ISLET/ .


Asunto(s)
Algoritmos , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/genética , Medicina de Precisión/métodos , Programas Informáticos , Diabetes Mellitus Tipo 1/genética , Perfilación de la Expresión Génica/métodos , Biología Computacional/métodos , Transcriptoma
6.
Int Urogynecol J ; 35(2): 259-271, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37917182

RESUMEN

INTRODUCTION AND HYPOTHESIS: The development of recurrent urinary tract infections (rUTIs) is not completely understood. This review is aimed at investigating the connection between genetics and rUTIs and summarizing the results of studies that have documented variations in gene expression among individuals with rUTIs compared with healthy individuals. METHODS: A systematic search was conducted in Cochrane, Ovid, and PubMed, limiting the results to articles published between 1 January 2000, and 5 July 2022. Only studies comparing the difference in gene expression between individuals with rUTI and healthy individuals utilizing molecular techniques to measure gene expression in blood or urine samples were included in this systematic review. Gene network and pathways analyses were performed using Cytoscape software, with input data obtained from our systematic review of differentially expressed genes in rUTIs. RESULTS: Six studies met our criteria for inclusion. The selected studies used molecular biology methods to quantify gene expression data from blood specimens. The analysis revealed that gene expressions of CXCR1 and TLR4 decreased, whereas CXCR2, TRIF, and SIGIRR increased in patients with rUTI compared with healthy controls. The analysis demonstrated that the most significant pathways were associated with TLR receptor signaling and tolerance, I-kappa B kinase/NF-kappa B signaling, and MyD88-independent TLR signaling. CONCLUSIONS: This systematic review uncovered gene expression variations in several candidate genes and identified a number of underlying biological pathways associated with rUTIs. These findings could shift the treatment and prevention strategies for rUTIs.


Asunto(s)
Redes Reguladoras de Genes , Transducción de Señal , Humanos
7.
Nat Commun ; 14(1): 6147, 2023 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-37783704

RESUMEN

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.


Asunto(s)
Neoplasias Colorrectales , Etnicidad , Humanos , Etnicidad/genética , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Herencia Multifactorial , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética
8.
bioRxiv ; 2023 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-37808714

RESUMEN

Real-world clinical samples are often admixtures of signal mosaics from multiple pure cell types. Using computational tools, bulk transcriptomics can be deconvoluted to solve for the abundance of constituent cell types. However, existing deconvolution methods are conditioned on the assumption that the whole study population is served by a single reference panel, which ignores person-to-person heterogeneity. Here we present imply, a novel algorithm to deconvolute cell type proportions using personalized reference panels. imply can borrow information across repeatedly measured samples for each subject, and obtain precise cell type proportion estimations. Simulation studies demonstrate reduced bias in cell type abundance estimation compared with existing methods. Real data analyses on large longitudinal consortia show more realistic deconvolution results that align with biological facts. Our results suggest that disparities in cell type proportions are associated with several disease phenotypes in type 1 diabetes and Parkinson's disease. Our proposed tool imply is available through the R/Bioconductor package ISLET at https://bioconductor.org/packages/ISLET/.

9.
Urolithiasis ; 51(1): 101, 2023 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-37561200

RESUMEN

BACKGROUND: Cystine stone is a Mendelian genetic disease caused by SLC3A1 or SLC7A9. In this study, we aimed to estimate the genetic prevalence of cystine stones and compare it with the clinical prevalence to better understand the disease etiology. METHODS: We analyzed genetic variants in the general population using the 1000 Genomes project and the Human Gene Mutation Database to extract all SLC3A1 and SLC7A9 pathogenic variants. All variants procured from both databases were intersected. Pathogenic allele frequency, carrier rate, and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium. RESULTS: We found that 9 unique SLC3A1 pathogenic variants were carried by 26 people and 5 unique SLC7A9 pathogenic variants were carried by 12 people, all of whom were heterozygote carriers. No homozygote, compoun d heterozygote, or double heterozygote was identified in the 1000 Genome database. Based on the Hardy-Weinberg equilibrium, the calculated genetic prevalence of cystine stone disease is 1 in 30,585. CONCLUSION: The clinical prevalence of cystine stone has been previously reported as 1 in 7,000, a notably higher figure than the genetic prevalence of 1 in 30,585 calculated in this study. This suggests that the etiology of cystine stone is more complex than what our current genetic knowledge can explain. Possible factors that may contribute to this difference include novel causal genes, undiscovered pathogenic variants, alternative inheritance models, founder effects, epigenetic modifications, environmental factors, or other modifying factors. Further investigation is needed to fully understand the etiology of cystine stone.


Asunto(s)
Sistemas de Transporte de Aminoácidos Básicos , Cistina , Cistinuria , Humanos , Sistemas de Transporte de Aminoácidos Básicos/genética , Cistina/metabolismo , Cistinuria/genética , Frecuencia de los Genes , Genética de Población , Mutación
10.
Artículo en Inglés | MEDLINE | ID: mdl-37355486

RESUMEN

BACKGROUND: Racial/ethnic disparities in metastatic colorectal cancer (mCRC) survival are well documented as is the impact that tumor mutation of KRAS and BRAF has on prognosis. It has been suggested that frequency differences of KRAS- and BRAF-mutated tumors may partially explain this disparity. Demographic differences in mutation frequency are not well established nor whether mutation and microsatellite instability (MSI) differentially impact survival among groups. METHODS: Using data for 11,117 patients diagnosed with de-novo mCRC from an electronic health record-derived database we estimated adjusted odds ratios (aOR) to characterize the association between demographics and MSI and KRAS/NRAS/BRAF-mutation status. Stratified Cox models were used to identify differences in overall survival (OS), adjusting for treatment and demographics. RESULTS: Being female, compared to male, (aORKRAS:1.33 (1.23-1.44); aORBRAF:1.84 (1.56-2.16)), and non-Hispanic Black race (NHB), compared to non-Hispanic White (NHW) (aORKRAS:1.62 (1.42-1.85); aORBRAF: 0.55 (0.38-0.77)) were associated with KRAS- or BRAF-mutant tumors. MSI prevalence was similar across race/ethnicity but higher in women. BRAF-mutant tumors were associated with poorer prognosis overall, especially among non-white patients. Among patients who had KRAS/NRAS/BRAF-WT tumors we observed no difference in OS by race or MSI. Among patients with KRAS-mutant tumors, Hispanic patients had more favorable prognosis adjusted hazards ratio (aHR) = 0.76 (0.65-0.89)) than their NHW counterparts. Among those with BRAF-mutant tumors, NHB patients had poorer prognosis than NHW patients (aHR:1.78 (1.08-2.93)). CONCLUSION: MSI and frequency of KRAS and BRAF mutations differed by demographics. Racial/ethnic disparities in OS differed by mutation. Future studies should explore biological and/or social determinants underlying these differences.

11.
Prostate ; 83(13): 1263-1269, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37301735

RESUMEN

BACKGROUND: Differences in DNA alterations in prostate cancer among White, Black, and Asian men have been widely described. This is the first description of the frequency of DNA alterations in primary and metastatic prostate cancer samples of self-reported Hispanic men. METHODS: We utilized targeted next-generation sequencing tumor genomic profiles from prostate cancer tissues that underwent clinical sequencing at academic centers (GENIE 11th). We decided to restrict our analysis to the samples from Memorial Sloan Kettering Cancer Center as it was by far the main contributor of Hispanic samples. The numbers of men by self-reported ethnicity and racial categories were analyzed via Fisher's exact test between Hispanic-White versus non-Hispanic White. RESULTS AND LIMITATIONS: Our cohort consisted of 1412 primary and 818 metastatic adenocarcinomas. In primary adenocarcinomas, TMPRSS2 and ERG gene alterations were less common in non-Hispanic White men than Hispanic White (31.86% vs. 51.28%, p = 0.0007, odds ratio [OR] = 0.44 [0.27-0.72] and 25.34% vs. 42.31%, p = 0.002, OR = 0.46 [0.28-0.76]). In metastatic tumors, KRAS and CCNE1 alterations were less prevalent in non-Hispanic White men (1.03% vs. 7.50%, p = 0.014, OR = 0.13 [0.03, 0.78] and 1.29% vs. 10.00%, p = 0.003, OR = 0.12 [0.03, 0.54]). No significant differences were found in actionable alterations and androgen receptor mutations between the groups. Due to the lack of clinical characteristics and genetic ancestry in this dataset, correlation with these could not be explored. CONCLUSION: DNA alteration frequencies in primary and metastatic prostate cancer tumors differ among Hispanic-White and non-Hispanic White men. Notably, we found no significant differences in the prevalence of actionable genetic alterations between the groups, suggesting that a significant number of Hispanic men could benefit from the development of targeted therapies.


Asunto(s)
Adenocarcinoma , Neoplasias de la Próstata , Humanos , Masculino , Adenocarcinoma/genética , ADN , Mutación , Neoplasias de la Próstata/genética , Hispánicos o Latinos , Blanco
12.
Cancer Causes Control ; 34(6): 521-531, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36882598

RESUMEN

PURPOSE: Previous literature shows that more bladder cancer patients overall die from causes other than the primary malignancy. Given known disparities in bladder cancer outcomes by race and sex, we aimed to characterize differences in cause-specific mortality for bladder cancer patients by these demographics. METHODS: We identified 215,252 bladder cancer patients diagnosed with bladder cancer from 2000 to 2017 in the SEER 18 database. We calculated cumulative incidence of death from seven causes (bladder cancer, COPD, diabetes, heart disease, external, other cancer, other) to assess differences in cause-specific mortality between race and sex subgroups. We used multivariable Cox proportional hazards regression and Fine-Gray competing risk models to compare risk of bladder cancer-specific mortality between race and sex subgroups overall and stratified by cancer stage. RESULTS: 17% of patients died from bladder cancer (n = 36,923), 30% died from other causes (n = 65,076), and 53% were alive (n = 113,253). Among those who died, the most common cause of death was bladder cancer, followed by other cancer and diseases of the heart. All race-sex subgroups were more likely than white men to die from bladder cancer. Compared to white men, white women (HR: 1.20, 95% CI: 1.17-1.23) and Black women (HR: 1.57, 95% CI: 1.49-1.66) had a higher risk of dying from bladder cancer, overall and stratified by stage. CONCLUSION: Among bladder cancer patients, death from other causes especially other cancer and heart disease contributed a large proportion of mortality. We found differences in cause-specific mortality by race-sex subgroups, with Black women having a particularly high risk of dying from bladder cancer.


Asunto(s)
Cardiopatías , Neoplasias de la Vejiga Urinaria , Masculino , Humanos , Femenino , Estados Unidos/epidemiología , Causas de Muerte , Modelos de Riesgos Proporcionales , Programa de VERF , Neoplasias de la Vejiga Urinaria/epidemiología
13.
medRxiv ; 2023 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-36789420

RESUMEN

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

14.
JAMA Netw Open ; 6(1): e2250030, 2023 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-36656585

RESUMEN

Importance: Professional society guidelines recommend treating patients with metastatic colorectal cancer with targeted therapies, including epithelial growth factor receptor (EGFR) inhibitors and vascular endothelial growth factor (VEGF) inhibitors, depending on the presence or absence of certain mutations. Since most studies of first-line targeted therapies have been limited by sample size, there is a need for larger studies using data from routine clinical care. Objectives: To identify factors associated with receipt of first-line targeted therapies among patients with metastatic colorectal cancer for whom RAS or BRAF mutation data in the tumor were available and investigate whether targeted therapy is associated with survival. Design, Setting, and Participants: This cohort study used deidentified data from an electronic health record-derived database to include patients from 800 sites of patient care across the US who were diagnosed with de novo metastatic colorectal cancer between January 1, 2013, and March 31, 2020 (n = 9134). Main Outcomes and Measures: Receipt of first-line targeted therapy, categorized as ever having received EGFR inhibitors, VEGF inhibitors, or neither. The secondary outcome was overall survival. Results: The study population included 9134 patients. The median age at diagnosis was 62 years (IQR, 53-71 years), 5019 (54.9%) were male, and 5692 (62.3%) were White. The median follow-up period was 15 months. Overall, 713 patients (7.8%) received EGFR inhibitors and 5081 patients (55.6%) received VEGF inhibitors as part of their first-line treatment. Among patients with RAS wild-type (RAS-WT) tumors, 625 patients (15.5%) received EGFR inhibitors and 2053 patients (50.9%) received VEGF inhibitors. In patients with RAS mutant (RAS-Mut) tumors, 50 patients (1.1%) received EGFR inhibitors and 2682 patients (59.7%) received VEGF inhibitors; among those with BRAF-mutant (BRAF-Mut) tumors, 38 patients (6.3%) received EGFR inhibitors and 346 patients (57.2%) received VEGF inhibitors. More than one-third of the patients (36.6%) received neither EGFR inhibitors nor VEGF inhibitors. Compared with patients younger than age 40 years, those aged 80 years or older had significantly lower odds to receive targeted therapies (EGFR or VEGF inhibitors in patients with RAS-WT tumors: adjusted odds ratio [aOR], 0.53; 95% CI, 0.36-0.79; and VEGF inhibitors in patients with RAS-Mut tumors: aOR, 0.62; 95% CI, 0.42-0.90). Improved survival was associated with EGFR inhibitor therapy in patients with RAS-WT tumors (adjusted hazard ratio [aHR], 0.85; 95% CI, 0.74-0.98). Unlike in clinical trials, however, no survival benefit was noted with use of VEGF inhibitors among patients with RAS-WT (aHR, 1.00; 95% CI, 0.91-1.11) or RAS-Mut (aHR, 1.01; 95% CI, 0.93-1.10) tumors. Conclusions and Relevance: The findings of this study showed mixed results on survival benefits associated with targeted therapy. In addition, given that some of the results differed from those of randomized clinical trials, this study highlights the importance of using data originating from routine clinical care.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Anticuerpos Monoclonales/uso terapéutico , Factor A de Crecimiento Endotelial Vascular , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/uso terapéutico , Estudios de Cohortes , Receptores ErbB/genética , Neoplasias del Colon/tratamiento farmacológico
15.
Cancer Med ; 12(2): 1850-1859, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35837788

RESUMEN

BACKGROUND: Standard clinical practice and national guidelines dictate somatic testing of metastatic colorectal cancer (mCRC) tumors to guide appropriate therapy; however, previous studies suggest that not all patients are tested. The objective of this study was to investigate potential differences in testing for mCRC by demographic and clinical factors. METHODS: We performed a retrospective review of de-identified patient data derived from electronic health records (EHRs) of 25,469 patients diagnosed with mCRC between the years 2013 and 2020. Our outcome was a receipt of the following tests: (a) biomarker testing (BRAF, KRAS, NRAS, MMR/MSI) and (b) next-generation sequencing (NGS). We interrogated our data using the machine-learning algorithm Classification and Regression Tree (CART), a unique approach to identifying combinations of, rather than individual demographic and clinical characteristics associated with receipt of testing. RESULTS: A total of 25,469 patients were identified with mCRC. Of these, 21,133 (83%) received either biomarker testing only (n = 12,485) or any testing (biomarker + NGS) (n = 8648). The proportion of patients who received any testing increased over calendar time for all age, race, and sex categories. Receipt of any testing was highest (90%) among younger and patients with better performance status, and there was no difference in receipt of any testing by race. The highest percentage of NGS testing was among those with better performance status, <70 years old, commercial or other governmental program payers, and low comorbidity burden; however, those who were Black or Hispanic had a lower prevalence of NGS testing than those who were White. CONCLUSIONS AND RELEVANCE: Considerable variations exist in somatic biomarker testing across subgroups of the population. Identification of genomic alterations can aid in determining targeted treatment and improving clinical outcomes; therefore, equitable use of these testing strategies, particularly NGS, is necessary.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Anciano , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Biomarcadores
16.
Am J Obstet Gynecol ; 228(1): 36-47.e3, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35932882

RESUMEN

OBJECTIVE: The contribution of genetic factors to the presence of an overactive bladder is recognized. This study aimed to (1) assemble and synthesize available data from studies assessing differential gene expression in patients with overactive bladder vs controls without overactive bladder and (2) determine possible correlations and functional pathways between genes. DATA SOURCES: We searched PubMed, Ovid or Medline, and Wiley Cochrane Central Register of Controlled Trials databases between January 1, 2000, and December 15, 2021. STUDY ELIGIBILITY CRITERIA: Studies were included if gene expression was detected and quantified using molecular approaches performed on human bladder tissue specimens directly and excluded if the gene expression analysis was carried out from blood and urine specimens alone. METHODS: A systematic review was completed to identify publications that reported differently expressed gene candidates among patients with overactive bladder vs healthy individuals. Gene networking connections and pathway analysis were performed employing Metascape software, where inputs were identified from our systematic review of differentially expressed genes in overactive bladder. RESULTS: A total of 9 studies were included in the final analysis and 11 genes were identified as being up-regulated (purinergic receptor P2X 2 [P2RX2], smoothelin [SMTN], growth-associated protein 43 [GAP43], transient receptor potential cation channel subfamily M member 8 [TRPM8], cadherin 11 [CDH1], gap junction protein gamma 1 [GJC1], cholinergic receptor muscarinic 2 [CHRM2], cholinergic receptor muscarinic 3 [CHRM3], and transient receptor potential cation channel subfamily V member 4 [TRPV4]) or down-regulated (purinergic receptor P2X 2 [P2RX3] and purinergic receptor P2X 5 [P2RX5]) in patients with overactive bladder. Gene network analysis showed that genes are involved in chemical synaptic transmission, smooth muscle contraction, blood circulation, and response to temperature stimulus. Network analysis demonstrated a significant genetic interaction between TRPV4, TRPM8, P2RX3, and PR2X2 genes. CONCLUSION: Outcomes of this systematic review highlighted potential biomarkers for treatment efficacy and have laid the groundwork for developing future gene therapies for overactive bladder in clinical settings.


Asunto(s)
Vejiga Urinaria Hiperactiva , Humanos , Vejiga Urinaria Hiperactiva/terapia , Canales Catiónicos TRPV/uso terapéutico , Marcadores Genéticos , Antagonistas Colinérgicos/uso terapéutico , Receptores Colinérgicos/uso terapéutico , Receptores Purinérgicos/uso terapéutico , Receptor Muscarínico M3/uso terapéutico
17.
Hum Mol Genet ; 32(10): 1589-1606, 2023 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-36519762

RESUMEN

Autism spectrum disorders (ASD) display both phenotypic and genetic heterogeneity, impeding the understanding of ASD and development of effective means of diagnosis and potential treatments. Genes affected by genomic variations for ASD converge in dozens of gene ontologies (GOs), but the relationship between the variations at the GO level have not been well elucidated. In the current study, multiple types of genomic variations were mapped to GOs and correlations among GOs were measured in ASD and control samples. Several ASD-unique GO correlations were found, suggesting the importance of co-occurrence of genomic variations in genes from different functional categories in ASD etiology. Combined with experimental data, several variations related to WNT signaling, neuron development, synapse morphology/function and organ morphogenesis were found to be important for ASD with macrocephaly, and novel co-occurrence patterns of them in ASD patients were found. Furthermore, we applied this gene ontology correlation analysis method to find genomic variations that contribute to ASD etiology in combination with changes in gene expression and transcription factor binding, providing novel insights into ASD with macrocephaly and a new methodology for the analysis of genomic variation.


Asunto(s)
Trastorno del Espectro Autista , Megalencefalia , Humanos , Trastorno del Espectro Autista/genética , Genómica , Megalencefalia/genética
18.
Nat Rev Urol ; 19(9): 547-561, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35945369

RESUMEN

In the past 20 years, new insights into the genomic pathogenesis of prostate cancer have been provided. Large-scale integrative genomics approaches enabled researchers to characterize the genetic and epigenetic landscape of prostate cancer and to define different molecular subclasses based on the combination of genetic alterations, gene expression patterns and methylation profiles. Several molecular drivers of prostate cancer have been identified, some of which are different in men of different races. However, the extent to which genomics can explain racial disparities in prostate cancer outcomes is unclear. Future collaborative genomic studies overcoming the underrepresentation of non-white patients and other minority populations are essential.


Asunto(s)
Neoplasias de la Próstata , Epigenómica , Genómica , Humanos , Masculino , Mutación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología
19.
JNCI Cancer Spectr ; 6(5)2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35947687

RESUMEN

BACKGROUND: The germline variant rs1047303 (HSD3B1[1245A/C]), restricting or enabling production of potent androgens and estrogens from adrenal precursors, affects outcomes of castration-resistant prostate cancer and is associated with estrogen receptor positivity in postmenopausal breast cancer. Like breast cancer, endometrial cancer is another malignancy with hormone-dependent and hormone-independent subtypes. We hypothesized that adrenal-restrictive HSD3B1 genotype would associate with hormone-independent cancer subtypes. METHODS: We employed a previously described classification of tumors in The Cancer Genome Atlas into genomic clusters. We determined HSD3B1 genotype frequencies by endometrial cancer genomic cluster and calculated the odds per adrenal-restrictive A allele for the largely hormone-independent copy-number (CN) high subtype vs other subtypes. An equivalent analysis was performed for the genomically similar, hormone-independent basal breast cancer subtype. Last, we performed survival analyses for UK Biobank participants with endometrial cancer by HSD3B1 genotype. All statistical tests were 2-sided. RESULTS: The adrenal-restrictive HSD3B1(1245A) allele was associated with the CN-high endometrial cancer subtype (odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.14 to 2.32; P = .007). Similarly, HSD3B1(1245A) was associated with the basal breast cancer subtype (OR = 1.54, 95% CI = 1.13 to 2.08; P = .006). In the UK Biobank, endometrial cancer patients homozygous for HSD3B1(1245A) had worse overall (hazard ratio [HR] = 1.39, 95% CI = 1.16 to 1.68; P < .001) and cancer-specific (HR = 1.39, 95% CI = 1.14 to 1.70; P = .001) survival, consistent with the A allele being enriched in the more aggressive CN-high subtype. CONCLUSIONS: These findings suggest roles for adrenal-restrictive vs adrenal-permissive steroidogenesis, by way of rs1047303 genotype, in the development of and/or outcomes from at least 3 commonly hormone-associated types of cancer: prostate, breast, and endometrial.


Asunto(s)
Neoplasias de la Mama , Neoplasias Endometriales , Complejos Multienzimáticos , Progesterona Reductasa , Esteroide Isomerasas , Antagonistas de Andrógenos , Andrógenos , Neoplasias de la Mama/genética , Neoplasias Endometriales/genética , Femenino , Humanos , Complejos Multienzimáticos/genética , Progesterona Reductasa/genética , Esteroide Isomerasas/genética
20.
J Biomed Mater Res B Appl Biomater ; 110(12): 2676-2685, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35779040

RESUMEN

Stress urinary incontinence (SUI) impacts ~1/3 of women over age 50. Negative publicity around PP meshes used in pelvic prolapse repair drives the need for identifying alternative biomaterials for SUI repair. Our study evaluated in vivo response to collagen sling implanted in an ovine model. Electrocompacted collagen threads were filament wound as slings and crosslinked in genipin. Collagen slings were implanted suburethrally mimicking the transvaginal tape technique. Main study groups were: Collagen sling (n = 3, 6 months) and PP sling (n = 3, 6 months). Collagen sling was also tested at 3-weeks (n = 1) to observe early-stage tissue response and 1-year (n = 2) to assess biomaterial longevity in a preliminary capacity. Collagen slings healed to a fibrous ligament texture at 6 months and maintained such texture to 1 year. Histological scoring indicated biocompatible responses to collagen slings with no adverse events. All study groups exhibited complete tissue ingrowth and interstitial de novo collagen deposition at all time points. Collagen threads induced orderly de novo collagen deposition that was aligned along long axes of threads. Tissue infiltrated collagen slings that were explanted at 6 and 12 months presented similar structural strength with native tissues such as vagina and fascia, and PP (Lynx) slings (p > .05). With the limitation of low number of animals per time point in hindsight, this preliminary study justifies evaluation of collagen slings in a larger sample size of animals, particularly to assess persistence of ligamentous tissue response over longer durations than 1-year.


Asunto(s)
Cabestrillo Suburetral , Incontinencia Urinaria de Esfuerzo , Animales , Materiales Biocompatibles , Colágeno/química , Colágeno/farmacología , Femenino , Ovinos , Cabestrillo Suburetral/efectos adversos , Vagina
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