POLD1 and POLE Gene Mutations in Jewish Cohorts of Early-Onset Colorectal Cancer and of Multiple Colorectal Adenomas.

Dis Colon Rectum. 2018 Sep;61(9):1073-1079

Authors: Rosner G, Gluck N, Carmi S, Bercovich D, Fliss-Issakov N, Ben-Yehoyada M, Aharon-Caspi S, Kellerman E, Strul H, Shibolet O, Kariv R

Abstract
BACKGROUND: Germline mutations in the DNA polymerase genes POLD1 and POLE confer high risk for multiple colorectal adenomas and colorectal cancer. However, prevalence and the clinical phenotype of mutation carriers are still not fully characterized.
OBJECTIVE: The purpose of this study was to assess the prevalence of germline mutations and to describe the genotype-phenotype correlation in POLD1 and POLE genes in Jewish subjects with multiple colorectal adenomas and/or early-onset mismatch repair proficient colorectal cancers.
DESIGN: This study is a comparison of genetic and clinical data from affected and control groups.
SETTINGS: The study was conducted at a high-volume tertiary referral center.
PATIENTS: The study cohort included 132 subjects: 68 with multiple colorectal adenomas and 64 with early-onset mismatch repair proficient colorectal cancers. The control group included 5685 individuals having no colorectal cancer or colorectal adenomas.
MAIN OUTCOME MEASURES: Study and control subjects were tested for POLD1 and POLE mutations and a clinical correlation was assessed.
RESULTS: Eleven of the 132 study subjects (8.3%) carried either a POLD1 or a POLE mutation: 7 of 68 (10.3%) subjects with multiple colorectal adenomas and 4 of 64 (6.2%) subjects with early-onset mismatch repair proficient colorectal cancer. Three mutations were detected, showing statistical significance in frequency between study and control groups (p < 0.001). Eight of the 11 mutation carriers were Ashkenazi Jews carrying the same POLD1 mutation (V759I), implicating it as a possible low-to-moderate risk founder mutation. Phenotype of mutation carriers was notable for age under 50 at diagnosis, a propensity toward left-sided colorectal cancer, and extracolonic tumors (64%, 100%, and 27% of cases).
LIMITATIONS: The study cohort was limited by its relatively small size.
CONCLUSIONS: Germline mutations in POLD1 and POLE were found to be relatively frequent in our Jewish cohorts. Further studies are needed to clarify the importance of POLD1 and POLE mutations and to define the most suitable surveillance program for Jewish and other POLD1 and POLE mutation carriers. See Video Abstract at http://links.lww.com/DCR/A658.

PMID: 30086056 [PubMed - in process]

Decoding the transcriptional programs activated by psychotropic drugs in the brain.

Genes Brain Behav. 2018 Aug 07;:e12511

Authors: Zygmunt M, Piechota M, Rodriguez Parkitna J, Korostynski M

Abstract
Analysis of drug-induced gene expression in the brain has long held the promise of revealing the molecular mechanisms of drug actions as well as predicting their long-term clinical efficacy. However, despite some successes, this promise has yet to be fulfilled. Here, we present an overview of the current state of understanding of drug-induced gene expression in the brain and consider the obstacles to achieving a robust prediction of the properties of psychoactive compounds based on gene expression profiles. We begin with a comprehensive overview of the mechanisms controlling drug-inducible transcription and the complexity resulting from expression of non-coding RNAs and alternative gene isoforms. Particular interest is placed on studies that examine the associations within drug classes with regard to the effects on gene transcription, alterations in cell signaling and neuropharmacological drug properties. While the ability of gene expression signatures to distinguish specific clinical classes of psychotropic and addictive drugs remains unclear, some reports show that under specific constraints, drug properties can be predicted based on gene expression. Such signatures offer a simple and effective way to classify psychotropic drugs and screen novel psychoactive compounds. Finally, we note that the amount of data regarding molecular programs activated in the brain by drug treatment has grown exponentially in recent years and that future advances may therefore come in large part from integrating the currently available high-throughput data-sets. This article is protected by copyright. All rights reserved.

PMID: 30084543 [PubMed - as supplied by publisher]

Hypersensitivity reactions to nonsteroidal anti-inflammatory drugs: an update on pharmacogenetics studies.

Pharmacogenomics. 2018 Aug 07;:

Authors: Plaza-Serón MDC, García-Martín E, Agúndez JA, Ayuso P

Abstract
Nonsteroidal anti-inflammatory drugs are the medications most frequently involved in hypersensitivity reactions to drugs. These can be induced by specific immunological and nonimmunological mechanisms, being the latter the most frequent. The nonimmunological mechanism is related to an imbalance of inflammatory mediators, which is aggravated by the cyclooxygenase inhibition. Genetic studies suggest that multiples genes and additional mechanisms might be involved. The proposals of this review is summarize the contribution of variations in genes involved in the arachidonic acid, inflammatory and immune pathways as well as the recent genome-wide association studies findings related to cross-intolerant nonsteroidal anti-inflammatory drugs hypersensitivity reactions. In addition, using integration of different genetic studies, we propose new target genes. This will help to understand the underlying mechanism of these reactions.

PMID: 30081739 [PubMed - as supplied by publisher]

Integrative clinico-biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological correlations in depressive and anxiety disorders.

Rom J Morphol Embryol. 2017;58(3):767-775

Authors: Hogea LM, Nussbaum LA, Chiriac DV, Ageu LŞ, Andreescu NI, Grigoraş ML, Folescu R, Bredicean AC, Puiu M, Roşca ECI, Simu MA, Levai CM

Abstract
We approach the theme of modern treatment strategies, based on clinico-biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological integrative correlations in the management of depressive and comorbid anxiety disorders. We target to evaluate the efficacy of the pharmacogenetic testing and the evolution, functioning of patients in correlation with specific neurobiological, neuroimagistic and neuroendocrinological markers. Our research was conducted between 2010-2016 on 80 children and adolescents with depressive and comorbid anxiety disorders - 40 children (G1 group), who benefited in choosing the pharmacotherapy from pharmacogenetic testing and 40 children without testing (G2 group). Also, the patients were evaluated through magnetic resonance (MR) spectroscopy at baseline and after pharmacotherapy. The efficacy of the chosen therapy in correlation with the pharmacogenetic testing was evaluated through the mean change in the CDRS (Children's Depression Rating Scale) total scores, in the CGI-S÷I (Clinical Global Impression - Severity÷Improvement), CGAS (Children's Global Assessment Scale) and through the change of the relevant neurobiological markers and MR spectroscopy metabolites. We evaluated the side effects through the PAERS (Pediatric Adverse Events Rating Scale)-Clinician. Our results show statistically significant differences of the clinical scores between the studied groups: for those subjects who benefited of pharmacogenetic testing, the CDRS, the global functioning scores prove a higher clinical improvement, a better compliance and lower PAERS side effects scores and also improvement concerning the MR spectroscopy dosed metabolites values. Our research was a proof sustaining the use of the pharmacogenetic testing in clinical practice and the value of investigating relevant neurobiological, neuroimagistic and neuroendocrinological markers for a personalized therapy in depressive disorders.

PMID: 29250653 [PubMed - indexed for MEDLINE]

Combinatorial pharmacogenomics and improved patient outcomes in depression: Treatment by primary care physicians or psychiatrists.

J Psychiatr Res. 2018 Jul 21;104:157-162

Authors: Tanner JA, Davies PE, Voudouris NC, Shahmirian A, Herbert D, Braganza N, Gugila A, Dechairo BM, Kennedy JL

Abstract
Failed medication trials are common in the treatment of major depressive disorder (MDD); however, the use of combinatorial pharmacogenomics to guide medication selection has been previously associated with improved outcomes in the psychiatric care setting. The utility of combinatorial pharmacogenomics in patients with MDD in primary care and psychiatric care settings was evaluated here. Patients enrolled in a naturalistic, open-label, prospective study [Individualized Medicine: Pharmacogenetics Assessment and Clinical Treatment (IMPACT)] with MDD were evaluated (N = 1871). Pharmacogenomic testing was performed for all patients and medications were categorized based on gene-drug interactions. Beck's Depression Inventory (BDI) was evaluated at baseline and follow-up (weeks 8-12). Symptom improvement (percent decrease in BDI), response (≥50% decrease in BDI), and remission (BDI≤10) at follow-up were evaluated according to provider type and whether medications were genetically congruent (little/no gene-drug interactions). There was a 27.9% reduction in depression symptoms at follow-up, as well as response and remission rates of 25.7% and 15.2%, respectively. Outcomes were significantly better among patients treated by primary care providers versus psychiatrists (symptom improvement 31.7% versus 24.9%, p < 0.01; response rate 30.1% versus 22.3%, p < 0.01; remission rate 19.5% versus 12.0%, p < 0.01). There was a 31% relative improvement in response rate among patients taking congruent versus incongruent medications, with slightly higher congruence among primary care providers (87.6%) versus psychiatrists (85.2%). Following combinatorial pharmacogenomic testing, outcomes were significantly improved among patients treated by primary care providers compared to psychiatrists, which supports the use of pharmacogenomics in broader treatment settings.

PMID: 30081389 [PubMed - as supplied by publisher]

Pharmacogenetics Analysis of Serotonin Receptor Gene Variants and Clinical Response to Risperidone in Han Chinese Schizophrenic Patients.

Neurosci Lett. 2018 Aug 03;:

Authors: Zhou W, Chang W, Yan Y, Shen L, Li W, Yi Z, Qin S

Abstract
Assessments of the pharmacological profiles of antipsychotic agents have shown that the serotonin receptor family is often involved in their pharmacodynamics. Response to antipsychotic therapy is highly variable, yet prognostic biomarkers are lacking. The aim of the study was to investigate the association of 14 single nucleotide polymorphisms (SNPs) selected from HTR3C, HTR3D, HTR5A and HTR6 with risperidone response in 201 Han Chinese schizophrenia patients. The results showed that the HTR6 rs6699866 was significantly associated with risperidone response and predicted greater positive symptom reduction in risperidone-treated subjects (P =  0.04 and 0.004, respectively). The current study provides insight into the relationship between genetic polymorphisms in serotonin receptor family and risperidone therapeutic response in Han Chinese population. To clarify the role of these SNPs in clinical response to antipsychotic medication, and risperidone in particular, the study warrants further investigation in larger well-characterized samples.

PMID: 30081060 [PubMed - as supplied by publisher]

Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients.

Br J Haematol. 2018 Aug 06;:

Authors: Macauda A, Castelli E, Buda G, Pelosini M, Butrym A, Watek M, Kruszewski M, Vangsted AJ, Rymko M, Jamroziak K, Abildgaard N, Haastrup EK, Mazur G, Ríos R, Jurczyszyn A, Zawirska D, Dudziński M, Raźny M, Dutka M, Tomczak W, Suska A, Druzd-Sitek A, Marques H, Petrini M, Markiewicz M, Martinez-Lopez J, Ebbesen LH, Iskierka-Jażdżewska E, Sainz J, Canzian F, Campa D

Abstract
Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.

PMID: 30079960 [PubMed - as supplied by publisher]

Glucocorticoid receptor single nucleotide polymorphisms are associated with acute crisis pain in sickle cell disease.

Pharmacogenomics. 2018 Aug 06;:

Authors: Jhun EH, Sadhu N, Yao Y, He Y, Molokie RE, Wilkie DJ, Wang ZJ

Abstract
AIM: Pain in sickle cell disease patients is heterogeneous and genetic polymorphisms may predispose an individual to varied vulnerability to painful events. We studied the association of SNPs in the glucocorticoid receptor gene (NR3C1) with pain in sickle cell disease.
METHOD: Acute pain was scored as the number of utilizations due to crisis pain in a 12-month period. Chronic pain was calculated as the Composite Pain Index score.
RESULTS & CONCLUSION: rs33389 T allele (IRR = 1.53, p = 0.014 additive; IRR = 1.64, p = 0.011 recessive), rs2963155 G allele (IRR = 1.80, p < 0.001 additive; IRR = 2.25, p = 0.021 dominant; IRR = 2.07, p < 0.001 recessive) and rs9324918 C allele (IRR = 1.43, p = 0.021 additive) were associated with higher utilization rates, indicating the potential contribution of NR3C1 polymorphisms to acute pain heterogeneity in sickle cell disease.

PMID: 30079801 [PubMed - as supplied by publisher]

17β-estradiol suppresses carboxylesterases by activating c-Jun/AP-1 pathway in primary human and mouse hepatocytes.

Eur J Pharmacol. 2018 Jan 15;819:98-107

Authors: Wu L, Hafiz MZ, Guan Y, He S, Xiong J, Liu W, Yan B, Li X, Yang J

Abstract
In order to study the influence of estrogen on carboxylesterases, we investigated the effects of 17β-estradiol on CES1 (Ces1d) and CES2 (Ces1e) in human and mouse hepatocytes. After being treated with 17β-estradiol, the mRNA levels of CES1 and CES2 decreased by 29-39% and 28-55%, respectively, in the human hepatocytes from four donors. Consistently, the hydrolysis of para-nitrophenylacetate decreased markedly by 32% induced by 17β-estradiol. Moreover, 17β-estradiol decreased CES1 and CES2 by 45% and 47% respectively at protein levels. The response of altered expression of Ces1d (CES1) and Ces1e (CES2) to 17β-estradiolin in mouse hepatocytes was very similar to that in the human hepatocytes. Further, the decreased Ces1d and Ces1e expression induced by 17β-estradiol could be abolished by SP600125, an inhibitor of AP-1, both at mRNA and protein levels. Likewise, the increased c-Jun expression induced by 17β-estradiol could almost be abolished by SP600125. In vivo, the expression of Ces1d, Ces1e and the hydrolytic activity of liver were higher in the ovariectomized female mice(OVX) than those in control mice(SHAM). However, when 17β-estradiol was administrated, the expression of Ces1d, Ces1e and the hydrolytic activity of liver in the ovariectomized female mice (OVX+E2) became restored to their normal levels. Taken together, 17β-estradiol suppresses carboxylesterases by activating c-Jun/AP-1 pathway in primary human and mouse hepatocytes. The findings can offer the potential gains in the safety and efficacy of pharmacotherapy for women, especially for pregnant and menopausal women.

PMID: 29175444 [PubMed - indexed for MEDLINE]

Pharmacoepigenetics and pharmacoepigenomics of gastrointestinal cancers.

Expert Rev Gastroenterol Hepatol. 2018 Jan;12(1):49-62

Authors: Lopomo A, Coppedè F

Abstract
INTRODUCTION: Our understanding of the epigenetic changes occurring in gastrointestinal cancers has gained tremendous advancements in recent years, and some epigenetic biomarkers are already translated into the clinics for cancer diagnostics. In parallel, pharmacoepigenetics and pharmacoepigenomics of solid tumors are relevant novel, but emerging and promising fields. Areas covered: A comprehensive review of the literature to summarize and update the emerging field of pharmacoepigenetics and pharmacoepigenomics of gastrointestinal cancers. Expert commentary: Several epigenetic modifications have been proposed to account for interindividual variations in drug response in gastrointestinal cancers. Similarly, single-agent or combined strategies with high doses of drugs that target epigenetic modifications (epi-drugs) were scarcely tolerated by the patients, and current research has moved to their combination with standard therapies to achieve chemosensitization, radiosensitization, and immune modulation of cancerous cells. In parallel, recent genome-wide technologies are revealing the pathways that are epigenetically deregulated during cancer-acquired resistance, including those targeted by non-coding RNAs. Indeed, novel, less toxic, and more specific molecules are under investigation to specifically target those pathways. The field is rapidly expanding and gathering together information coming from these investigations has the potential to lead to clinical applications in the coming new years.

PMID: 28856927 [PubMed - indexed for MEDLINE]

Therapeutic drug monitoring of voriconazole for treatment and prophylaxis of invasive fungal infection in children.

Br J Clin Pharmacol. 2018 Jan;84(1):197-203

Authors: Allegra S, Fatiguso G, De Francia S, Favata F, Pirro E, Carcieri C, De Nicolò A, Cusato J, Di Perri G, D'Avolio A

Abstract
Voriconazole therapeutic drug monitoring is not consistently recommended due to its high interpatient and intrapatient variability. Here, we aimed to describe our experience with voriconazole for treatment and prophylaxis of invasive fungal infections in paediatric patients. A fully validated high-performance liquid chromatography-mass spectrometry method was used to quantify voriconazole concentration in plasma, at the end of dosing interval. A high interindividual variability was shown. We enrolled 237 children, 83 receiving intravenous and 154 oral voriconazole. A positive correlation between drug dose and drug plasma exposure was observed. Considering intravenous route, patients with higher serum creatinine had higher voriconazole concentrations; a positive correlation was found among drug exposure and age. Sex significantly influenced drug levels: males had higher median drug concentrations than females (P < 0.001). Close voriconazole pharmacokinetics monitoring should help individualize antifungal therapy for children.

PMID: 28805964 [PubMed - indexed for MEDLINE]

[Inhalational analgosedation in the intensive care unit : Risk of malignant hyperthermia].

Med Klin Intensivmed Notfmed. 2018 Aug 03;:

Authors: Klingler W, Pfenninger E

Abstract
BACKGROUND: According to the 2010 S3 Guidelines, analgosedation is an option for ventilated patients in intensive care units (ICU). Therefore, adverse effects of volatile anesthetics can occur in areas outside of surgical medical fields.
OBJECTIVE: The aim is to inform ICU physicians about the clinical and legal challenges of a life-threatening pharmacogenetic reaction to inhalational anesthetics, malignant hyperthermia (MH).
DISCUSSION: Consequences of an MH crisis for doctors, patients, and relatives regarding patient rights legislation, as well as insurance and employment issues with respect to the German Genetic Diagnostics Act are discussed.

PMID: 30076433 [PubMed - as supplied by publisher]

Genetic Association of Single Nucleotide Polymorphisms with Acetaminophen-Induced Hepatotoxicity.

J Pharmacol Exp Ther. 2018 Aug 03;:

Authors: Heruth DP, Shortt K, Zhang N, Li DY, Zhang LQ, Ye SQ

Abstract
Acetaminophen is commonly used to reduce pain and fever. Unfortunately, overdose of acetaminophen is a leading cause of acute liver injury and failure in many developed countries. The majority of acetaminophen is safely metabolized in the liver and excreted in the urine; however a small percentage is converted to the highly reactive N-acetyl-p-benzoquinone imine (NAPQI). At therapeutic doses, NAPQI is inactivated by glutathione S-transferases, but at toxic levels, excess NAPQI forms reactive protein adducts that lead to hepatotoxicity. Individual variability in the response to both therapeutic and toxic levels of acetaminophen suggests a genetic component is involved in acetaminophen metabolism. In this review, we evaluate the genetic association studies that have identified 147 single nucleotide polymorphisms (SNPs) linked to acetaminophen-induced hepatotoxicity. The identification of novel genetic markers for acetaminophen-induced hepatotoxicity provides a rich resource for further evaluation and may lead to improved prognosis, prevention, and treatment.

PMID: 30076262 [PubMed - as supplied by publisher]

Host genetic profiling to increase drug safety in colorectal cancer from discovery to implementation.

Drug Resist Updat. 2018 Jul;39:18-40

Authors: Cecchin E, De Mattia E, Ecca F, Toffoli G

Abstract
Adverse events affect the pharmacological treatment of approximately 90% of colorectal cancer (CRC) patients at any stage of the disease. Chemotherapy including fluoropyrimidines, irinotecan, and oxaliplatin is the cornerstone of the pharmacological treatment of CRC. The introduction of novel targeted agents, as anti-EGFR (i.e. cetuximab, panitumumab) and antiangiogenic (i.e. bevacizumab, ziv-aflibercept, regorafenib, and ramucirumab) molecules, into the oncologist's toolbox has led to significant improvements in the life expectancy of advanced CRC patients, but with a substantial increase in toxicity burden. In this respect, pharmacogenomics has largely been applied to the personalization of CRC chemotherapy, focusing mainly on the study of inhered polymorphisms in genes encoding phase I and II enzymes, ATP-binding cassette (ABC)/solute carrier (SLC) membrane transporters, proteins involved in DNA repair, folate pathway and immune response. These research efforts have led to the identification of some validated genetic markers of chemotherapy toxicity, for fluoropyrimidines and irinotecan. No validated genetic determinants of oxaliplatin-specific toxicity, as peripheral neuropathy, has thus far been established. The contribution of host genetic markers in predicting the toxicity associated with novel targeted agents' administration is still controversial due to the heterogeneity of published data. Pharmacogenomics guidelines have been published by some international scientific consortia such as the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) strongly suggesting a pre-treatment dose adjustment of irinotecan based on UGT1A1*28 genotype and of fluoropyrimidines based on some DPYD genetic variants, to increase treatment safety. However, these recommendations are still poorly applied at the patient's bedside. Several ongoing projects in the U.S. and Europe are currently evaluating how pharmacogenomics can be implemented successfully in daily clinical practice. The majority of drug-related adverse events are still unexplained, and a great deal of ongoing research is aimed at improving knowledge of the role of pharmacogenomics in increasing treatment safety. In this review, the issue of pre-treatment identification of CRC patients at risk of toxicity via the analysis of patients' genetic profiles is addressed. Available pharmacogenomics guidelines with ongoing efforts to implement them in clinical practice and new exploratory markers for clinical validation are described.

PMID: 30075835 [PubMed - in process]

RIF1 promotes human epithelial ovarian cancer growth and progression via activating human telomerase reverse transcriptase expression.

J Exp Clin Cancer Res. 2018 Aug 03;37(1):182

Authors: Liu YB, Mei Y, Long J, Zhang Y, Hu DL, Zhou HH

Abstract
BACKGROUND: Human telomerase reverse transcriptase (hTERT) is highly expressed in over 80% of tumors, including human epithelial ovarian cancer (EOC). However, the mechanisms through which hTERT is up-regulated in EOC and promotes tumor progression remain unclear. The aim of this study is to identify RIF1 as a novel molecular target that modulate hTERT signaling and EOC growth.
METHODS: RIF1 expression in ovarian cancer, benign and normal ovarian tissues was examined by immunohistochemistry. The biological role of RIF1 was revealed by MTS, colony formation and sphere formation assays. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify RIF1 as a novel hTERT promoter-binding protein in EOC cells. The role of RIF1 on tumorigenesis in vivo was detected by the xenograft model.
RESULTS: RIF1 expression is upregulated in EOC tissues and is closely correlated with FIGO stage and prognosis of EOC patients. Functionally, RIF1 knockdown suppressed the expression and promoter activity of hTERT and consequently inhibited the growth and CSC-like traits of EOC cells. RIF1 knockdown also inhibited tumorigenesis in xenograft model. RIF1 overexpression had the opposite effect. Luciferase reporter assay and ChIP assay verified RIF1 directly bound to hTERT promoter to upregulate its expression. The rescue experiments suggested hTERT overexpression rescued the inhibition of EOC cell growth and CSC-like traits mediated by RIF1 knockdown. Consistently, hTERT knockdown abrogated the RIF1-induced promotion of EOC cell growth and CSC-like traits.
CONCLUSIONS: RIF1 promotes EOC progression by activating hTERT and the RIF1/hTERT pathway may be a potential therapeutic target for EOC patients.

PMID: 30075819 [PubMed - in process]

Medullary Breast Carcinoma, a Triple-Negative Breast Cancer Associated with BCLG Overexpression.

Am J Pathol. 2018 Jul 31;:

Authors: Romero P, Benhamo V, Deniziaut G, Fuhrmann L, Berger F, Manié E, Bhalshankar J, Vacher S, Laurent C, Marangoni E, Gruel N, MacGrogan G, Rouzier R, Delattre O, Popova T, Reyal F, Stern MH, Stoppa-Lyonnet D, Marchiò C, Bièche I, Vincent-Salomon A

Abstract
Medullary breast carcinoma (MBC) is a rare subtype of triple-negative breast cancer with specific genomic features within the spectrum of basal-like carcinoma (BLC). In this study including 19 MBC and 36 non-MBC BLC, we refined the transcriptomic and genomic knowledge about this entity. Unsupervised and supervised analysis of transcriptomic profiles confirmed that MBC clearly differs from non-MBC BLC, with 92 genes overexpressed and 154 genes underexpressed in MBC compared to non-MBC BLC. Immunity-related pathways are the most differentially represented pathways in MBC compared to non-MBC BLC. Pro-apoptotic gene BCLG (official name BCL2L14) is by far the most intensely overexpressed gene in MBC. A RT-qPCR validation study conducted in 526 breast tumors corresponding to all molecular subtypes documented the specificity of BCLG overexpression in MBC, which was confirmed at the protein level by immunohistochemistry. We also showed that the majority of MBC belong to the immunomodulatory triple-negative breast cancer subtype. Using pan-genomic analysis, we showed that MBC harbors more losses of heterozygosity than non-MBC BLC. Our observations corroborate the notion that MBC remains a distinct entity that could benefit from specific treatment strategies (like de-escalation or targeted therapy) adapted to this rare tumor type.

PMID: 30075151 [PubMed - as supplied by publisher]

Synthesis, Anti-Proliferative Activity Evaluation and 3D-QSAR Study of Naphthoquinone Derivatives as Potential Anti-Colorectal Cancer Agents.

Molecules. 2018 Jan 17;23(1):

Authors: Acuña J, Piermattey J, Caro D, Bannwitz S, Barrios L, López J, Ocampo Y, Vivas-Reyes R, Aristizábal F, Gaitán R, Müller K, Franco L

Abstract
Colorectal cancer (CRC) is a disease with high incidence and mortality, constituting the fourth most common cause of death from cancer worldwide. Naphthoquinones are attractive compounds due to their biological and structural properties. In this work, 36 naphthoquinone derivatives were synthesized and their activity evaluated against HT-29 cells. Overall, high to moderate anti-proliferative activity was observed in most members of the series, with 15 compounds classified as active (1.73 < IC50 < 18.11 μM). The naphtho[2,3-b]thiophene-4,9-dione analogs showed potent cytotoxicity, 8-hydroxy-2-(thiophen-2-ylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione being the compound with the highest potency and selectivity. Our results suggest that the toxicity is improved in molecules with tricyclic naphtho[2,3-b]furan-4,9-dione and naphtho[2,3-b]thiophene-4,9-dione systems 2-substituted with an electron-withdrawing group. A 3D-QSAR study of comparative molecular field analysis (CoMFA) was carried out, resulting in the generation of a reliable model (r² = 0.99 and q² = 0.625). This model allowed proposing five new compounds with two-fold higher theoretical anti-proliferative activity, which would be worthwhile to synthesize and evaluate. Further investigations will be needed to determine the mechanism involved in the effect of most active compounds which are potential candidates for new anticancer agents.

PMID: 29342104 [PubMed - indexed for MEDLINE]

Glucocorticoid Receptor Genetic Variants and Response to Fluoxetine in Major Depressive Disorder.

J Neuropsychiatry Clin Neurosci. 2018;30(1):45-50

Authors: Nouraei H, Firouzabadi N, Mandegary A, Zomorrodian K, Bahramali E, Shayesteh MRH, Ansari S

Abstract
Hyperactivity of the hypothalamic pituitary adrenocortical (HPA) axis is one of the main clinical findings in depression. The HPA axis is interrelated with glucocorticoid signaling via glucocorticoid receptors (GCRs). Thus, functional genetic variants on GCRs might influence therapeutic outcomes in depression. The aim of the present study was to investigate the association between three functional polymorphisms (rs41423247, rs6195, and rs6189/rs6190) on GCR and response to fluoxetine in a group of depressed patients. One hundred newly diagnosed patients completed 6 weeks of fluoxetine treatment. Response to treatment was defined as a 50% decrease in the Hamilton Depression Rating Scale score. Variants of rs41423247, rs6195, and rs6189/rs6190 polymorphisms were determined in extracted DNAs using PCR-RFLP method. Regarding rs41423247 polymorphism, carriers of the CG and GG genotype responded significantly better to fluoxetine compared with CC carriers (p=0.008, OR=3.3, 95% CI=1.35-8.07). Moreover, the G allele of rs41423247 polymorphism was strongly associated with response to fluoxetine (p=0.032, OR=2.2, 95% CI=1.09-4.44). There was no significant association between different genotypes and alleles of rs6195, rs6189/rs6190 variants, and response to fluoxetine (p=0.213 and 0.99, respectively). In conclusion, rs41423247 polymorphism might be a predictor for better response to fluoxetine. These findings support the idea that some variants of the GCR might contribute to interindividual variability of response to antidepressants.

PMID: 28641498 [PubMed - indexed for MEDLINE]

DNA methylation and gene expression profiling reveal MFAP5 as a regulatory driver of extracellular matrix remodeling in varicose vein disease.

Epigenomics. 2018 Aug 02;:

Authors: Smetanina MA, Kel AE, Sevost'ianova KS, Maiborodin IV, Shevela AI, Zolotukhin IA, Stegmaier P, Filipenko ML

Abstract
AIM: To integrate transcriptomic and DNA-methylomic measurements on varicose versus normal veins using a systems biological analysis to shed light on the interplay between genetic and epigenetic factors.
MATERIALS & METHODS: Differential expression and methylation were measured using microarrays, supported by real-time quantitative PCR and immunohistochemistry confirmation for relevant gene products. A systems biological 'upstream analysis' was further applied.
RESULTS: We identified several potential key players contributing to extracellular matrix remodeling in varicose veins. Specifically, our analysis suggests MFAP5 acting as a master regulator, upstream of integrins, of the cellular network affecting the varicose vein condition. Possible mechanism and pathogenic model were outlined.
CONCLUSION: A coherent model proposed incorporates the relevant signaling networks and will hopefully aid further studies on varicose vein pathogenesis.

PMID: 30070582 [PubMed - as supplied by publisher]

CYP2D6 allele frequencies, copy number variants, and tandems in the population of Hong Kong.

J Clin Lab Anal. 2018 Aug 01;:e22634

Authors: Chan W, Li MS, Sundaram SK, Tomlinson B, Cheung PY, Tzang CH

Abstract
BACKGROUND: CYP2D6 plays a crucial role in drug metabolism of several drugs. It is known to be highly polymorphic with enzymatic activity ranging from poor to ultrarapid metabolic rates. While the frequencies of CYP2D6 alleles are generally known in different Asian populations, data on frequencies of the copy number variations (CNV) and tandems in CYP2D6 in which they occur are less well studied in these populations.
METHODS: A cohort of 800 consecutive, unrelated individuals were referred to Prenetics Limited (Prenetics) iGenes test by physicians in Hong Kong as part of their care with informed consent. These clinical samples were deidentified prior to further analysis. Genotyping and copy number determination of CYP2D6 were performed using target specific TaqMan® SNP genotyping and copy number assays. The phenotypes of CYP2D6 were predicted based on its genotypes and is dependent on the biallelic expression of alleles.
RESULTS: Among the Asian group (n = 735, 92%), the observed frequency of CYP2D6*36-*10 tandems was 34.1%. We also identified duplication of CYP2D6 alleles in 86 (11.7%) individuals of the study cohort. The frequency of all CYP2D6 duplicated alleles was 154 (10.5%) while only 28 (1.9%) of the duplications were of functional alleles (ie CYP2D6*1 and CYP2D6*2).
CONCLUSION: The present study provides a comprehensive analysis on the occurrences of CNV and tandems of the CYP2D6 gene in the Hong Kong population. The results contribute to the overall knowledge of pharmacogenomics and may accelerate the implementation of precision medicine in Asia.

PMID: 30069923 [PubMed - as supplied by publisher]