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BACKGROUND: While the association of chronological age with DNA methylation (DNAm) in whole blood has been extensively studied, the tissue-specificity of age-related DNAm changes remains an active area of research. Studies investigating the association of age with DNAm in tissues such as brain, skin, immune cells, fat, and liver have identified tissue-specific and non-specific effects, thus, motivating additional studies of diverse human tissue and cell types. RESULTS: Here, we performed an epigenome-wide association study, leveraging DNAm data (Illumina EPIC array) from 961 tissue samples representing 9 tissue types (breast, lung, colon, ovary, prostate, skeletal muscle, testis, whole blood, and kidney) from the Genotype-Tissue Expression (GTEx) project. We identified age-associated CpG sites (false discovery rate < 0.05) in 8 tissues (all except skeletal muscle, n = 47). This included 162,002 unique hypermethylated and 90,626 hypomethylated CpG sites across all tissue types, with 130,137 (80%) hypermethylated CpGs and 74,703 (82%) hypomethylated CpG sites observed in a single tissue type. While the majority of age-associated CpG sites appeared tissue-specific, the patterns of enrichment among genomic features, such as chromatin states and CpG islands, were similar across most tissues, suggesting common mechanisms underlying cellular aging. Consistent with previous findings, we observed that hypermethylated CpG sites are enriched in regions with repressed polycomb signatures and CpG islands, while hypomethylated CpG sites preferentially occurred in non-CpG islands and enhancers. To gain insights into the functional effects of age-related DNAm changes, we assessed the correlation between DNAm and local gene expression changes to identify age-related expression quantitative trait methylation (age-eQTMs). We identified several age-eQTMs present in multiple tissue-types, including in the CDKN2A, HENMT1, and VCWE regions. CONCLUSION: Overall, our findings will aid future efforts to develop biomarkers of aging and understand mechanisms of aging in diverse human tissue types.
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Envelhecimento , Ilhas de CpG , Metilação de DNA , Especificidade de Órgãos , Humanos , Envelhecimento/genética , Feminino , Masculino , Adulto , Estudo de Associação Genômica Ampla , Pessoa de Meia-Idade , Idoso , Epigênese Genética , EpigenomaRESUMO
RNA-Seq data analysis stands as a vital part of genomics research, turning vast and complex datasets into meaningful biological insights. It is a field marked by rapid evolution and ongoing innovation, necessitating a thorough understanding for anyone seeking to unlock the potential of RNA-Seq data. In this chapter, we describe the intricate landscape of RNA-seq data analysis, elucidating a comprehensive pipeline that navigates through the entirety of this complex process. Beginning with quality control, the chapter underscores the paramount importance of ensuring the integrity of RNA-seq data, as it lays the groundwork for subsequent analyses. Preprocessing is then addressed, where the raw sequence data undergoes necessary modifications and enhancements, setting the stage for the alignment phase. This phase involves mapping the processed sequences to a reference genome, a step pivotal for decoding the origins and functions of these sequences.Venturing into the heart of RNA-seq analysis, the chapter then explores differential expression analysis-the process of identifying genes that exhibit varying expression levels across different conditions or sample groups. Recognizing the biological context of these differentially expressed genes is pivotal; hence, the chapter transitions into functional analysis. Here, methods and tools like Gene Ontology and pathway analyses help contextualize the roles and interactions of the identified genes within broader biological frameworks. However, the chapter does not stop at conventional analysis methods. Embracing the evolving paradigms of data science, it delves into machine learning applications for RNA-seq data, introducing advanced techniques in dimension reduction and both unsupervised and supervised learning. These approaches allow for patterns and relationships to be discerned in the data that might be imperceptible through traditional methods.
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Biologia Computacional , RNA-Seq , Software , RNA-Seq/métodos , Humanos , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Genômica/métodos , Análise de Dados , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodosRESUMO
Cell-free DNA (cfDNA) fragmentation pattern represents a promising non-invasive biomarker for disease diagnosis and prognosis. Numerous fragmentation features, such as end motif and window protection score (WPS), have been characterized in cfDNA genomic sequencing. However, the analytical tools developed in these studies are often not released to the liquid biopsy community or are inefficient for genome-wide analysis in large datasets. To address this gap, we have developed FinaleToolkit, a fast and memory efficient Python package designed to generate comprehensive fragmentation features from large cfDNA genomic sequencing data. For instance, FinaleToolkit can generate genome-wide WPS features from a ~100X cfDNA whole-genome sequencing (WGS) dataset in 1.2 hours using 16 CPU cores, offering up to a ~50-fold increase in processing speed compared to original implementations in the same dataset. We have benchmarked FinaleToolkit against original studies or implementations where possible, confirming its efficacy. Furthermore, FinaleToolkit enabled the genome-wide analysis of fragmentation patterns over arbitrary genomic intervals, significantly boosting the performance for cancer early detection. FinaleToolkit is open source and thoroughly documented with both command line interface and Python application programming interface (API) to facilitate its widespread adoption and use within the research community: https://github.com/epifluidlab/FinaleToolkit.
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Introduction: Maximal grip strength, a measure of how much force a person's hand can generate when squeezing an object, may be an effective method for understanding potential neurobiological differences during motor tasks. Grip strength in autistic individuals may be of particular interest due to its unique developmental trajectory. While autism-specific differences in grip-brain relationships have been found in adult populations, it is possible that such differences in grip-brain relationships may be present at earlier ages when grip strength is behaviorally similar in autistic and non-autistic groups. Further, such neural differences may lead to the later emergence of diagnostic-group grip differences in adolescence. The present study sought to examine this possibility, while also examining if grip strength could elucidate the neuro-motor sources of phenotypic heterogeneity commonly observed within autism. Methods: Using high resolution, multi-shell diffusion, and quantitative R1 relaxometry imaging, this study examined how variations in key sensorimotor-related white matter pathways of the proprioception input, lateral grasping, cortico-cerebellar, and corticospinal networks were associated with individual variations in grip strength in 68 autistic children and 70 non-autistic (neurotypical) children (6-11 years-old). Results: In both groups, results indicated that stronger grip strength was associated with higher proprioceptive input, lateral grasping, and corticospinal (but not cortico-cerebellar modification) fractional anisotropy and R1, indirect measures concordant with stronger microstructural coherence and increased myelination. Diagnostic group differences in these grip-brain relationships were not observed, but the autistic group exhibited more variability particularly in the cortico-cerebellar modification indices. An examination into the variability within the autistic group revealed that attention-deficit/hyperactivity disorder (ADHD) features moderated the relationships between grip strength and both fractional anisotropy and R1 relaxometry in the premotor-primary motor tract of the lateral grasping network and the cortico-cerebellar network tracts. Specifically, in autistic children with elevated ADHD features (60% of the autistic group) stronger grip strength was related to higher fractional anisotropy and R1 of the cerebellar modification network (stronger microstructural coherence and more myelin), whereas the opposite relationship was observed in autistic children with reduced ADHD features. Discussion: Together, this work suggests that while the foundational elements of grip strength are similar across school-aged autistic and non-autistic children, neural mechanisms of grip strength within autistic children may additionally depend on the presence of ADHD features. Specifically, stronger, more coherent connections of the cerebellar modification network, which is thought to play a role in refining and optimizing motor commands, may lead to stronger grip in children with more ADHD features, weaker grip in children with fewer ADHD features, and no difference in grip in non-autistic children. While future research is needed to understand if these findings extend to other motor tasks beyond grip strength, these results have implications for understanding the biological basis of neuromotor control in autistic children and emphasize the importance of assessing co-occurring conditions when evaluating brain-behavior relationships in autism.
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BACKGROUND: Computer-aided diagnosis (CADx) allows prediction of polyp histology during colonoscopy, which may reduce unnecessary removal of nonneoplastic polyps. However, the potential benefits and harms of CADx are still unclear. PURPOSE: To quantify the benefit and harm of using CADx in colonoscopy for the optical diagnosis of small (≤5-mm) rectosigmoid polyps. DATA SOURCES: Medline, Embase, and Scopus were searched for articles published before 22 December 2023. STUDY SELECTION: Histologically verified diagnostic accuracy studies that evaluated the real-time performance of physicians in predicting neoplastic change of small rectosigmoid polyps without or with CADx assistance during colonoscopy. DATA EXTRACTION: The clinical benefit and harm were estimated on the basis of accuracy values of the endoscopist before and after CADx assistance. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The outcome measure for benefit was the proportion of polyps predicted to be nonneoplastic that would avoid removal with the use of CADx. The outcome measure for harm was the proportion of neoplastic polyps that would be not resected and left in situ due to an incorrect diagnosis with the use of CADx. Histology served as the reference standard for both outcomes. DATA SYNTHESIS: Ten studies, including 3620 patients with 4103 small rectosigmoid polyps, were analyzed. The studies that assessed the performance of CADx alone (9 studies; 3237 polyps) showed a sensitivity of 87.3% (95% CI, 79.2% to 92.5%) and specificity of 88.9% (CI, 81.7% to 93.5%) in predicting neoplastic change. In the studies that compared histology prediction performance before versus after CADx assistance (4 studies; 2503 polyps), there was no difference in the proportion of polyps predicted to be nonneoplastic that would avoid removal (55.4% vs. 58.4%; risk ratio [RR], 1.06 [CI, 0.96 to 1.17]; moderate-certainty evidence) or in the proportion of neoplastic polyps that would be erroneously left in situ (8.2% vs. 7.5%; RR, 0.95 [CI, 0.69 to 1.33]; moderate-certainty evidence). LIMITATION: The application of optical diagnosis was only simulated, potentially altering the decision-making process of the operator. CONCLUSION: Computer-aided diagnosis provided no incremental benefit or harm in the management of small rectosigmoid polyps during colonoscopy. PRIMARY FUNDING SOURCE: European Commission. (PROSPERO: CRD42023402197).
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Pólipos do Colo , Colonoscopia , Diagnóstico por Computador , Humanos , Pólipos do Colo/patologia , Pólipos do Colo/diagnóstico por imagem , Neoplasias Colorretais/patologia , Neoplasias Colorretais/diagnósticoRESUMO
Importance: Declining treatment negatively affects health outcomes among patients with cancer. Limited research has investigated national trends of and factors associated with treatment declination or its association with overall survival (OS) among patients with breast cancer. Objectives: To examine trends and racial and ethnic disparities in treatment declination and racial and ethnic OS differences stratified by treatment decision in US patients with breast cancer. Design, Setting, and Participants: This retrospective cross-sectional study used data for patients with breast cancer from the 2004 to 2020 National Cancer Database. Four treatment modalities were assessed: chemotherapy, hormone therapy (HT), radiotherapy, and surgery. The chemotherapy cohort included patients with stage I to IV disease. The HT cohort included patients with stage I to IV hormone receptor-positive disease. The radiotherapy and surgery cohorts included patients with stage I to III disease. Data were analyzed from March to November 2023. Exposure: Race and ethnicity and other sociodemographic and clinicopathologic characteristics. Main Outcomes and Measures: Treatment decision, categorized as received or declined, was modeled using logistic regression. OS was modeled using Cox regression. Models were controlled for year of initial diagnosis, age, sex, health insurance, median household income, facility type, Charlson-Deyo comorbidity score, histology, American Joint Committee on Cancer stage, molecular subtype, and tumor grade. Results: The study included 2â¯837â¯446 patients (mean [SD] age, 61.6 [13.4] years; 99.1% female), with 1.7% American Indian, Alaska Native, or other patients; 3.5% Asian or Pacific Islander patients; 11.2% Black patients; 5.6% Hispanic patients; and 78.0% White patients. Of 1â¯296â¯488 patients who were offered chemotherapy, 124â¯721 (9.6%) declined; 99â¯276 of 1â¯635â¯916 patients (6.1%) declined radiotherapy; 94â¯363 of 1â¯893â¯339 patients (5.0%) declined HT; and 15â¯846 of 2â¯590â¯963 patients (0.6%) declined surgery. Compared with White patients, American Indian, Alaska Native, or other patients (adjusted odds ratio [AOR], 1.47; 95% CI, 1.26-1.72), Asian or Pacific Islander patients (AOR, 1.29; 95% CI, 1.15-1.44), and Black patients (AOR, 2.01; 95% CI, 1.89-2.14) were more likely to decline surgery; American Indian, Alaska Native, or other patients (AOR, 1.13; 95% CI, 1.05-1.21) and Asian or Pacific Islander patients (AOR, 1.21; 95% CI, 1.16-1.27) were more likely to decline chemotherapy; and Black patients were more likely to decline radiotherapy (AOR, 1.05; 95% CI, 1.02-1.08). Asian or Pacific Islander patients (AOR, 0.81; 95% CI, 0.77-0.85), Black patients (AOR, 0.86; 95% CI, 0.83-0.89), and Hispanic patients (AOR, 0.66; 95% CI, 0.63-0.69) were less likely to decline HT. Furthermore, Black patients who declined chemotherapy had a higher mortality risk than White patients (adjusted hazard ratio [AHR], 1.07; 95% CI, 1.02-1.13), while there were no OS differences between Black and White patients who declined HT (AHR, 1.05; 95% CI, 0.97-1.13) or radiotherapy (AHR, 0.98; 95% CI, 0.92-1.04). Conclusions and Relevance: This cross-sectional study highlights racial and ethnic disparities in treatment declination and OS, suggesting the need for equity-focused interventions, such as patient education on treatment benefits and improved patient-clinician communication and shared decision-making, to reduce disparities and improve patient survival.
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Neoplasias da Mama , Disparidades em Assistência à Saúde , Humanos , Feminino , Neoplasias da Mama/terapia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/etnologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Estados Unidos/epidemiologia , Estudos Transversais , Idoso , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Adulto , Etnicidade/estatística & dados numéricosRESUMO
Splicing-based transcriptome-wide association studies (splicing-TWASs) of breast cancer have the potential to identify susceptibility genes. However, existing splicing-TWASs test the association of individual excised introns in breast tissue only and thus have limited power to detect susceptibility genes. In this study, we performed a multi-tissue joint splicing-TWAS that integrated splicing-TWAS signals of multiple excised introns in each gene across 11 tissues that are potentially relevant to breast cancer risk. We utilized summary statistics from a meta-analysis that combined genome-wide association study (GWAS) results of 424,650 women of European ancestry. Splicing-level prediction models were trained in GTEx (v.8) data. We identified 240 genes by the multi-tissue joint splicing-TWAS at the Bonferroni-corrected significance level; in the tissue-specific splicing-TWAS that combined TWAS signals of excised introns in genes in breast tissue only, we identified nine additional significant genes. Of these 249 genes, 88 genes in 62 loci have not been reported by previous TWASs, and 17 genes in seven loci are at least 1 Mb away from published GWAS index variants. By comparing the results of our splicing-TWASs with previous gene-expression-based TWASs that used the same summary statistics and expression prediction models trained in the same reference panel, we found that 110 genes in 70 loci that are identified only by the splicing-TWASs. Our results showed that for many genes, expression quantitative trait loci (eQTL) did not show a significant impact on breast cancer risk, whereas splicing quantitative trait loci (sQTL) showed a strong impact through intron excision events.
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Neoplasias da Mama , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Splicing de RNA , Transcriptoma , Humanos , Neoplasias da Mama/genética , Feminino , Splicing de RNA/genética , Íntrons/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Perfilação da Expressão GênicaRESUMO
We performed genome-wide association studies of breast cancer including 18,034 cases and 22,104 controls of African ancestry. Genetic variants at 12 loci were associated with breast cancer risk (P < 5 × 10-8), including associations of a low-frequency missense variant rs61751053 in ARHGEF38 with overall breast cancer (odds ratio (OR) = 1.48) and a common variant rs76664032 at chromosome 2q14.2 with triple-negative breast cancer (TNBC) (OR = 1.30). Approximately 15.4% of cases with TNBC carried six risk alleles in three genome-wide association study-identified TNBC risk variants, with an OR of 4.21 (95% confidence interval = 2.66-7.03) compared with those carrying fewer than two risk alleles. A polygenic risk score (PRS) showed an area under the receiver operating characteristic curve of 0.60 for the prediction of breast cancer risk, which outperformed PRS derived using data from females of European ancestry. Our study markedly increases the population diversity in genetic studies for breast cancer and demonstrates the utility of PRS for risk prediction in females of African ancestry.
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População Negra , Neoplasias da Mama , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Humanos , Feminino , Estudo de Associação Genômica Ampla/métodos , Neoplasias da Mama/genética , População Negra/genética , Estudos de Casos e Controles , Fatores de Risco , Neoplasias de Mama Triplo Negativas/genética , Alelos , Herança Multifatorial/genética , Pessoa de Meia-Idade , Loci Gênicos , População Branca/genéticaRESUMO
PURPOSE: We aimed to update the trend of hypofractionated whole-breast irradiation (HF-WBI) use over time in the US and examine factors associated with lack of HF-WBI adoption for patients with early-stage invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) undergoing a lumpectomy. METHODS AND MATERIALS: Among patients who underwent a lumpectomy, we identified 928,034 patients with early-stage IBC and 330,964 patients with DCIS in the 2004 to 2020 National Cancer Database. We defined HF-WBI as 2.5-3.33 Gy/fraction to the breast and conventionally fractionated WBI as 1.8-2.0 Gy/fraction. We evaluated the trend of HF-WBI utilization using a generalized linear model with the log link and binomial distribution. Factors associated with HF-WBI utilization were assessed using multivariable logistic regression in patients diagnosed between 2018 and 2020. RESULTS: Among patients with IBC, HF-WBI use has significantly increased from 0.7% in 2004 to 63.9% in 2020. Similarly, HF-WBI usage among patients with DCIS has also increased significantly from 0.4% in 2004 to 56.6% in 2020. Black patients with IBC were less likely than White patients to receive HF-WBI (adjusted odds ratio [AOR] 0.81; 95% CI, 0.77-0.85). Community cancer programs were less likely to administer HF-WBI to patients with IBC (AOR, 0.80; 95% CI, 0.77-0.84) and to those with DCIS (AOR, 0.87; 95% CI, 0.79-0.96) than academic/research programs. Younger age, positive nodes, larger tumor size, low volume programs, and facility location were also associated with lack of HF-WBI adoption in both patient cohorts. CONCLUSIONS: HF-WBI utilization among postlumpectomy patients has significantly increased from 2004 to 2020 and can finally be considered standard of care in the US. We found substantial disparities in adoption within patient and facility subgroups. Reducing disparities in HF-WBI adoption has the potential to further alleviate health care costs while improving patients' quality of life.
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The foregut, which includes the esophagus, stomach and duodenum, represents one of the most common sites for neuroendocrine neoplasms. These are highly heterogenous with different risk of progression depending on location, cell-type of origin, size, grade and other factors. Various endoscopic and imaging modalities exist to inform therapeutic decision-making, which may be in the form of surgical or endoscopic resection and medical therapy depending on the extent of the disease after diagnostic evaluation. This narrative review aims to explore the literature on the multimodal management of such foregut neuroendocrine neoplasms.
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Tumores Neuroendócrinos , Neoplasias Gástricas , Trato Gastrointestinal Superior , Humanos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/terapia , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/terapia , AbdomeRESUMO
Attention-deficit/hyperactivity disorder (ADHD) commonly co-occurs in autistic children. However, additional research is needed to explore the differences in motor skills and sensory features in autistic children with and without ADHD, as well as the impacts of these factors on daily living skills (DLS). This observational study sought to fill this gap with 67 autistic children (6.14-10.84 years-old), 43 of whom had ADHD. Autistic children with ADHD demonstrated higher sensory features and lower motor skills than autistic children without ADHD. In examining autism and ADHD features dimensionally, we found that overall sensory features, seeking, and hyporesponsiveness were driven by both autism and ADHD features, whereas motor skills, enhanced perception, and hyperresponsiveness were driven by only autism features. Additionally, in using these dimensional variables of autism and ADHD features, we found that differences in motor skills, sensory and autism features, but not ADHD features, impact DLS of autistic children, with autism features and motor skills being the strongest individual predictors of DLS. Together, these results demonstrate the uniqueness of motor skills and sensory features in autistic children with and without ADHD, as well as how autism features, sensory features, and motor skills contribute to DLS, emphasizing the importance of a comprehensive understanding of each individual and complexities of human development when supporting autistic children.
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BACKGROUND: Although several transcriptome-wide association studies (TWASs) have been performed to identify genes associated with overall breast cancer (BC) risk, only a few TWAS have explored the differences in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer. Additionally, these studies were based on gene expression prediction models trained primarily in breast tissue, and they did not account for alternative splicing of genes. METHODS: In this study, we utilized two approaches to perform multi-tissue TWASs of breast cancer by ER subtype: (1) an expression-based TWAS that combined TWAS signals for each gene across multiple tissues and (2) a splicing-based TWAS that combined TWAS signals of all excised introns for each gene across tissues. To perform this TWAS, we utilized summary statistics for ER + BC from the Breast Cancer Association Consortium (BCAC) and for ER- BC from a meta-analysis of BCAC and the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). RESULTS: In total, we identified 230 genes in 86 loci that were associated with ER + BC and 66 genes in 29 loci that were associated with ER- BC at a Bonferroni threshold of significance. Of these genes, 2 genes associated with ER + BC at the 1q21.1 locus were located at least 1 Mb from published GWAS hits. For several well-studied tumor suppressor genes such as TP53 and CHEK2 which have historically been thought to impact BC risk through rare, penetrant mutations, we discovered that common variants, which modulate gene expression, may additionally contribute to ER + or ER- etiology. CONCLUSIONS: Our study comprehensively examined how differences in common variation contribute to molecular differences between ER + and ER- BC and introduces a novel, splicing-based framework that can be used in future TWAS studies.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Transcriptoma , Predisposição Genética para Doença , Estrogênios , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g., AHRR). To identify smoking-associated DNAm features in typically inaccessible tissues, we generated array-based DNAm data for 916 tissue samples from the GTEx (Genotype-Tissue Expression) project representing 9 tissue types (lung, colon, ovary, prostate, blood, breast, testis, kidney, and muscle). We identified 6,350 smoking-associated CpGs in lung tissue (n = 212) and 2,735 in colon tissue (n = 210), most not reported previously. For all 7 other tissue types (sample sizes 38-153), no clear associations were observed (false discovery rate 0.05), but some tissues showed enrichment for smoking-associated CpGs reported previously. For 1,646 loci (in lung) and 22 (in colon), smoking was associated with both DNAm and local gene expression. For loci detected in both lung and colon (e.g., AHRR, CYP1B1, CYP1A1), top CpGs often differed between tissues, but similar clusters of hyper- or hypomethylated CpGs were observed, with hypomethylation at regulatory elements corresponding to increased expression. For lung tissue, 17 hallmark gene sets were enriched for smoking-associated CpGs, including xenobiotic- and cancer-related gene sets. At least four smoking-associated regions in lung were impacted by lung methylation quantitative trait loci (QTLs) that co-localize with genome-wide association study (GWAS) signals for lung function (FEV1/FVC), suggesting epigenetic alterations can mediate the effects of smoking on lung health. Our multi-tissue approach has identified smoking-associated regions in disease-relevant tissues, including effects that are shared across tissue types.
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Fumar Cigarros , Metilação de DNA , Masculino , Feminino , Humanos , Metilação de DNA/genética , Epigênese Genética , Estudo de Associação Genômica Ampla , Fumar/efeitos adversos , Fumar/genética , Expressão GênicaRESUMO
BACKGROUND: Although genome-wide association studies (GWAS) of breast cancer (BC) identified common variants which differ between intrinsic subtypes, genes through which these variants act to impact BC risk have not been fully established. Transcriptome-wide association studies (TWAS) have identified genes associated with overall BC risk, but subtype-specific differences are largely unknown. METHODS: We performed two multi-tissue TWAS for each BC intrinsic subtype, including an expression-based approach that collated TWAS signals from expression quantitative trait loci (eQTLs) across multiple tissues and a novel splicing-based approach that collated signals from splicing QTLs (sQTLs) across intron clusters and subsequently across tissues. We used summary statistics for five intrinsic subtypes including Luminal A-like, Luminal B-like, Luminal B/HER2-negative-like, HER2-enriched-like, and triple-negative BC, generated from 106â278 BC cases and 91â477 controls in the Breast Cancer Association Consortium. RESULTS: Overall, we identified 235 genes in 88 loci that were associated with at least one of the five intrinsic subtypes. Most genes were subtype-specific, and many have not been reported in previous TWAS. We discovered common variants that modulate expression of CHEK2 confer increased risk to Luminal A-like BC, in contrast to the viewpoint that CHEK2 primarily harbors rare, penetrant mutations. Additionally, our splicing-based TWAS provided population-level support for MDM4 splice variants that increased the risk of triple-negative BC. CONCLUSION: Our comprehensive, multi-tissue TWAS corroborated previous GWAS loci for overall BC risk and intrinsic subtypes, while underscoring how common variation that impacts expression and splicing of genes in multiple tissue types can be used to further elucidate the etiology of BC.
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Neoplasias da Mama , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Transcriptoma , Humanos , Feminino , Neoplasias da Mama/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica , Biomarcadores Tumorais/genéticaRESUMO
Background and Aims: GI stromal tumors (GISTs) represent the most common mesenchymal tumors of the GI tract. Guidelines recommend the removal of histologically proven gastric GISTs >2 cm. While the conventional treatment of a gastric GIST involves surgical excision, endoscopic full-thickness resection (EFTR) has been described as an acceptable alternative. We aim to outline how the key steps used in endoscopic submucosal dissection (ESD) can be adapted to the performance of exposed EFTR and discuss the variations in technical aspects between the 2 procedures. Methods: We use a video case illustration with a comprehensive narrative to highlight the similarities and differences in equipment used and techniques in EFTR and ESD. Images and graphical illustrations are also used to describe these techniques. Results: ESD techniques and equipment can be adapted for use in EFTR of gastric GISTs. Principles such as deep mucosal incision, the appropriate use of traction, and identification of vessels for prophylactic coagulation help to ensure a safe and efficient procedure. The main difference in EFTR is the need for general anesthesia, starting the mucosal incision as close to the tumor margin as possible, submucosal dissection around the surface of the tumor capsule, and a strong closure method for the muscle defect. Conclusions: The equipment and techniques in ESD can be adapted to EFTR for gastric GISTs by endoscopists who are familiar with ESD techniques.
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Racial/ethnic differences in pathologic complete response (pCR), and in overall survival (OS) by pCR status, among early-stage, erb-b2 receptor tyrosine kinase 2 (ERBB2)-low breast cancer patients after neoadjuvant chemotherapy (NACT) are unknown. Data were from the 2010-2020 National Cancer Database that included Asian/Pacific Islander (API), American Indian/Alaska Native/Other (AIANO), Black, Hispanic, and White patients. pCR and OS were modeled using logistic regression and Cox regression, respectively. Of 25,577 patients, Black patients achieved a 17.4% pCR rate, Hispanic 16.0%, White 14.7%, API 13.5%, and AIANO 10.9%. AIANO patients had lower odds of pCR than White patients (adjusted odds ratio, 0.66; 95% confidence interval [CI], 0.48-0.91). Among patients without pCR, API (adjusted hazard ratio [aHR], 0.62; 95% CI, 0.51-0.76) and Hispanic (aHR, 0.77; 95% CI, 0.67-0.89) patients had lower mortality risks than White patients. Among patients with pCR, similar OS rates were observed between Hispanic (aHR, 1.08; 95% CI, 0.66-1.78), Black (aHR, 0.77; 95% CI, 0.55-1.09), API (aHR, 0.41; 95% CI, 0.15-1.12), or AIANO (aHR, 0.35; 95% CI, 0.05-2.50) and White patients. Post-NACT pCR rates were similar across racial/ethnic groups of early-stage, ERBB2-low breast cancer patients. Among patients without pCR, API and Hispanic patients had better OS; among patients with pCR, there was no differential OS by race/ethnicity. Our findings suggest the need for longitudinal studies of OS differences in this patient population.
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Aim: Bacterial vaginosis (BV) is a common vaginal dysbiosis associated with adverse clinical sequelae, most notably, increased risk of sexually transmitted infections (STIs). The aims of this study were to estimate the frequency of BV recurrence, treatment patterns, other gynecological (GYN) conditions, and the associated healthcare resource utilization (HCRU) and costs among commercially insured patients in the USA. Patients & methods: Female patients aged 12-49 years with an incident vaginitis diagnosis and ≥1 pharmacy claim for a BV medication (fungal treatment only excluded) were selected from the Merative™ MarketScan commercial database (2017-2020). During a minimum 12-month follow-up, additional treatment courses, treatment patterns, frequency of other GYN conditions, and HCRU and costs were assessed. Generalized linear models were used to identify baseline predictors of total all-cause healthcare costs and number of treatment courses. Results: The study population included 140,826 patients (mean age: 31.5 years) with an incident vaginitis diagnosis and ≥1 BV medication claim. During the follow-up, 64.2% had 1 treatment course, 22.0% had 2, 8.1% had 3, and 5.8% had ≥4; 35.8% had a BV recurrence (≥2 BV medication claims). The most commonly prescribed BV medication was oral metronidazole (73.6%). Approximately 12% (n = 16,619) of patients had a new diagnosis of another GYN condition in the follow-up; 8.2% had a new STI, which were more common among patients with ≥4 treatment courses (12.9%). During follow-up, total all-cause healthcare costs averaged $8987 per patient per year (PPPY) of which $470 was BV-related. BV-related healthcare costs increased from $403 PPPY among those with 1 treatment course to $806 PPPY among those with ≥4 with nearly half the costs attributed to outpatient office visits. Conclusion: BV recurrence among this population represented a substantial clinical and healthcare economic burden warranting improvements in women's healthcare.
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Vaginose Bacteriana , Humanos , Feminino , Estados Unidos/epidemiologia , Adulto , Vaginose Bacteriana/tratamento farmacológico , Vaginose Bacteriana/epidemiologia , Vaginose Bacteriana/induzido quimicamente , Estresse Financeiro , Metronidazol/efeitos adversos , Custos de Cuidados de Saúde , Atenção à Saúde , Estudos RetrospectivosRESUMO
OBJECTIVE: To estimate workplace productivity loss and indirect costs in the year after birth among individuals who deliver preterm in the United States. METHODS: This retrospective, observational cohort study estimated workplace productivity loss and indirect costs for individuals aged 18-55 years with an inpatient delivery between January 1, 2016, and September 30, 2021, using data from the Merative MarketScan Commercial Claims and Encounters database and the Health and Productivity Management database. Workdays lost and costs attributable to medical-related absenteeism, workplace absenteeism (defined as sick leave, leave, recreational leave, Family Medical Leave Act); disability (defined as short-term and long-term disability), and aggregate workplace productivity loss, a combined outcome measure, were compared between propensity-score-matched birth cohorts: preterm birth (before 37 weeks of gestation) and full-term birth (at or after 37 weeks of gestation). Outcomes were also compared between the full-term birth cohort and preterm birth subgroups (before 32 weeks of gestation and before 34 weeks of gestation). Estimations of indirect costs assumed an 8-hour workday. Costs were inflated to December 2021 U.S. dollars. RESULTS: In total, 37,522 individuals were eligible for medical-related absenteeism, 1,028 for workplace absenteeism, 7,880 for disability, and 396 for aggregate workplace productivity loss after propensity score matching. Compared with full-term birth, preterm birth was associated with more workdays lost and costs in the year after childbirth attributable to medical-related absenteeism (differences of 4.2 days and $1,045, P <.001) and disability (differences of 2.8 days and $422, P <.001). Preterm birth was not associated with workplace absenteeism (differences of 1.4 days and $347, P =.787) and aggregate workplace productivity loss (differences of 5.2 days [ P =.080] and $1,021 [ P =.093]). Numerical differences were greater in magnitude and inversely related to gestational age at birth across outcomes. CONCLUSION: Preterm birth was associated with medical-related absenteeism, disability claims, and indirect costs in the year after birth compared with full-term birth.