Obstruction of the Inferior Vena Cava Following Coronary Artery Bypass Grafting.

Obstruction of the inferior vena cava (IVC) following coronary artery bypass grafting (CABG) is a rare complication. We describe a case of IVC outflow obstruction secondary to inferior cavoatrial junction injury during CABG. The diagnostic and management approaches used to care for this patient are discussed. (Level of Difficulty: Intermediate.).

Outcomes of Cardiogenic Shock With Autoimmune Rheumatological Disorders.

AIMS: Data on cardiogenic shock (CS) in autoimmune diseases (AID) is limited. Our study aims to evaluate in-hospital outcomes of CS in hospitalized patients with underlying AID compared with patients without AID. METHODS: The National Inpatient Sample (NIS) database years 2011-17 was used to identify hospitalizations for CS. We retrospectively compared in-hospital outcomes of CS in patients with underlying AID versus non-AID. RESULTS: Of 863,239 patients diagnosed with CS, 23,127 (2.7%) had underlying AID. The AID population was older with more women and African American patients (P < 0.001 for all). There was a significant increase in in-hospital mortality in patients with AID vs non-AID that persisted after adjustment for demographics, comorbidities, insurance, socioeconomic status and hospital characteristics (38.3% vs 36.3%, aOR 1.06; 95% CI: 1.02-1.09, P = 0.001). Patients with AID had a lower rate of respiratory complications (11.5% vs 13.1%), acute stroke (6.0% vs 6.8%), use of mechanical circulatory support (12.0% vs 14.5%) and discharge to an outside facility (29.1% vs 28.8%) (P ≤ 0.001 for all). Using multivariable logistic regression, we identified female gender, Native American ethnicity, heart failure, coagulopathy, pulmonary circulation disorders, metastatic cancer, and fluid and electrolytes disorders as independent predictors of mortality in patients with AID who were diagnosed with CS. CONCLUSION: Patients with AID hospitalized with CS have increased mortality which may be related to their underlying disease process and lack of effective disease-directed therapy for CS related to AID.

Comprehensive evaluation of cardiovascular efficacy and safety outcomes of SGLT2 inhibitors in high risk patients of cardiovascular disease: systematic review and meta-analysis.

OBJECTIVES: To demonstrate a magnitude of the cardiovascular benefits, concomitantly analyzing the safety outcomes of sodium-glucose cotransporter 2 inhibitor (SGLT2-I) comprehensively, as a class effect in a larger sample size combined from recent randomized control trials. METHODS: We searched electronic databases using specific terms and evaluated 6 efficacy and 10 safety outcomes. Odds ratios (ORs) and 95% confidence interval (CI) were used to compare two interventions. RESULTS: Five studies (n = 41 267) were included, among which 23 539 received SGLT2-I. The SGLT2-I group favored reduction in major adverse cardiovascular events (OR, 0.78; 95% CI, 0.62-0.98; P = 0.03), cardiovascular death (CVD) or heart failure hospitalization (OR, 0.60; 95% CI, 0.46-0.80; P = 0.0004), rate of hospitalization for heart failure (OR, 0.56; 95% CI, 0.44-0.72; P < 0.00001), CVD (OR, 0.68; 95% CI, 0.50-0.93; P = 0.01), all-cause mortality (OR, 0.67; 95% CI, 0.48-0.93; P = 0.02) and myocardial infarction (OR, 0.79; 95% CI, 0.64-0.99; P = 0.04) when compared to the placebo group. Safety analysis showed higher diabetic ketoacidosis (DKA) rate in SGLT2-I group (OR, 2.33; 95% CI, 1.40-3.90; P = 0.001); in contrast, major hypoglycemic events were significantly lower (OR, 0.79; 95% CI, 0.73-0.87; P < 0.00001). AKI was significantly higher in the placebo group (OR, 0.76; 95% CI, 0.65-0.88; P = 0.0004). There were no statistically significant effects on other outcomes. CONCLUSION: In selected high-risk patients of cardiovascular disease, the SGLT2-I is a potential effective class of drugs for improving cardiovascular outcomes and all-cause mortality without an increased risk of all other major complications except DKA on this meta-analysis.

Impact of chronic kidney disease on in-hospital outcomes and readmission rate after edge-to-edge transcatheter mitral valve repair.

BACKGROUND: Transcatheter mitral valve repair (TMVR) is a treatment option for patients with 3+ or greater mitral regurgitation who cannot undergo mitral valve surgery. Outcomes in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD) are unclear. We sought to evaluate the TMVR in-hospital outcomes, readmission rates and its impact on kidney function. METHODS: Data from 2016 National Readmission Database was used to obtain all patients who underwent TMVR. Patients were classified by their CKD status: no CKD, CKD, or ESRD. The primary outcomes were: in-hospital mortality, 30- and 90-day readmission rate, and change in CKD status on readmission. Multivariable logistic regression analysis was used to assess in-hospital, readmission outcomes and kidney function stage. RESULTS: A total of 4,645 patients were assessed (mean age 78.5 ± 10.3 years). In-hospital mortality was higher in patients with CKD (4.0%, odds ratio [OR]:2.01 [95% CI, confidence interval: 1.27-3.18]) and ESRD (6.6%, OR: 6.38 [95% CI: 1.49-27.36]) compared with non-CKD (2.4%). 30-day readmission rate was higher in ESRD versus non-CKD patients (17.8% vs. 10.4%, OR: 2.24 [95% CI: 1.30-3.87]) as was 90-day readmission (41.2% vs. 21% OR: 2.51 [95% CI:1.70-3.72]). Kidney function improved in 25% of patients with CKD stage 3 and in 50% with CKD stage 4-5 at 30-and 90-day readmission. Incidence of AKI, major bleeding, and respiratory failure were higher in CKD group. CONCLUSIONS: Patients with CKD and ESRD have worse outcomes and higher readmission rate after TMVR. In patients who were readmitted after TMVR, renal function improved in some patients, suggesting that TMVR could potentially improve CKD stage.

Comprehensive Outcomes Evaluation After Percutaneous Coronary Intervention in Stable Ischemic Heart Disease and Acute Coronary Syndrome for Short- Versus Standard-Term Dual Antiplatelet Therapy: A Systematic Review and Meta-analysis of Randomized Control Trials.

Newer generation drug eluting stents (DES) and pharmacotherapy have decreased thrombotic events post-percutaneous coronary intervention (PCI). There is lack of wide-ranging safety and efficacy evaluation in both stable ischemic heart disease and acute coronary syndrome in short-term (3-6 months) versus Standard-term (12 months) dual antiplatelet therapy (DAPT). We searched electronic databases using specific terms to identify randomized control trials comparing different durations of DAPT after PCI with DES. The outcomes of interest included all-cause mortality, myocardial infarction, stent thrombosis, major bleeding, target lesion and vessel revascularization, and stroke at follow-up duration ≥12 months post index PCI. Studies that compared DAPT <3 months or DAPT ≥12 months were excluded. Thirteen randomized control trials (n = 31,831) were included; 8401 patients received DAPT for 3 months and 7482 patients received DAPT in the 6 months group. Major bleeding rate was lower in the short-term (3-6 months) versus Standard-term (12 months) group (risk ratio 0.66; 95% confidence interval, 0.52-0.84, P < 0.05). Repeat revascularization rate was higher in the short-term (3-6 months) versus Standard-term (12 months) (risk ratio 1.17; 95% confidence interval, 1.01-1.36, P < 0.05) of DAPT duration after PCI with DES. No difference in other outcomes were observed when comparing short versus standard duration of DAPT in both stable ischemic heart disease and acute coronary syndrome.

Complete Versus Culprit-Only Revascularization in Patients Presenting With ST-Segment Elevation Myocardial Infarction: A Meta-Analysis of Randomized Control Trials.

BACKGROUND: In patients with ST elevation myocardial infarction (STEMI), primary percutaneous coronary intervention (PCI) of the culprit vessel is the preferred treatment option. For patients with multivessel disease, the benefit of revascularization of the non-culprit artery is not well known. This meta-analysis aims to assess the efficacy and safety of complete versus culprit vessel only revascularization. METHODS: Randomized control trials (RCT) that compared head-to-head complete versus culprit-vessel only revascularization in STEMI patients and reported main outcomes of interest such as mortality, myocardial infarction, and revascularization, were included in this meta-analysis. RESULTS: We found ten RCTs satisfying our inclusion criteria. Data was extracted and used to estimate the risk ratio (RR) and 95% confidence interval (CI) for dichotomous variables. Our study included 7030 patients (3426 complete revascularization, and 3604 culprit-only revascularization). Complete revascularization (CR) (both immediate and staged) significantly reduced the risk of MACE compared with culprit only (CO) revascularization (10.7% vs 20.1%, RR 0.53; 95% CI 0.43 to 0.64; P < 0.0001), reinfarction (5.0% vs 6.9%, RR 0.69; 95 CI 0.51 to 0.93; P < 0.01), and revascularization (4.2% vs 12.7%, RR 0.37; 95 CI 0.26 to 0.54; P < 0.0001). Our analysis did not find any significant difference in all-cause mortality between CR and CO (4.6% vs 5.0%, RR 0.89; 95 CI 0.72 to 0.1.10; P = 0.27). CONCLUSION: In conclusion, complete revascularization was associated with a significant reduction in major adverse cardiovascular events, revascularization and reinfarction.

Clinical outcomes of adjunctive posterior wall isolation in persistent atrial fibrillation: A meta-analysis.

BACKGROUND: Pulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation but the recurrence rate remains relatively high in persistent patients with AF. Therefore, posterior wall isolation (PWI) in addition to PVI has been proposed to increase freedom from AF. OBJECTIVE: To evaluate the success of adjunctive PWI in persistent AF. METHODS: We searched electronic database using specific terms. The primary outcomes are recurrence rate of AF and recurrence of atrial arrhythmias. The secondary outcomes were atrial flutter/tachycardia (AFL/AT), procedure time, fluoroscopy time, and procedure related complications. Estimated risk ratios (RRs) and 95% confidence intervals (CIs) were evaluated. RESULTS: Six studies were included (1334 patients with persistent AF). Adjunctive PWI resulted in a significant reduction in the recurrence rate of AF compared with patients who had PVI only (19.8% vs 29.1%; RR, 0.64; 95% CI, 0.42-0.97; P < .04; I2 = 76%). There was a significant reduction in the recurrence rate of all atrial arrhythmia (30.8% vs 41.1%; RR, 0.75; 95% CI, 0.60-0.94; P < .01; I2 = 60%). Compared with PVI only, adjunctive PWI did not increase the rate of AFL or AT (11.6% vs 13.9%; RR, 0.85; 95% CI, 0.54-1.32; P < .46; I2 = 47%) or the rate of procedure related complications (4.6% vs 3.6%; RR, 1.25; 95% CI, 0.72-2.17; P < .44; I2 = 0%). CONCLUSION: In patients with persistent AF, adjunctive PWI was associated with decreased recurrence of AF and atrial arrhythmias compared with PVI alone without an increased risk of AFL or AT or procedure related complications.

The Ubiquitous Premature Ventricular Complex.

Premature ventricular complexes (PVCs) are one of the most commonly encountered arrhythmias and are ubiquitous in clinical practice, both in the outpatient and inpatient settings. They are often discovered incidentally in asymptomatic patients, however, can cause myriad symptoms acutely and chronically. Long thought to be completely benign, PVCs have been historically disregarded without pursuing any further evaluation. Newer data have revealed that a high burden of PVCs with specific characteristics can significantly increase a patient's risk of developing PVC-induced cardiomyopathy. The aim of this literature review is to provide further clarification on the identification of high-risk PVCs, subsequent workup, and the currently available treatment options. PVCs arise from an ectopic focus within the ventricles. Patients with PVCs can be either asymptomatic or have severe disabling symptoms. The diagnostic workup for PVCs includes electrocardiogram (ECG) and 24-h Holter monitor to assess the QRS morphology and its frequency. A transthoracic echocardiogram (TTE) is done to look for structural heart disease and cardiomyopathy. Management of PVCs should be focused on identifying and treating the underlying causes, such as electrolyte abnormalities, substance use, and underlying structural heart disease. Beta-blockers are first-line therapy for symptomatic PVCs. Nondihydropyridine calcium channel blockers, classic antiarrhythmic agents, and amiodarone can be considered as second-line agents. Patients who are unable to tolerate medical therapy should undergo catheter ablation of the PVC focus to prevent PVC-induced cardiomyopathy. PVCs are common in clinical practice, and it is vital to identify patients at higher risk for PVC-induced cardiomyopathy to facilitate early intervention. Patients with no evidence of structural heart disease and infrequent PVCs should be monitored closely, while those who are symptomatic should be treated medically. For those who have failed medical therapy, catheter ablation of the PVCs focus is recommended. Catheter ablation has been shown to reduce PVCs burden and improve left ventricular ejection fraction (LVEF) in those with PVC-induced cardiomyopathy.

Echocardiographic Derived Parameters Association With Long-Term Outcomes After Transcatheter Valve Replacement.

BACKGROUND: Transaortic flow, maximum velocity (V max), mean gradient (MG), left ventricular ejection fraction (LVEF), Aortic valve area (AVA) and dimensional index (DI) are important determinants of prognosis in patients with severe aortic stenosis. The specific role of these echocardiography-derived values in predicting prognosis of severe aortic stenosis patients undergoing Transcatheter aortic valve replacement (TAVR) is less defined. METHODS: We identified all severe AS patients who underwent TAVR between 01/2012 and 6/2016. Baseline characteristics, clinical, procedural and one year follow-up data were obtained. Hierarchical logistic regression was used to assess predictors of 1-year mortality after TAVR. Normal flow (NF) was defined as having stroke volume index (SVI) of ≥35 ml/m2; while low Flow (LF) was defined as SVI < 35 ml/m2. High gradient (HG) was defined as mean gradient of ≥40 mmHg; while low gradient (LG) was defined as <40 mmHg. RESULTS: A total of 399 patients were analyzed. There were no significant differences in baseline characteristics. LVEF less than 35% was associated with higher rate of 1-year mortality (17.6% LVEF <35% vs. 8.9% LVEF≥35%; RR = 2.19; CI 1.05 to 4.54; P = 0.03). There was no difference in 1-year mortality outcomes after TAVR in relation to: Mean Gradient MG, transaortic flow/Stroke Volume Index SVI, DI, V max or AVA. CONCLUSION: Low LVEF <35% remains the strongest parameter associated with 1 year mortality after TAVR.

HOSPITAL Score, LACE Index and LACE+ Index as predictors of 30-day readmission in patients with heart failure.

This study aimed to evaluate the accuracy of the HOSPITAL Score (Haemoglobin level at discharge, Oncology at discharge, Sodium level at discharge, Procedure during hospitalization, Index admission, number of hospital admissions, Length of stay) LACE index (Length of stay, Acute/emergent admission, Charlson comorbidy index score, Emerency department visits in previous 6 months) and LACE+ index in predicting 30-day readmission in patients with diastolic dysfunction. Heart failure remains one of the most common hospital readmissions in adults, leading to significant morbidity and mortality. Different models have been used to predict 30-day hospital readmissions. All adult medical patients discharged from the SIU School of Medicine Hospitalist service from 12 June 2016 to 12 June 2018 with an International Classification of Disease, 10th Revision, Clinical Modification diagnosis of diastolic heart failure were studied retrospectively to evaluate the performance of the HOSPITAL Score, LACE index and LACE+ index readmission risk prediction tools in this patient population. Of the 730 patient discharges with a diagnosis of heart failure with preserved ejection fraction (HFpEF), 692 discharges met the inclusion criteria. Of these discharges, 189 (27%) were readmitted to the same hospital within 30 days. A receiver operating characteristic evaluation showed C-statistic values to be 0.595 (95% CI 0.549 to 0.641) for the HOSPITAL Score, 0.551 (95% CI 0.503 to 0.598) for the LACE index and 0.568 (95% CI 0.522 to 0.615) for the LACE+ index, indicating poor specificity in predicting 30-day readmission. The result of this study demonstrates that the HOSPITAL Score, LACE index and LACE+ index are not effective predictors of 30-day readmission for patients with HFpEF. Further analysis and development of new prediction models are needed to better estimate the 30-day readmission rates in this patient population.

Meta-Analysis Evaluating Outcomes of Surgical Left Atrial Appendage Occlusion During Cardiac Surgery.

Surgical left atrial appendage occlusion (S-LAAO) has become a common procedure performed in patients undergoing cardiac surgery; however, evidence to support this procedure remains inconclusive. This meta-analysis aims to assess the efficacy of S-LAAO in terms of ischemic stroke, postoperative atrial fibrillation, and all-cause mortality. A thorough literature review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We identified 10 relevant studies for our meta-analysis. It included 6,779 patients who underwent S-LAAO and 6,573 who did not undergo LAAO. In terms of ischemic stroke, the S-LAAO cohort had a lower events (pooled odds ratio [OR] 0.655 (0.518 to 0.829), p = 0.0004) compared with the non-LAAO cohort. S-LAAO cohort also had lower events of all-cause mortality (pooled OR 0.74 (95% confidence interval 0.55 to 0.99), p = 0.0408) when compared with the non-LAAO cohort. In regards to postoperative atrial fibrillation, there was no difference between the 2 groups (pooled OR 1.29 (95% confidence interval 0.81 to 2.06), p = 0.2752). In conclusion, S-LAAO was associated with lower events of ischemic stroke or systemic embolism and all-cause mortality when compared to the non-LAAO group.

Trimethoprim-sulfamethoxazole Induced Pancytopenia: A Common Occurrence but A Rare Diagnosis.

Trimethoprim-sulfamethoxazole (TMP-SMX) is a bacteriostatic antimicrobial medication used for the treatment of a variety of infections and has many reported skin and hematologic side effects. Due to the easy availability and cost effectiveness, TMP-SMX is one of the medications commonly used for treatment of skin and soft tissue in patients with methicillin-resistant Staphylococcus aureus (MRSA) infection. One of the rare hematologic manifestations of TMP-SMX is pancytopenia, which is a reduction in all cell lines. In this case report, we are documenting a case of pancytopenia due to severe drug reaction to TMP-SMX in a 70-year-old female after two weeks of medication use. Upon initial stabilization she underwent a thorough workup and was subsequently diagnosed with severe drug-induced pancytopenia. Detailed history, early diagnosis, prompt discontinuation of the offending medication along with supportive care remain the mainstay of treatment in the management of TMP-SMX induced pancytopenia.

Malignant Peritoneal Mesothelioma: A Rare Cause of Ascites.

Malignant peritoneal mesothelioma (MPM) is a rare diagnosis that presents with difficulties in diagnosis and management. This article reports a case of an 88-year-old male who presented with a 2-week history of abdominal distention and bloating. He worked at an insulation production factory between the ages of 23 and 25 years with presumed asbestos exposure. On the computed tomography scan of the abdomen/pelvis, the patient was found to have diffuse omental, peritoneal, and mesenteric nodularity with moderate to large ascites. Omental biopsy revealed MPM. The overall prognosis of MPM remains poor, with a median survival time of 12 months at the time of diagnosis. Treatment modalities offered in the United States include chemotherapy alone, cytoreductive surgery alone, or cytoreductive surgery/chemotherapy combination.

Hepatic Involvement in Systemic Sarcoidosis.

BACKGROUND Sarcoidosis is a systemic disease that can affect any organ, including the liver. It is manifested by the presence of non-caseating granulomas within involved organs, most commonly the pulmonary, lymphatic, and hepatic system. Unlike pulmonary or lymphatic involvement, hepatic involvement is usually asymptomatic and it is underdiagnosed. Here, we report a case of a patient with a history of pulmonary sarcoidosis who developed hepatic sarcoidosis. CASE REPORT 68-year-old female with pulmonary sarcoidosis with a 2-week history of severe abdominal pain and epigastric tenderness presented to our center. Abdominal magnetic resonance imaging (MRI) demonstrated mild hepatic fibrosis and cirrhosis. A thorough workup was performed including a liver biopsy which showed chronic non-necrotizing granulomas consistent with sarcoidosis. She was started on prednisone and subsequently improved. The patient was symptom-free on follow-up 1 month later. CONCLUSIONS The majority of patients with hepatic sarcoidosis are usually asymptomatic, with only 5-30% presenting with abdominal pain, jaundice, nausea, vomiting, and hepatosplenomegaly. In rare cases, hepatic sarcoidosis can lead to cholestasis, portal hypertension, cirrhosis, or Budd-Chiari syndrome. Treatment with steroids is the mainstay of therapy; however, in severe cases, patients may require liver transplantation. This case report demonstrates that hepatic sarcoidosis is a serious condition, and if not treated, can lead to portal hypertension and cirrhosis. In patients with sarcoidosis, early detection and longitudinal follow-up is important in preventing overt liver failure.

Rhabdomyolysis Associated with Influenza A Virus Infection.

Influenza A associated with rhabdomyolysis has become more commonly recognized in recent years. It requires prompt recognition and treatment in order to prevent heme pigment-induced acute kidney injury. Here we report a 50-year-old female without a significant past medical history who presented with a one-week history of fevers, chills, fatigue, and generalized body aches. She was on no prior medication. Laboratory studies were significant for leukocytosis and elevated creatinine kinase up to a peak of 28,216 IU/L. Rapid influenza antigen testing was positive for influenza A virus. The patient was diagnosed with influenza A-induced rhabdomyolysis. According to our literature review, we are the first to report a case of influenza A-induced rhabdomyolysis in the 2017-2018 flu season. This case highlights the importance of considering rhabdomyolysis as a manifestation of an influenza infection.

Acute Pericarditis as a Presentation of Adrenal Insufficiency.

Acute pericarditis as a presenting sign of adrenal insufficiency is rarely reported. We present a rare case that highlights pericarditis as a clinical presentation of secondary adrenal insufficiency later complicated by cardiac tamponade. A 44-year-old lady who presented to the hospital with a one-day history of pleuritic chest pain and shortness of breath. In the emergency room, she had a blood pressure of 70/35 mmHg. Laboratory evaluation revealed white blood cell count of 16.08 k/cumm with neutrophilia, normal renal function and elevated troponin (0.321 ng/mL, normal 0.000-0.028). An electrocardiogram (EKG) showed sinus tachycardia, low voltage, PR suppression and ST changes consistent with acute pericarditis. Echocardiogram showed small pericardial effusion without tamponade physiology. Infectious workup was negative; she was thought to have acute adrenal insufficiency likely secondary to viral pericarditis. We treated the patient with high dose nonsteroidal anti-inflammatory drugs (NSAIDS) and hydrocortisone. Three weeks later, she presented to emergency room with complaints of persistent nausea, vomiting, chills, weakness. Her blood pressure was 49/23 mmHg. Random serum cortisol level was <1.2 mcg/dl (normal A.M. specimens 3.7-19.4 mcg/dl). Echocardiogram showed loculated pericardial fluid adjacent to the right ventricle with echocardiographic evidence of tamponade. Emergent pericardiocentesis yielded 250 ml of straw color fluid. Blood pressure improved after the procedure. The patient was initially started on IV stress dose steroids, but following clinical stabilization, hydrocortisone was switched to a physiological dose of 15 mg in am and 10 mg in pm. Although the mechanism of pericarditis in adrenal failure is unknown, this clinical presentation may help early diagnosis of adrenal failure and pericarditis. Early recognition and prompt treatment of this rare presentation are critical to prevent morbidity and mortality.

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.

Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P = 2.30 × 10-11, OR = 1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r2 = 0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (ß = 0.26, P = 0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ∼6 kb upstream of DIS3 Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.

Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A.

Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic normal (n = 10) and tumor (n = 8) derived tissue samples, as well as in pancreatic cancer cell lines (n = 9), to determine differential gene expression (DE) patterns. Sub-network enrichment analyses identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in pancreatic tumor tissues and cells (median P = 7.56×10(-7), median rank = 1, range = 1-25). To explore the effects of HNF1A expression in pancreatic tumor-derived cells, we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines (PANC-1 and MIA PaCa-2) and observed growth inhibition (5.3-fold, P = 4.5×10(-5) for MIA PaCa-2 clones; 7.2-fold, P = 2.2×10(-5) for PANC-1 clones), and a G0/G1 cell cycle arrest and apoptosis upon induction. These effects correlated with HNF1A-induced down-regulation of 51 of 84 cell cycle genes (e.g. E2F1, CDK2, CDK4, MCM2/3/4/5, SKP2 and CCND1), decreased expression of anti-apoptotic genes (e.g. BIRC2/5/6 and AKT) and increased expression of pro-apoptotic genes (e.g. CASP4/9/10 and APAF1). In light of the established role of HNF1A in the regulation of pancreatic development and homeostasis, our data suggest that it also functions as an important tumor suppressor in the pancreas.

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.