Sex Differences in Bladder Management, Symptoms, and Satisfaction After Spinal Cord Injury.

PURPOSE: We sought to characterize sex-stratified differences in bladder management and bladder symptoms and satisfaction after spinal cord injury. MATERIALS AND METHODS: This study was a prospective, cross-sectional, observational study; eligibility included: age ≥18 years and acquired spinal cord injury. Bladder management was grouped as (1) clean intermittent catheterization, (2) indwelling catheter, (3) surgery, and (4) voiding. Primary outcome was Neurogenic Bladder Symptom Score. Secondary outcomes were subdomains of the Neurogenic Bladder Symptom Score and bladder-related satisfaction. Multivariable regression was used in sex-stratified models to establish associations between participant characteristics and outcomes. RESULTS: A total of 1,479 participants enrolled in the study. Of the patients 843 (57%) were paraplegic and 585 (40%) were women. Median age and time from injury were 44.9 (IQR 34.3, 54.1) and 11 (IQR 5.1, 22.4) years. Women utilized clean intermittent catheterization at a lower rate (42.6% vs 56.5%) and surgery at a higher rate (22.6% vs 7.0%), especially catheterizable channel creation with or without augmentation cystoplasty (11.0% vs 1.9%). Women had worse measures of bladder symptoms and satisfaction across all outcomes. In adjusted analyses, women and men utilizing indwelling catheters had fewer associated overall symptoms (Neurogenic Bladder Symptom Score), less incontinence, and fewer storage and voiding symptoms. Surgery was associated with fewer bladder symptoms (Neurogenic Bladder Symptom Score) and less incontinence in women, and was also associated with better satisfaction in both sexes. CONCLUSIONS: There are significant sex-stratified differences in bladder management after spinal cord injury, which included a much higher use of surgery. Bladder symptoms and satisfaction are worse across all measurements in women. Women have a substantial associated benefit with surgery, while both sexes have fewer bladder symptoms with indwelling catheters compared to clean intermittent catheterization.

Factors associated with antihypertensive monotherapy among US adults with treated hypertension and uncontrolled blood pressure overall and by race/ethnicity, National Health and Nutrition Examination Survey 2013-2018.

BACKGROUND: Treating hypertension with antihypertensive medications combinations, rather than one medication (ie, monotherapy), is underused in the United States, particularly in certain race/ethnic groups. Identifying factors associated with monotherapy use despite uncontrolled blood pressure (BP) overall and within race/ethnic groups may elucidate intervention targets in under-treated populations. METHODS: Cross-sectional analysis of National Health and Nutrition Examination Surveys (NHANES; 2013-2014 through 2017-2018). We included participants age ≥20 years with hypertension, taking at least one antihypertensive medication, and uncontrolled BP (systolic BP [SBP] ≥ 140 mmHg or diastolic BP [DBP] ≥ 90 mmHg). Demographic, clinical, and healthcare-access factors associated with antihypertensive monotherapy were determined using multivariable-adjusted Poisson regression. RESULTS: Among 1,597 participants with hypertension and uncontrolled BP, age- and sex- adjusted prevalence of monotherapy was 42.6% overall, 45.4% among non-Hispanic White, 31.9% among non-Hispanic Black, 39.6% among Hispanic, and 50.9% among non-Hispanic Asian adults. Overall, higher SBP was associated with higher monotherapy use, while older age, having a healthcare visit in the previous year, higher body mass index, and having heart failure were associated with lower monotherapy use. CONCLUSION: Clinical and healthcare-access factors, including a healthcare visit within the previous year and co-morbid conditions were associated with a higher likelihood of combination antihypertensive therapy.

The Role of Health Insurance in Patient Reported Satisfaction with Bladder Management in Neurogenic Lower Urinary Tract Dysfunction Due to Spinal Cord Injury.

PURPOSE: Neurogenic lower urinary tract dysfunction is a significant source of morbidity for individuals with spinal cord injury and is managed with a range of treatment options that differ in efficacy, tolerability and cost. The effect of insurance coverage on bladder management, symptoms and quality of life is not known. We hypothesized that private insurance is associated with fewer bladder symptoms and better quality of life. MATERIALS AND METHODS: This is a cross-sectional, retrospective analysis of 1,226 surveys collected as part of the prospective Neurogenic Bladder Research Group SCI Registry. We included patients with complete insurance information, which was classified as private or public insurance. The relationship between insurance and bladder management, bladder symptoms and quality of life was modeled using multinomial logistic regression analysis. Spinal cord injury quality of life was measured by the Neurogenic Bladder Symptom Score. RESULTS: We identified 654 privately insured and 572 publicly insured individuals. The demographics of these groups differed by race, education, prevalence of chronic pain and bladder management. Publicly insured patients were more likely to be treated with indwelling catheters or spontaneous voiding and less likely to take bladder medication compared to those with private insurance. On multivariate analysis insurance type was not associated with differences in bladder symptoms (total Neurogenic Bladder Symptom Score) or in urinary quality of life. CONCLUSIONS: There is an association between insurance coverage and the type of bladder management used following spinal cord injury, as publicly insured patients are more likely to be treated with indwelling catheters. However, insurance status, controlling for bladder management, did not impact bladder symptoms or quality of life.

Long-Term Treatment Outcomes after Behavioral Speech Therapy for Chronic Refractory Cough.

INTRODUCTION: Current literature reveals that up to 88% of individuals undergoing behavioral speech therapy (BST) for chronic refractory cough (CRC) demonstrate benefit at 4-8 weeks post-treatment. However, investigations of BST are confounded by overlapping use of neuromodulators, missing follow-up data, and an absence of long-term outcomes. This study investigated treatment outcomes beyond 6 months in individuals diagnosed with CRC, and whose treatment outcomes were clinically undocumented. METHODS: Participants with CRC 6 months or greater beyond treatment completion were recruited. Participants completed a post-treatment Leicester Cough Questionnaire (LCQ) and a telephone interview. Demographic data, cough characteristics, treatment adherence, BST outcomes, and pre- and post-treatment LCQ scores were evaluated. RESULTS: 80 individuals met inclusion criteria and 29 consented to participate. Of these, 27 were recommended BST. The majority were female (19/27) with average age of 58 years (SD = 12). Mean cough duration was 60 months (SD = 98) and mean post-BST duration was 20 months (SD = 9). A significant increase in pre- to post-treatment LCQ scores occurred [4.4 (SD = 4.2)] (p < 0.0001). CONCLUSION: This study addressed long-term BST benefit for CRC and demonstrated a significant improvement in long-term post-treatment LCQ total scores more than a year after BST for CRC. More than half of participants indicated improvement or elimination of their cough. These findings further support the benefit of BST for CRC. Future research should consider patient perspectives about treatment outcomes given that 44% of participants reported no benefit from BST.

Determining the impact of the Zika pandemic on primary care providers' contraceptive counseling of non-pregnant patients in the US: a mixed methods study.

BACKGROUND: Global pandemics like Zika (ZIKV) factor into pregnancy planning and avoidance, yet little is known about how primary care providers (PCPs) incorporate public health guidance into contraceptive counseling. Study objectives include: 1) determining the impact of the ZIKV pandemic on contraceptive counseling changes; and 2) assessing PCP knowledge and practice regarding contraception, ZIKV, and CDC ZIKV guidelines. METHODS: Study components included: (1) a retrospective review of electronic health records of non-pregnant, reproductive age women presenting for preventive health visits between 2014 and 2017 assessed using interrupted time series analyses (ITSA) to identify changes in documentation of ZIKV risk assessment and contraceptive counseling; and (2) a sequential, cross-sectional study with quantitative surveys and qualitative, semi-structured interviews of PCPs providing preventive care to non-pregnant patients at eight federally qualified health centers in Utah. We performed descriptive analyses on survey data and analyzed qualitative data for dominant themes using a modified Health Belief Model. RESULTS: We conducted 6634 chart reviews yielding 9840 visits. The ITSA did not reveal changes in ZIKV risk assessment or contraceptive counseling. Twenty-two out of 40 (55%) eligible providers participated in the provider component. Participants averaged 69 and 81% correct on contraceptive and ZIKV knowledge questions, respectively. Sixty-five percent reported counseling consistent with CDC ZIKV guidelines. Qualitative analysis found providers unlikely to prioritize ZIKV risk assessment in contraceptive counseling for non-pregnant patients. CONCLUSIONS: PCPs who care for non-pregnant women are knowledgeable about contraception and ZIKV; however, there was no change in ZIKV risk assessment or contraceptive counseling. This stresses the importance of developing strategies to improve guideline uptake.

Reasons for cessation of clean intermittent catheterization after spinal cord injury: Results from the Neurogenic Bladder Research Group spinal cord injury registry.

INTRODUCTION: Clean intermittent catheterization (CIC) is recommended for bladder management after spinal cord injury (SCI) since it has the lowest complication rate. However, transitions from CIC to other less optimal strategies, such as indwelling catheters (IDCs) are common. In individuals with SCI who stopped CIC, we sought to determine how individual characteristics affect the bladder-related quality of life (QoL) and the reasons for CIC cessation. METHODS: The Neurogenic Bladder Research Group registry is an observational study, evaluating neurogenic bladder-related QoL after SCI. From 1479 participants, those using IDC or urinary conduit were asked if they had ever performed CIC, for how long, and why they stopped CIC. Multivariable regression, among participants discontinuing CIC, established associations between demographics, injury characteristics, and SCI complications with bladder-related QoL. RESULTS: There were 176 participants who had discontinued CIC; 66 (38%) were paraplegic and 110 (63%) were male. The most common reasons for CIC cessation among all participants were inconvenience, urinary leakage, and too many urine infections. Paraplegic participants who discontinued CIC had higher mean age, better fine motor scores, and lower educational attainment and employment. Multivariable regression revealed years since SCI was associated with worse bladder symptoms (neurogenic bladder symptom score), ≥4 urinary tract infections (UTIs) in a year was associated with worse satisfaction and feelings about bladder symptoms (SCI-QoL difficulties), while tetraplegia was associated better satisfaction and feelings about bladder symptoms (SCI-QoL difficulties). CONCLUSIONS: Tetraplegics who have discontinued CIC have an improved QoL compared with paraplegics. SCI individuals who have discontinued CIC and have recurrent UTIs have worse QoL.

Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation.

BACKGROUND: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up. METHODS: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up. RESULTS: In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions. CONCLUSIONS: Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.

The p53-signaling pathway and colorectal cancer: Interactions between downstream p53 target genes and miRNAs.

INTRODUCTION: We examined expression of genes in the p53-signaling pathway. We determine if genes that have significantly different expression in carcinoma tissue compared to normal mucosa also have significantly differentially expressed miRNAs. We utilize a sample of 217 CRC cases. METHODS: We focused on fold change (FC) > 1.50 or <0.67 for genes and miRNAs, that were statistically significant after adjustment for multiple comparisons. We evaluated the linear association between the differential expression of miRNA and mRNA. miRNA:mRNA seed-region matches also were determined. RESULTS: Eleven dysregulated genes were associated with 37 dysregulated miRNAs; all were down-stream from the TP53 gene. MiR-150-5p (HR = 0.82) and miR-196b-5p (HR 0.73) significantly reduced the likelihood of dying from CRC when miRNA expression increased in rectal tumors. CONCLUSIONS: Our data suggest that activation of p53 from cellular stress, could target downstream genes that in turn could influence cell cycle arrest, apoptosis, and angiogenesis through mRNA:miRNA interactions.

Mutation analysis of adenomas and carcinomas of the colon: Early and late drivers.

Colorectal cancer (CRC) accounts for about 8% of all new cancer cases diagnosed in the US. We used whole exome sequence data from triplet samples (colon carcinoma, colon adenoma, and normal tissue) from 18 individuals to assess gene mutation rates. Of the 2 204 genes that were mutated, APC, TTN, TP53, KRAS, OBSCN, SOX9, PCDH17, SIGLEC10, MYH6, and BRD9 were consistent with genes being an early driver of carcinogenesis, in that they were mutated in multiple adenomas and multiple carcinomas. Fifty-two genes were mutated in ≥12.5% of microsatellite stable (MSS) carcinomas but not in any of the adenomas, in line with the profile of a late driver event involved in tumor progression. Thirty-eight genes were sequenced in a larger independent set of 148 carcinoma/normal tissue pairs to obtain more precise mutation frequencies. Eight of the genes, APC, TP53, ATM, CSMD3, LRP1B, RYR2, BIRC6, and MUC17, contained mutations in >20% of the carcinomas. Interestingly, mutations in four genes in addition to APC that are associated with dysregulation of Wnt signaling, were all classified as early driver events. Most of the genes that are commonly associated with colon cancer, including APC, TP53, and KRAS, were all classified as being early driver genes being mutated in both adenomas and carcinomas. Classifying genes as potential early and late driver events points to candidate genes that may help dissect pathways involved in both tumor initiation and progression.

MicroRNA-transcription factor interactions and their combined effect on target gene expression in colon cancer cases.

Transcription factors (TFs) and microRNAs (miRNAs) regulate gene expression: TFs by influencing messenger RNA (mRNA) transcription and miRNAs by influencing mRNA translation and transcript degradation. Additionally, miRNAs and TFs alter each other's expression, making it difficult to ascertain the effect either one has on target gene (TG) expression. In this investigation, we use a two-way interaction model with the TF and miRNA as independent variables to investigate whether miRNAs and TFs work together to influence TG expression levels in colon cancer subjects. We used known TF binding sites and validated miRNA targets to determine potential miRNA-TF-TG interactions, restricting interactions to those with a TF previously associated with altered risk of colorectal cancer death. We analyzed interactions using normal colonic mucosa expression as well as differential expression, which is measured as colonic carcinoma expression minus normal colonic mucosa expression. We analyzed 3518 miRNA-TF-TG triplets using normal mucosa expression and 617 triplets using differential expression. Normal colonic RNA-Seq data were available for 168 individuals; of these, 159 also had carcinoma RNA-Seq data. Thirteen unique miRNA-TF-TG interactions, comprising six miRNAs, four TFs, and 11 TGs, were statistically significant after adjustment for multiple comparisons in normal colonic mucosa, and 14 unique miRNA-TF-TG interactions, comprising two miRNAs, two TFs, and 13 TGs, were found for carcinoma-normal differential expression. Our results show that TG expression is influenced by both miRNAs as well as TFs, and the influence of one regulator impacts the effect of the other on the shared TG expression.

Power in pairs: assessing the statistical value of paired samples in tests for differential expression.

BACKGROUND: When genomics researchers design a high-throughput study to test for differential expression, some biological systems and research questions provide opportunities to use paired samples from subjects, and researchers can plan for a certain proportion of subjects to have paired samples. We consider the effect of this paired samples proportion on the statistical power of the study, using characteristics of both count (RNA-Seq) and continuous (microarray) expression data from a colorectal cancer study. RESULTS: We demonstrate that a higher proportion of subjects with paired samples yields higher statistical power, for various total numbers of samples, and for various strengths of subject-level confounding factors. In the design scenarios considered, the statistical power in a fully-paired design is substantially (and in many cases several times) greater than in an unpaired design. CONCLUSIONS: For the many biological systems and research questions where paired samples are feasible and relevant, substantial statistical power gains can be achieved at the study design stage when genomics researchers plan on using paired samples from the largest possible proportion of subjects. Any cost savings in a study design with unpaired samples are likely accompanied by underpowered and possibly biased results.

Dysregulated genes and miRNAs in the apoptosis pathway in colorectal cancer patients.

Apoptosis is genetically regulated and involves intrinsic and extrinsic pathways. We examined 133 genes within these pathways to identify whether they are expressed differently in colorectal carcinoma (CRC) and normal tissue (N = 217) and if they are associated with similar differential miRNA expression. Gene expression data (RNA-Seq) and miRNA expression data (Agilent Human miRNA Microarray V19.0) were generated. We focused on dysregulated genes with a fold change (FC) of > 1.50 or < 0.67, that were significant after adjustment for multiple comparisons. miRNA:mRNA seed-region matches were determined. Twenty-three genes were significantly downregulated (FC < 0.67) and 18 were significantly upregulated (FC > 1.50). Of these 41 genes, 11 were significantly associated with miRNA differential expression. BIRC5 had the greatest number of miRNA associations (14) and the most miRNAs with a seed-region match (10). Four of these matches, miR-145-5p, miR-150-5p, miR-195-5p, and miR-650, had a negative beta coefficient. CSF2RB was associated with ten total miRNAs (five with a seed-region match, and one miRNA, miR-92a-3p, with a negative beta coefficient). Of the three miRNAs associated with CTSS, miR-20b-5p, and miR-501-3p, had a seed-region match and a negative beta coefficient between miRNA:mRNA pairs. Several miRNAs that were associated with dysregulated gene expression, seed-region matches, and negative beta coefficients also were associated with CRC-specific survival. Our data suggest that miRNAs could influence several apoptosis-related genes. BIRC5, CTSS, and CSF2R all had seed-region matches with miRNAs that would favor apoptosis. Our study identifies several miRNA associated with apoptosis-related genes, that if validated, could be important therapeutic targets.

The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer.

The PI3K/AKT-signaling pathway is one of the most frequently activated signal-transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC). We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of >1.5 or <0.67) that were statistically significant after adjustment for multiple comparisons. Of the 304 genes evaluated, 76 had a FC of <0.67, and 57 had a FC of >1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed-region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed-region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR-203a with ITGA4, miR-6071 with ITGAV, and miR-375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks. Gene expression in the PI3K/Akt-signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner.

Infrequently expressed miRNAs in colorectal cancer tissue and tumor molecular phenotype.

This corrects the article DOI: 10.1038/modpathol.2017.38.

The TGFß-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs.

BACKGROUND: The TGFß-signaling pathway plays an important role in the pathogenesis of colorectal cancer (CRC). Loss of function of several genes within this pathway, such as bone morphogenetic proteins (BMPs) have been seen as key events in CRC progression. METHODS: In this study we comprehensively evaluate differential gene expression (RNASeq) of 81 genes in the TGFß-signaling pathway and evaluate how dysregulated genes are associated with miRNA expression (Agilent Human miRNA Microarray V19.0). We utilize paired carcinoma and normal tissue from 217 CRC cases. We evaluate the associations between differentially expressed genes and miRNAs and sex, age, disease stage, and survival months. RESULTS: Thirteen genes were significantly downregulated and 14 were significantly upregulated after considering fold change (FC) of > 1.50 or < 0.67 and multiple comparison adjustment. Bone morphogenetic protein genes BMP5, BMP6, and BMP2 and growth differentiation factor GDF7 were downregulated. BMP4, BMP7, INHBA (Inhibin beta A), TGFBR1, TGFB2, TGIF1, TGIF2, and TFDP1 were upregulated. In general, genes with the greatest dysregulation, such as BMP5 (FC 0.17, BMP6 (FC 0.25), BMP2 (FC 0.32), CDKN2B (FC 0.32), MYC (FC 3.70), BMP7 (FC 4.17), and INHBA (FC 9.34) showed dysregulation in the majority of the population (84.3, 77.4, 81.1, 80.2, 82.0, 51.2, and 75.1% respectively). Four genes, TGFBR2, ID4, ID1, and PITX2, were un-associated or slightly upregulated in microsatellite-stable (MSS) tumors while downregulated in microsatellite-unstable (MSI) tumors. Eight dysregulated genes were associated with miRNA differential expression. E2F5 and THBS1 were associated with one or two miRNAs; RBL1, TGFBR1, TGIF2, and INHBA were associated with seven or more miRNAs with multiple seed-region matches. Evaluation of the joint effects of mRNA:miRNA identified interactions that were stronger in more advanced disease stages and varied by survival months. CONCLUSION: These data support an interaction between miRNAs and genes in the TGFß-signaling pathway in association with CRC risk. These interactions are associated with unique clinical characteristics that may provide targets for further investigations.

Single nucleotide polymorphisms within MicroRNAs, MicroRNA targets, and MicroRNA biogenesis genes and their impact on colorectal cancer survival.

We have shown that single nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes, miRNA target genes, and miRNA biogenesis genes minimally contribute to colon cancer risk. It is possible that these SNPs alter survival. We analyzed 565 SNPs in or adjacent to microRNAs, target genes, or biogenesis genes, using 1,115 cases and 1,173 controls; 837 cases had survival information. We tested SNPs for associations with colorectal cancer (CRC) survival using a Cox proportional hazard model adjusting for age, study center, gender, AJCC disease stage, and MSI tumor status. Multiple comparison adjustments were made using the step-down Bonferroni correction. SNPs associated with survival (Praw  < 0.05) also were assessed with messenger RNA (mRNA). Seven of the 565 SNPs analyzed were associated significantly with CRC survival after adjustment for multiple comparisons. Six of these increased risk of dying, and one, rs12140 (ADAMTS1) decreased risk of dying from CRC (HRR = 0.44, 95% CI (0.24, 0.83; PHolm  = 0.011). Six SNPs altered colon cancer risk and five were associated with altered mRNA expression across genotypes. One SNP, rs2059691 (PRKRA), was associated with increased mRNA expression and worse survival, and one SNP, rs6598964 (LIN28A), decreased risk of developing colon cancer [OR = 0.77 95% CI (0.61, 0.98)] and increased risk of dying from CRC (HRR = 2.26 95% CI (1.52, 3.36). PHolm  = 0.003). The few SNPs associated with CRC survival, colon cancer risk, or with mRNA expression, resided in genes that influence metastasis and angiogenesis. © 2017 Wiley Periodicals, Inc.

The co-regulatory networks of tumor suppressor genes, oncogenes, and miRNAs in colorectal cancer.

Tumor suppressor genes (TSGs) and oncogenes (OG) are involved in carcinogenesis. MiRNAs also contribute to cellular pathways leading to cancer. We use data from 217 colorectal cancer (CRC) cases to evaluate differences in TSGs and OGs expression between paired CRC and normal mucosa and evaluate how TSGs and OGs are associated with miRNAs. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were used. We focus on genes most strongly associated with CRC (fold change (FC) of ≥1.5 or ≤0.67) that were statistically significant after adjustment for multiple comparisons. Of the 74 TSGs evaluated, 22 were associated with carcinoma/normal mucosa differential expression. Ten TSGs were up-regulated (FAM123B, RB1, TP53, RUNX1, MSH2, BRCA1, BRCA2, SOX9, NPM1, and RNF43); six TSGs were down-regulated (PAX5, IZKF1, GATA3, PRDM1, TET2, and CYLD); four were associated with MSI tumors (MLH1, PTCH1, and CEBPA down-regulated and MSH6 up-regulated); and two were associated with MSS tumors (PHF6 and ASXL1 up-regulated). Thirteen of these TSGs were associated with 44 miRNAs. Twenty-seven of the 59 OGs evaluated were dysregulated: 14 down-regulated (KLF4, BCL2, SSETBP1, FGFR2, TSHR, MPL, KIT, PDGFRA, GNA11, GATA2, FGFR3, AR, CSF1R, and JAK3), seven up-regulated (DNMT1, EZH2, PTPN11, SKP2, CCND1, MET, and MYC); three down-regulated for MSI (FLT3, CARD11, and ALK); two up-regulated for MSI (IDH2 and HRAS); and one up-regulated with MSS tumors (CTNNB1). These findings suggest possible co-regulatory function between TSGs, OGs, and miRNAs, involving both direct and indirect associations that operate through feedback and feedforward loops.

The miRNA landscape of colorectal polyps.

The genomic landscape of adenomas and polyps may help define disease pathways. Expression of miRNAs in adenomas and polyps may importantly contribute to these pathways. We evaluated miRNA expression in 293 polyp-normal colorectal mucosa pairs. Polyps were classified as either adenomatous polyp (AD), hyperplastic polyp (HP), or sessile serrated polyp (SSP). We compared these miRNA expression profiles in polyps to miRNA expression in microsatellite unstable (MSI) and stable (MSS) tumors. A False Discovery Rate of 0.05 based on Benjamini and Hochberg was used to adjust for multiple comparisons. There were 70 miRNAs with differential expression by polyp type with a fold change <0.75 or >1.34 after adjusting for multiple comparisons. The major differences in miRNA expression were observed between AD and SSP and AD and HP, with few differences in expression noted for SSP and HP. AD polyps were more likely to be upregulated from normal colonic mucosa, while SSP and HP were more likely to be downregulated from normal colonic mucosa. MiRNA expression in the SSP and HP tumors almost uniformly go in opposite directions from the MSS tumor miRNA expression and was mixed with MSI tumors. We conclude that different types of polyps have unique miRNA expression profiles. © 2017 Wiley Periodicals, Inc.

Transcription factor-microRNA associations and their impact on colorectal cancer survival.

MicroRNAs (miRNAs) and Transcription Factors (TFs) both influence messenger RNA (mRNA) expression, disrupting biological pathways involved in carcinogenesis and prognosis. As many miRNAs target multiple mRNAs, thus influencing a multitude of biological pathways, deciphering which miRNAs are important for cancer development and survival is difficult. In this study, we (i) determine associations between TF and survival (N = 168 colon cancer cases); (ii) identify miRNAs associated with TFs related to survival; and (iii) determine if factors derived from TF-specific miRNA principal component analysis (PCA) influence survival. Cox Proportional hazard models were run for each PCA factor to determine Hazard Ratios (HR) and 95% Confidence Intervals (CI) adjusting for age, center, and AJCC stage. Thirty TFs improved survival when differential expression increased; 27 of these were associated significantly with normal colonic mucosa expression of 65 unique miRNAs when an FDR q-value of <0.05 was applied. Five factors, comprising 21 miRNAs, altered survival in rectal cancer subjects; four of these five factors improved survival and one factor reduced survival. One factor comprising four miRNAs reduced survival in colon cancer subjects. In summary, our data suggest that expression of TFs and their related miRNAs influence survival after diagnosis with colorectal cancer.

Alterations in microRNA expression associated with alcohol consumption in rectal cancer subjects.

PURPOSE: Alcohol consumption has been purported to influence many diseases. MicroRNAs (miRNAs) may be influenced by compounds found in alcohol. In this investigation, we test the hypothesis that total alcohol, beer, wine, and hard liquor influence miRNA expression. METHODS: We studied 1447 colorectal (CR) cancer cases with normal CR mucosa and carcinoma miRNA expression data along with alcohol consumption data. We analyzed long-term and long-term and current (LTC) alcohol use for beer, liquor, and wine with miRNA expression between paired carcinoma and normal colon and rectal tissues, adjusting for multiple comparisons using the positive false discovery rate q-value. MiRNAs associated significantly with alcohol were examined with all-cause mortality (ACM). MiRNAs associated significantly with ACM were examined with RNA-Seq data. RESULTS: Expression of 84 miRNAs was associated significantly with LTC wine use in normal rectal mucosa. Higher expression of two of these miRNAs significantly worsened ACM: hsa-miR-210 (Hazard Ratio [HR] 1.12, 95% CI (1.03, 1.21), p-value = 0.004), and hsa-miR-92a-1-5p (HR 1.20, 95% CI (1.04, 1.38), p-value = 0.013). These miRNAs were downregulated across levels of LTC wine consumption. CONCLUSIONS: Our results suggest that wine influences miRNA expression in rectal cancer, supporting the hypothesis that components in alcohol influence miRNA expression.