Clinical application of next-generation sequencing to the practice of neurology.

Lancet Neurol. 2019 May;18(5):492-503

Authors: Rexach J, Lee H, Martinez-Agosto JA, Németh AH, Fogel BL

Abstract
Next-generation sequencing technologies allow for rapid and inexpensive large-scale genomic analysis, creating unprecedented opportunities to integrate genomic data into the clinical diagnosis and management of neurological disorders. However, the scale and complexity of these data make them difficult to interpret and require the use of sophisticated bioinformatics applied to extensive datasets, including whole exome and genome sequences. Detailed analysis of genetic data has shown that accurate phenotype information is essential for correct interpretation of genetic variants and might necessitate re-evaluation of the patient in some cases. A multidisciplinary approach that incorporates bioinformatics, clinical evaluation, and human genetics can help to address these challenges. However, despite numerous studies that show the efficacy of next-generation sequencing in establishing molecular diagnoses, pathogenic mutations are generally identified in fewer than half of all patients with genetic neurological disorders, exposing considerable gaps in the understanding of the human genome and providing opportunities to focus research on improving the usefulness of genomics in clinical practice. Looking forward, the emergence of precision health in neurological care will increasingly apply genomic data analysis to pharmacogenetics, preventive medicine, and patient-targeted therapies.

PMID: 30981321 [PubMed - in process]

Increased expression of SLC46A3 to oppose the progression of hepatocellular carcinoma and its effect on sorafenib therapy.

Biomed Pharmacother. 2019 Apr 10;114:108864

Authors: Zhao Q, Zheng B, Meng S, Xu Y, Guo J, Chen LJ, Xiao J, Zhang W, Tan ZR, Tang J, Chen L, Chen Y

Abstract
Hepatocellular carcinoma (HCC) prognosis remains dismal due to postsurgical recurrence and distant metastasis. Therefore, novel prognostic biomarkers and therapeutic targets for HCC therapy are urgently needed to improve the survival of liver cancer patients. Our evidence suggests that SLC46A3 (the gene solute carrier family 46 (sodium phosphate), member 3) is a member of the SLC46 family and has a potential role in the progression and treatment of HCC. The objective of the present study was to estimate the expression pattern and biological function of SLC46A3 in the progression of HCC, which may serve as a promising biomarker for diagnosis and therapy. In order to determine the expression pattern of SLC46A3 in HCC, several public HCC databases and tissue chips were used to examine 129 sets of primary HCC and non-tumor adjacent tissues from patients who had undergone surgery. The expression of SLC46A3 in 80 sets of HCC and non-tumor adjacent tissues were then compared by RT-PCR and Western Blot. The proliferation, invasion, migration and sphere-forming abilities of SLC46A3 knock-down and overexpressing cell lines were evaluated and the expression of related molecules in the epithelial mesenchymal transition (EMT) were detected by RT-PCR, western blot and immunofluorescence assay. The IC50 value was used to evaluate the effect of SLC46A3 on sorafenib resistance. A lung metastasis model of mice HCC was constructed to test the potential effect of SLC46A3 on cancer metastasis and a subcutaneous xenografted tumor mice model was designed to verify the effect of SLC46A3 on the resistance of HCC cell lines to sorafenib. The expression of SLC46A3 was down-regulated in 83.2% of human HCC tissues compared to non-tumor adjacent tissues. Tumors that expressed low levels of SLC46A3 had more aggressive phenotypes, and patients with these tumors had shorter survival times after surgery compared to patients whose tumors expressed high levels of SLC46A3. Hepatocellular carcinoma cell lines that stably overexpressed SLC46A3 inhibited the levels of migration and invasion compared with control HCC cells, and formed smaller xenograft tumors with more metastases in mice compared with HCC cells that did not overexpress SLC46A3. In addition, overexpression of SLC46A3 obviously inhibited epithelial-to-mesenchymal transition-activating transcription factors such as N-cadherin and Vimentin. Furthermore, descended of IC50 showed that overexpressed SLC46A3 could reduce sorafenib resistance and improve drug response in vivo and in vitro. In conclusion, increased expression of SLC46A3 could favor a better clinical prognosis for patients with HCC, ameliorate sorafenib resistance, and improve drug response. SLC46A3 might serve as a potential prognostic biomarker and therapeutic target in HCC.

PMID: 30981107 [PubMed - as supplied by publisher]

Tacrolimus Therapy in Steroid-Refractory Ulcerative Colitis: A Review.

Inflamm Bowel Dis. 2019 Apr 13;:

Authors: Wu B, Tong J, Ran Z

Abstract
Inflammatory bowel diseases are known for a chronic inflammatory process of the gastrointestinal tract and include Crohn's disease and ulcerative colitis (UC). Patients who are dependent on or resistant to corticosteroids account for about 20% of severe UC patients. Tacrolimus is a calcineurin inhibitor that has recently been used in the treatment of steroid-refractory ulcerative colitis. Tacrolimus has been demonstrated to have remarkable therapeutic efficacy in UC patients, without increased risk of severe adverse effects such as induction of remission and maintenance therapy. This article reviews the mechanism of action, pharmacogenetics, efficacy, and safety of tacrolimus for patients with steroid-refractory ulcerative colitis.

PMID: 30980713 [PubMed - as supplied by publisher]

Modulation of YrdC promotes hepatocellular carcinoma progression via MEK/ERK signaling pathway.

Biomed Pharmacother. 2019 Apr 09;114:108859

Authors: Huang S, Zhu P, Sun B, Guo J, Zhou H, Shu Y, Li Q

Abstract
Accumulating evidence suggested that YrdC involved in growth, telomere homeostasis, translation and the N6-threonylcarbamoylation (t6A) of tRNA was abnormally expressed in the progression of tumor. However, the role of YrdC in hepatocellular carcinoma remained elusive. Our study aimed to investigate the clinical significance and oncogenic phenotypes of YrdC in hepatocellular carcinoma, and to determine its related mechanism of this disease. With the usage of GEO datasets, we analyzed the expression of YrdC in hepatocellular carcinoma (HCC). Kaplan-Meier survival analysis was used to evaluate the prognostic significance of hepatocellular carcinoma patients in TCGA. Gain- and loss-of-function analyses in vitro of YrdC were also performed to evaluate its effects on oncogenic phenotypes and relevant signaling pathways. YrdC expression was not only dysregulated in hepatocellular carcinoma tissue but also related to the prognosis of patients with hepatocellular carcinoma. In addition, YrdC depletion suppressed the capability of proliferation, migration and invasion of huh7 cells, while there was opposite result for YrdC overexpression. Our data also unraveled that YrdC promoted the progression of HCC by activating MEK/ERK signaling pathways. Together, our findings indicated that YrdC was a potential prognosis marker for hepatocellular carcinoma, and therapeutic strategies targeting YrdC might hold promise in improving the treatment of hepatocellular carcinoma.

PMID: 30978526 [PubMed - as supplied by publisher]

RASA1 loss in a BRAF-mutated Langerhans cell sarcoma: a mechanism of resistance to BRAF inhibitor.

Ann Oncol. 2019 Apr 12;:

Authors: Jouenne F, De Moura CR, Lorillon G, Meignin V, Dumaz N, Lebbe C, Mourah S, Tazi A

PMID: 30977771 [PubMed - as supplied by publisher]

Are Randomized Controlled Trials Necessary to Establish the Value of Implementing Pharmacogenomics in the Clinic?

Clin Pharmacol Ther. 2019 Apr 12;:

Authors: Huddart R, Sangkuhl K, Whirl-Carrillo M, Klein TE

PMID: 30977517 [PubMed - as supplied by publisher]

The LRP6 functional mutation rs2302685 contributes to individual susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway.

Arch Toxicol. 2019 Apr 11;:

Authors: Xu Y, Chen D, Lin XX, Zhao Q, Guo J, Chen LJ, Zhang W, Xiao J, Lian GH, Peng SF, Guo D, Yang H, Obianom O, Shu Y, Chen Y

Abstract
Low-density lipoprotein receptor-related protein 6 (LRP6) is an important coreceptor in the Wnt/β-catenin upstream signaling pathway. Rs2302685 is a common functional mutation of LRP6 that has been previously associated with reduced alcoholic liver injury among alcoholic liver disease (ALD) patients, and the present research was designed to study the underlying mechanisms of that finding. A total of 107 ALD patients and 138 non-ALD patients were recruited from hospitalized alcoholics in China. Their venous blood samples were collected for DNA extraction and genotyped using Sequenom MassARRAY. We found that the rs2302685 mutation, which impaired the function of LRP6, was present in higher frequency among alcoholics with ALD than those without ALD. We also conducted a mouse model experiment in which LRP6(+/-) knockdown mice and LRP6(+/+) wild-type mice received daily intragastric doses of ethanol (2.4 g/kg) as well as a larger dose of ethanol (4 g/kg) every 7 days for 28 days. The mouse blood and liver specimens were subsequently collected for laboratory analysis, and cell experiments were performed to compare the inhibition, activation, over-expression, and siRNA of LRP6 in the treatment versus the control HL7702 cells. Expression of the targeted molecules was detected by real-time PCR or western blot analysis. Stably transfected cells with pRL3-CYP2E1 vector were used to further study the underlying mechanisms. The total bile acid (TBA), direct bilirubin, total bilirubin (TBIL), aspartate aminotransferase (AST), mitochondrial aspartate aminotransferase, and AST/ALT values were significantly lower in carriers of the rs2302685 mutation than in the wild-type patients, by 63.4, 60.6, 82.1, 44.8, 45.7, and 21.4%, respectively. Compared to the LRP6(+/+) wild-type mice, the LRP6(+/-) knockdown mice had lower ALT, TBIL, TBA, and ALB/GLO values, as well reduced liver tissue damage, in accordance with their reduced expressions of LRP6, β-catenin, and CYP2E1. In HL7702 cells exposed to ethanol, AST, ALT, lipid accumulation, and ROS generation decreased in cells that were treated with LRP6 inhibitors or siRNA but increased in cells treated with LRP6 activators or over-expressed LRP6. TCF1 was the transcriptional factor most likely to connect the LRP6-Wnt/β-catenin signaling pathway to the regulation of CYP2E1. We concluded that the LRP6 functional mutation rs2302685 contributes to individual differences in susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway.

PMID: 30976847 [PubMed - as supplied by publisher]

The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.

Clin Pharmacol Ther. 2018 03;103(3):409-418

Authors: Denny JC, Van Driest SL, Wei WQ, Roden DM

Abstract
Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine.

PMID: 29171014 [PubMed - indexed for MEDLINE]

Polytropic Influence of TRIB3 rs2295490 Genetic Polymorphism on Response to Antihypertensive Agents in Patients With Essential Hypertension.

Front Pharmacol. 2019;10:236

Authors: Zhou J, He F, Sun B, Liu R, Gao Y, Ren H, Shu Y, Chen X, Liu Z, Zhou H, Deng S, Xu H, Li J, Xu L, Zhang W

Abstract
Tribbles homolog 3 (TRIB3) mediating signaling pathways are closely related to blood pressure regulation. Our previous findings suggested a greater benefit on vascular outcomes in patients carrying TRIB3 (251, A > G, rs2295490) G allele with good glucose and blood pressure control. And TRIB3 (rs2295490) AG/GG genotypes were found to reduce primary vascular events in type 2 diabetic patients who received intensive glucose treatment as compared to those receiving standard glucose treatment. However, the effect of TRIB3 genetic variation on antihypertensives was not clear in essential hypertension patients. A total of 368 patients treated with conventional dosage of antihypertensives (6 groups, grouped by atenolol/bisoprolol, celiprolol, doxazosin, azelnidipine/nitrendipine, imidapril, and candesartan/irbesartan) were enrolled in our study. Genetic variations were successfully identified by sanger sequencing. A linear mixed model analysis was performed to evaluate blood pressures among TRIB3 (251, A > G) genotypes and adjusted for baseline age, gender, body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol and other biochemical factors appropriately. Our data suggested that TRIB3 (251, A > G) AA genotype carriers showed better antihypertensive effect than the AG/GG genotype carriers [P = 0.014 for DBP and P = 0.042 for mean arterial pressure (MAP)], with a maximal reduction of DBP by 4.2 mmHg and MAP by 3.56 mmHg after azelnidipine or nitrendipine treatment at the 4th week. Similar tendency of DBP-change and MAP-change was found for imidapril (ACEI) treatment, in which marginally significances were achieved (P = 0.073 and 0.075, respectively). Against that, we found that TRIB3 (251, A > G) AG/GG genotype carriers benefited from antihypertensive therapy of ARBs with a larger DBP-change during the period of observation (P = 0.036). Additionally, stratified analysis revealed an obvious difference of the maximal blood pressure change (13 mmHg for the MAP between male and female patients with AA genotype who took ARBs). Although no significant difference in antihypertensive effect between TRIB3 (251, A > G) genotypes in patients treated with α, β-ADRs was observed, we found significant difference in age-, sex-dependent manner related to α, β-ADRs. In conclusion, our data supported that TRIB3 (251, A > G) genetic polymorphism may serve as a useful biomarker in the treatment of hypertension.

PMID: 30971918 [PubMed]

A Screening Test for HLA-B∗15:02 in a Large United States Patient Cohort Identifies Broader Risk of Carbamazepine-Induced Adverse Events.

Front Pharmacol. 2019;10:149

Authors: Fang H, Xu X, Kaur K, Dedek M, Zhu GD, Riley BJ, Espin FG, Del Tredici AL, Moreno TA

Abstract
Purpose: HLA-B∗15:02 is strongly associated with life-threatening severe skin hypersensitivity reactions in patients treated with carbamazepine (CBZ) and structurally related medications. FDA-approved labeling recommends HLA-B∗15:02 screening before CBZ therapy in patients of Asian ancestry. In this study, we aimed to (a) identify a direct method for screening HLA-B∗15:02, and (b) evaluate prevalence in a large cohort of United States patients. Methods: Candidate genetic markers were identified by mining public data. Association was tested in 28,897 individuals by comparing SNP results with high-resolution HLA typing. Retrospective analysis of de-identified SNP and ethnicity data from 130,460 individuals was performed to evaluate the ethnic distribution of HLA-B∗15:02 in the United States. Results: 28,897 United States individuals showed 100% concordance between HLA-B∗15:02 and the minor allele of rs144012689 (100% sensitivity/99.97% specificity). Retrospective analysis of 160 positive individuals (66 with physician-reported ethnicity) notably included 28 Asians (42%), 15 African Americans (22%), 11 Caucasians (17%), 2 Hispanics (3%), and 10 "Other" (15%). Conclusion: Screening United States patients for HLA-B∗15:02 without ethnicity-based preselection identifies more than twice the number of carriers at risk of CBZ-related adverse events than screening patients of Asian ancestry alone. Risk assessment based on ethnicity assumptions may not identify a large portion of at-risk patients in the ethnically diverse United States population.

PMID: 30971914 [PubMed]

The Crocus sativus Compounds trans-Crocin 4 and trans-Crocetin Modulate the Amyloidogenic Pathway and Tau Misprocessing in Alzheimer Disease Neuronal Cell Culture Models.

Front Neurosci. 2019;13:249

Authors: Chalatsa I, Arvanitis DA, Koulakiotis NS, Giagini A, Skaltsounis AL, Papadopoulou-Daifoti Z, Tsarbopoulos A, Sanoudou D

Abstract
Crocus sativus L. natural compounds have been extensively used in traditional medicine for thousands of years. Recent research evidence is now emerging in support of its therapeutic potential for different pathologies including neurodegenerative diseases. Herein, the C. sativus L. natural compounds trans-crocin 4 and trans-crocetin were selected for in depth molecular characterization of their potentially protective effects against Alzheimer's Disease (AD), utilizing two AD neuronal cell culture models (SH-SY5Y overexpressing APP and PC12 expressing hyperphosphorylated tau). Biologically relevant concentrations, ranging from 0.1 μM to 1 mM, applied for 24 h or 72 h, were well tolerated by differentiated wild type SH-SY5Y and PC12 cells. When tested on neuronally differentiated SH-SY5Y-APP both trans-crocin 4 and trans-crocetin had significant effects against amyloidogenic pathways. Trans-crocin 4 significantly decreased of β-secretase, a key enzyme of the amyloidogenic pathway, and APP-C99, while it decreased γ-secretases that generate toxic beta-amyloid peptides. Similarly, trans-crocetin treatment led to a reduction in β- and γ-secretases, as well as to accumulation of cellular AβPP. When tested on the neuronally differentiated PC12-htau cells, both compounds proved effective in suppressing the active forms of GSK3β and ERK1/2 kinases, as well as significantly reducing total tau and tau phosphorylation. Collectively, our data demonstrate a potent effect of trans-crocin 4 and trans-crocetin in suppressing key molecular pathways of AD pathogenesis, rendering them a promising tool in the prevention and potentially the treatment of AD.

PMID: 30971876 [PubMed]

A genome-wide association study of tramadol metabolism from post-mortem samples.

Pharmacogenomics J. 2019 Apr 11;:

Authors: Wendt FR, Rahikainen AL, King JL, Sajantila A, Budowle B

Abstract
Phase I tramadol metabolism requires cytochrome p450 family 2, subfamily D, polypeptide 6 (CYP2D6) to form O-desmethyltramadol (M1). CYP2D6 genetic variants may infer metabolizer phenotype; however, drug ADME (absorption, distribution, metabolism, and excretion) and response depend on protein pathway(s), not CYP2D6 alone. There is a paucity of data regarding the contribution of trans-acting proteins to idiosyncratic phenotypes following drug exposure. A genome-wide association study identified five markers (rs79983226/kgp11274252, rs9384825, rs62435418/kgp10370907, rs72732317/kgp3743668, and rs184199168/exm1592932) associated with the conversion of tramadol to M1 (M1:T). These SNPs reside within five genes previously implicated with adverse reactions. Analysis of accompanying toxicological meta-data revealed a significant positive linear relationship between M1:T and degree of sample polypharmacy. Taken together, these data identify candidate loci for potential clinical inferences of phenotype following exposure to tramadol and highlight sample polypharmacy as a possible diagnostic covariate in post-mortem genetic studies.

PMID: 30971809 [PubMed - as supplied by publisher]

Identification of SAMD9L as a susceptibility locus for intravenous immunoglobulin resistance in Kawasaki disease by genome-wide association analysis.

Pharmacogenomics J. 2019 Apr 11;:

Authors: Kim JJ, Yun SW, Yu JJ, Yoon KL, Lee KY, Kil HR, Kim GB, Han MK, Song MS, Lee HD, Ha KS, Sohn S, Ebata R, Hamada H, Suzuki H, Ito K, Onouchi Y, Hong YM, Jang GY, Lee JK, and the Korean Kawasaki Disease Genetics Consortium

Abstract
Kawasaki disease (KD) is a systemic vasculitis affecting infants and children; it manifests as fever and signs of mucocutaneous inflammation. Intravenous immunoglobulin (IVIG) treatment effectively attenuates the fever and systemic inflammation. However, 10-20% patients are unresponsive to IVIG. To identify genetic variants influencing IVIG non-response in KD, a genome-wide association study (GWAS) and a replication study were performed using a total of 148 IVIG non-responders and 845 IVIG-responders in a Korean population. rs28662 in the sterile alpha motif domain-containing protein 9-like (SAMD9L) locus showed the most significant result in the joint analysis of GWAS and replication samples (odds ratio (OR) = 3.47, P = 1.39 × 10-5). The same SNP in the SAMD9L locus was tested in the Japanese population, and it revealed a more significant association in a meta-analysis with Japanese data (OR = 4.30, P = 5.30 × 10-6). These results provide new insights into the mechanism of IVIG response in KD.

PMID: 30971808 [PubMed - as supplied by publisher]

Drug-induced QT Interval Prolongation in the Intensive Care Unit.

Curr Clin Pharmacol. 2017;12(4):210-222

Authors: Etchegoyen CV, Keller GA, Mrad S, Cheng S, Di Girolamo G

Abstract
BACKGROUND: The most common acquired cause of Long QT syndrome (LQTS) is drug induced QT interval prolongation. It is an electrophysiological entity, which is characterized by an extended duration of the ventricular repolarization. Reflected as a prolonged QT interval in a surface ECG, this syndrome increases the risk for polymorphic ventricular tachycardia (Torsade de Pointes) and sudden death.
METHOD: Bibliographic databases as MEDLINE and EMBASE, reports and drug alerts from several regulatory agencies (FDA, EMEA, ANMAT) and drug safety guides (ICH S7B, ICH E14) were consulted to prepare this article. The keywords used were: polymorphic ventricular tachycardia, adverse drug events, prolonged QT, arrhythmias, intensive care unit and Torsade de Pointes. Such research involved materials produced up to December 2017.
RESULTS: Because of their mechanism of action, antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are associated to the prolongation of the QTc interval. For this reason, they require constant monitoring when administered. Other noncardiovascular drugs that are widely used in the Intensive Care Unit (ICU), such as ondansetron, macrolide and fluoroquinolone antibiotics, typical and atypical antipsychotics agents such as haloperidol, thioridazine, and sertindole are also frequently associated with the prolongation of the QTc interval. As a consequence, critical patients should be closely followed and evaluated.
CONCLUSION: ICU patients are particularly prone to experience a QTc interval prolongation mainly for two reasons. In the first place, they are exposed to certain drugs that can prolong the repolarization phase, either by their mechanism of action or through the interaction with other drugs. In the second place, the risk factors for TdP are prevalent clinical conditions among critically ill patients. As a consequence, the attending physician is expected to perform preventive monitoring and ECG checks to control the QTc interval.

PMID: 29473523 [PubMed - indexed for MEDLINE]

Regulation of Cholesterol Sulfotransferase SULT2B1b by Hepatocyte Nuclear Factor 4α Constitutes a Negative Feedback Control of Hepatic Gluconeogenesis.

Mol Cell Biol. 2018 04 01;38(7):

Authors: Bi Y, Shi X, Zhu J, Guan X, Garbacz WG, Huang Y, Gao L, Yan J, Xu M, Ren S, Ren S, Liu Y, Ma X, Li S, Xie W

Abstract
The cholesterol sulfotransferase SULT2B1b converts cholesterol to cholesterol sulfate (CS). We previously reported that SULT2B1b inhibits hepatic gluconeogenesis by antagonizing the gluconeogenic activity of hepatocyte nuclear factor 4α (HNF4α). In this study, we showed that the SULT2B1b gene is a transcriptional target of HNF4α, which led to our hypothesis that the induction of SULT2B1b by HNF4α represents a negative feedback to limit the gluconeogenic activity of HNF4α. Indeed, downregulation of Sult2B1b enhanced the gluconeogenic activity of HNF4α, which may have been accounted for by the increased acetylation of HNF4α as a result of decreased expression of the HNF4α deacetylase sirtuin 1 (Sirt1). The expression of Sult2B1b was also induced by HNF4α upon fasting, and the Sult2B1b null (Sult2B1b-/-) mice showed increased gluconeogenic gene expression and an elevated fasting glucose level, suggesting that SULT2B1b also plays a restrictive role in HNF4α-mediated fasting-responsive gluconeogenesis. We also developed thiocholesterol, a hydrolysis-resistant derivative of CS, which showed superior activity to that of the native CS in inhibiting gluconeogenesis and improving insulin sensitivity in high-fat-diet-induced diabetic mice. We conclude that the HNF4α-SULT2B1b-CS axis represents a key endogenous mechanism to prevent uncontrolled gluconeogenesis. Thiocholesterol may be used as a therapeutic agent to manage hyperglycemia.

PMID: 29378829 [PubMed - indexed for MEDLINE]

Population Pharmacogenomics for Precision Public Health in Colombia.

Front Genet. 2019;10:241

Authors: Nagar SD, Moreno AM, Norris ET, Rishishwar L, Conley AB, O'Neal KL, Vélez-Gómez S, Montes-Rodríguez C, Jaraba-Álvarez WV, Torres I, Medina-Rivas MA, Valderrama-Aguirre A, Jordan IK, Gallo JE

Abstract
While genomic approaches to precision medicine hold great promise, they remain prohibitively expensive for developing countries. The precision public health paradigm, whereby healthcare decisions are made at the level of populations as opposed to individuals, provides one way for the genomics revolution to directly impact health outcomes in the developing world. Genomic approaches to precision public health require a deep understanding of local population genomics, which is still missing for many developing countries. We are investigating the population genomics of genetic variants that mediate drug response in an effort to inform healthcare decisions in Colombia. Our work focuses on two neighboring populations with distinct ancestry profiles: Antioquia and Chocó. Antioquia has primarily European genetic ancestry followed by Native American and African components, whereas Chocó shows mainly African ancestry with lower levels of Native American and European admixture. We performed a survey of the global distribution of pharmacogenomic variants followed by a more focused study of pharmacogenomic allele frequency differences between the two Colombian populations. Worldwide, we found pharmacogenomic variants to have both unusually high minor allele frequencies and high levels of population differentiation. A number of these pharmacogenomic variants also show anomalous effect allele frequencies within and between the two Colombian populations, and these differences were found to be associated with their distinct genetic ancestry profiles. For example, the C allele of the single nucleotide polymorphism (SNP) rs4149056 [Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1)∗5], which is associated with an increased risk of toxicity to a commonly prescribed statin, is found at relatively high frequency in Antioquia and is associated with European ancestry. In addition to pharmacogenomic alleles related to increased toxicity risk, we also have evidence that alleles related to dosage and metabolism have large frequency differences between the two populations, which are associated with their specific ancestries. Using these findings, we have developed and validated an inexpensive allele-specific PCR assay to test for the presence of such population-enriched pharmacogenomic SNPs in Colombia. These results serve as an example of how population-centered approaches to pharmacogenomics can help to realize the promise of precision medicine in resource-limited settings.

PMID: 30967898 [PubMed]

Effects of RNA binding protein QKI on pancreatic cancer ductal epithelial cells and surrounding activation fibroblasts.

J Cell Biochem. 2019 Apr 10;:

Authors: Chu L, Hu Y, Jiang YH, Xu C, Liu WC, Lu ZF

Abstract
To determine the correlation between QKI and pancreatic cancer tissues, the QKI expression of pancreatic cancer cells and fibroblasts in the tumor-surrounding microenvironment were detected. Then, QKI overexpression and interference with QKI short hairpin RNA in LX-2 (a fibroblast cell line) were established in vitro. Meanwhile, to observe the cell proliferation, invasion, migration, and other changes, QKI, and related epithelial-mesenchymal transition (EMT) molecules were detected by a polymerase chain reaction and Western blot analysis. In addition, an in vivo tumorigenicity test in node mice was performed to confirm whether QKI expression can promote the proliferation, invasion, and metastasis of pancreatic cancer ductal epithelial cells. Finally, the autophagy levels of fibroblasts with QKI overexpression were observed by electron microscopy to further explore the QKI pathogenic mechanism. It was found that cell proliferation, invasion, migration, and EMT-related markers were increased in QKI-overexpressed fibroblasts LX-2. Furthermore, in vivo, liver and peritoneal metastasis decreased overall survival rate and increasing autophagy levels in QKI-overexpressing nude mice were observed. Meanwhile, knock down QKI with small interfering RNA can reverse all the above effects. QKI can promote the proliferation, metastasis, and invasion of pancreatic cancer through activating fibroblasts surrounding pancreatic cancer and accelerating EMT and increasing the autophagy in pancreatic cancer. QKI may become a potential target for the treatment of pancreatic cancer.

PMID: 30968977 [PubMed - as supplied by publisher]

Prognostic impact of genetic variants of CYP19A1 and UGT2B17 in a randomized trial for endocrine-responsive postmenopausal breast cancer.

Pharmacogenomics J. 2019 Apr 10;:

Authors: Johansson H, Aristarco V, Gandini S, Gjerde J, Macis D, Guerrieri-Gonzaga A, Serrano D, Lazzeroni M, Rajasekaran A, Williard CV, Mellgren G, DeCensi A, Bonanni B

Abstract
Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with "any event" was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2 was associated with higher levels of 17-hydroxy exemestane (P = 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20-1.01; P = 0.05) compared with homozygote UGT2B17 wt. The CYP19A1 rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P = 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P < 0.004). After a median follow-up of 7 years, women carrying the "low estrogen" alleles rs10046 G and rs4646 A had a better prognosis compared with homozygote wt for both polymorphisms (HR = 0.40; 95% CI: 0.17-0.93; P = 0.03). Our analysis points to an impact of UGT2B17 and CYP19A1 in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2 and CYP19A1 low estrogen variants may have better prognosis, supporting studies addressing the role of these polymorphisms in optimizing endocrine therapy. Trial registration: http://www.isrctn.com/ISRCTN86894592 .

PMID: 30967597 [PubMed - as supplied by publisher]

The Italian Rare Pancreatic Exocrine Cancer Initiative.

Tumori. 2019 Apr 09;:300891619839461

Authors: Brunetti O, Luchini C, Argentiero A, Tommasi S, Mangia A, Aprile G, Marchetti P, Vasile E, Casadei Gardini A, Scartozzi M, Barni S, Delfanti S, De Vita F, Di Costanzo F, Milella M, Cella CA, Berardi R, Cataldo I, Santini D, Doglioni C, Maiello E, Lawlor RT, Mazzaferro V, Lonardi S, Giuliante F, Brandi G, Scarpa A, Cascinu S, Silvestris N

Abstract
INTRODUCTION: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available.
METHODS: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays.
CONCLUSIONS: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.

PMID: 30967031 [PubMed - as supplied by publisher]

Functional Effects of let-7g Expression in Colon Cancer Metastasis.

Cancers (Basel). 2019 Apr 06;11(4):

Authors: Chang CM, Wong HS, Huang CY, Hsu WL, Maio ZF, Chiu SJ, Tsai YT, Chen BK, Wan YY, Wang JY, Chang WC

Abstract
MicroRNA regulation is crucial for gene expression and cell functions. It has been linked to tumorigenesis, development and metastasis in colorectal cancer (CRC). Recently, the let-7 family has been identified as a tumor suppressor in different types of cancers. However, the function of the let-7 family in CRC metastasis has not been fully investigated. Here, we focused on analyzing the role of let-7g in CRC. The Cancer Genome Atlas (TCGA) genomic datasets of CRC and detailed data from a Taiwanese CRC cohort were applied to study the expression pattern of let-7g. In addition, in vitro as well as in vivo studies have been performed to uncover the effects of let-7g on CRC. We found that the expression of let-7g was significantly lower in CRC specimens. Our results further supported the inhibitory effects of let-7g on CRC cell migration, invasion and extracellular calcium influx through store-operated calcium channels. We report a critical role for let-7g in the pathogenesis of CRC and suggest let-7g as a potential therapeutic target for CRC treatment.

PMID: 30959863 [PubMed]