Pharmacogenetic associations with cytochrome P450 in antiretroviral therapy: what does the future hold?

Expert Opin Drug Metab Toxicol. 2018 May 18;:

Authors: Stillemans G, Belkhir L, Hesselink DA, Haufroid V, Elens L

Abstract
INTRODUCTION: Several antiretroviral drugs used to treat infection with the Human Immunodeficiency Virus (HIV) are substrates of enzymes belonging to the cytochrome P450 (CYP) superfamily, which are polymorphically expressed. It may therefore be useful to take into account the genetic variation in these enzymes to predict the likelihood of anti-HIV treatment success, toxicity and the potential for drug-drug interactions. Areas covered: In this manuscript, the authors discuss the current state of knowledge regarding pharmacogenetic associations between CYP and all major antiretrovirals, as well as the importance of these associations. Expert opinion: While many pharmacogenetic associations for CYP have been described in the literature, replication studies are sometimes lacking. The implementation of this knowledge in clinical practice also remains difficult. Further efforts are required both to expand this field of knowledge and to enable its use in everyday clinical practice.

PMID: 29775551 [PubMed - as supplied by publisher]

The Expression Alteration of BC1 RNA and its Interaction with Eukaryotic Translation Initiation Factor eIF4A Post-Status Epilepticus.

Neurochem Res. 2018 May 17;:

Authors: Zeng X, Zong W, Gao Q, Chen S, Chen L, Zeng G, Huang W, Li Z, Zeng C, Xie Y, Li X, Xiao B, Dongsheng-Ouyang, Hu K

Abstract
Abnormal dendritic sprouting and synaptic remodelling are important pathological features of temporal lobe epilepsy. BC1 RNA is a translation repressor involved in the regulation of the dendritic protein synthesis and mRNA transport, which is essential for dendritic development and plasticity. The expression alteration of BC1 RNA in the pilocarpine induced epilepsy model remains unknown. It is unclear if the interactions between BC1 RNA and eukaryotic initiation factor 4A (eIF4A) exists in this model. The purpose of this study was to investigate the expression changes of BC1 RNA and its interactions with eIF4A post-status epilepticus (SE). Chloride lithium and pilocarpine were used to induce the SE rat model. Either a whole brain or hippocampus tissues were collected at different time points after SE. The expression patterns of BC1 was detected by qPCR and in situ hybridization. The levels of eIF4AI/II protein expression were analyzed via western blotting and immunohistochemistry. The BC1 RNA-eIF4AI/II interaction was determined by electrophoretic mobility shift assay (EMSA). We found that the BC1 RNA levels decreased in hippocampus 3d, 1w and 2w post-SE before the levels recovered. The eIF4AI/II began to rise 3d post-SE and reached the maximum level 1w post-SE. After 1w post-SE the levels decreased in the hippocampal CA1, CA3 and DG subregions. EMSA analysis showed that BC1 RNA specifically interacted with the eIF4AI/II. The BC1 RNA-eIF4AI/II complex reduced to the lowest level 1w post-SE. Our results suggested that BC1 has a negative regulatory correlation with eIF4AI/II, where BC1 RNA could be involved in epileptogenesis by regulating dendritic protein synthesis.

PMID: 29774448 [PubMed - as supplied by publisher]

Plectin-targeted liposomes enhance the therapeutic efficacy of a PARP inhibitor in the treatment of ovarian cancer.

Theranostics. 2018;8(10):2782-2798

Authors: Dasa SSK, Diakova G, Suzuki R, Mills AM, Gutknecht MF, Klibanov AL, Slack-Davis JK, Kelly KA

Abstract
Advances in genomics and proteomics drive precision medicine by providing actionable genetic alterations and molecularly targeted therapies, respectively. While genomic analysis and medicinal chemistry have advanced patient stratification with treatments tailored to the genetic profile of a patient's tumor, proteomic targeting has the potential to enhance the therapeutic index of drugs like poly(ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors in breast and ovarian cancer patients with BRCA1/2 mutations have shown promise. About 10% of the patients who received Olaparib (PARP inhibitor) showed adverse side effects including neutropenia, thrombocytopenia and in some cases resulted in myelodysplastic syndrome, indicating that off-target effects were substantial in these patients. Through proteomic analysis, our lab previously identified plectin, a cytolinker protein that mislocalized onto the cell surface during malignant transformation of healthy ovarian tissue. This cancer specific phenotype allowed us to image pancreatic cancer successfully using plectin targeted peptide (PTP) conjugated to nanoparticles or displayed on capsid protein of adeno-associated virus (AAV) particles. Objective: The goal of this study was to integrate the available pharmacogenomics and proteomic data to develop effective anti-tumor therapies using a targeted drug delivery approach. Methods: Plectin expression and localization in human ovarian tumor specimens were analyzed followed by in vitro confirmation of cell surface plectin localization in healthy and ovarian cancer cell lines. PTP-conjugated liposomes were prepared and their specificity for plectin+ cells was determined in vitro and in vivo. A remote loading method was employed to encapsulate a PARP inhibitor (AZ7379) into liposomes. An ideal buffer exchange method and remote loading conditions were determined based on the amount of lipid and drug recovered at the end of a remote loading process. Finally, in vivo tumor growth studies were performed to determine the efficacy of PTP liposomes in preventing PARP activity in mice bearing OVCAR8 (high grade epithelial ovarian cancer (EOC)) tumors. Results: PTP liposomal AZ7379 delivery not only enhanced PARP inhibition but also resulted in decelerated tumor growth in mice bearing subcutaneous and intraperitoneal OVCAR8 tumors. In mice bearing subcutaneous or intraperitoneal tumors, treatment with PTP liposomes resulted in a 3- and 1.7-fold decrease in tumor volume, respectively, compared to systemic drug treatment. Conclusion: Targeted drug delivery assisted by genomic and proteomic data provides an adaptable model system that can be extended to effectively treat other cancers and diseases.

PMID: 29774075 [PubMed - in process]

Insurance Coverage Policies for Pharmacogenomic and Multi-Gene Testing for Cancer.

J Pers Med. 2018 May 16;8(2):

Authors: Lu CY, Loomer S, Ceccarelli R, Mazor KM, Sabin J, Clayton EW, Ginsburg GS, Wu AC

Abstract
Insurance coverage policies are a major determinant of patient access to genomic tests. The objective of this study was to examine differences in coverage policies for guideline-recommended pharmacogenomic tests that inform cancer treatment. We analyzed coverage policies from eight Medicare contractors and 10 private payers for 23 biomarkers (e.g., HER2 and EGFR) and multi-gene tests. We extracted policy coverage and criteria, prior authorization requirements, and an evidence basis for coverage. We reviewed professional society guidelines and their recommendations for use of pharmacogenomic tests. Coverage for KRAS, EGFR, and BRAF tests were common across Medicare contractors and private payers, but few policies covered PML/RARA, CD25, or G6PD. Thirteen payers cover multi-gene tests for nonsmall lung cancer, citing emerging clinical recommendations. Coverage policies for single and multi-gene tests for cancer treatments are consistent among Medicare contractors despite the lack of national coverage determinations. In contrast, coverage for these tests varied across private payers. Patient access to tests is governed by prior authorization among eight private payers. Substantial variations in how payers address guideline-recommended pharmacogenomic tests and the common use of prior authorization underscore the need for additional studies of the effects of coverage variation on cancer care and patient outcomes.

PMID: 29772692 [PubMed]

A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica.

Nat Commun. 2018 May 16;9(1):1929

Authors: Estrada K, Whelan CW, Zhao F, Bronson P, Handsaker RE, Sun C, Carulli JP, Harris T, Ransohoff RM, McCarroll SA, Day-Williams AG, Greenberg BM, MacArthur DG

Abstract
Neuromyelitis optica (NMO) is a rare autoimmune disease that affects the optic nerve and spinal cord. Most NMO patients ( > 70%) are seropositive for circulating autoantibodies against aquaporin 4 (NMO-IgG+). Here, we meta-analyze whole-genome sequences from 86 NMO cases and 460 controls with genome-wide SNP array from 129 NMO cases and 784 controls to test for association with SNPs and copy number variation (total N = 215 NMO cases, 1244 controls). We identify two independent signals in the major histocompatibility complex (MHC) region associated with NMO-IgG+, one of which may be explained by structural variation in the complement component 4 genes. Mendelian Randomization analysis reveals a significant causal effect of known systemic lupus erythematosus (SLE), but not multiple sclerosis (MS), risk variants in NMO-IgG+. Our results suggest that genetic variants in the MHC region contribute to the etiology of NMO-IgG+ and that NMO-IgG+ is genetically more similar to SLE than MS.

PMID: 29769526 [PubMed - in process]

Functional characterization of 21 allelic variants of dihydropyrimidine dehydrogenase identified in 1,070 Japanese individuals.

Drug Metab Dispos. 2018 May 16;:

Authors: Hishinuma E, Narita Y, Saito S, Maekawa M, Akai F, Nakanishi Y, Yasuda J, Nagasaki M, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M

Abstract
Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2), encoded by the DPYD gene, is the rate-limiting enzyme in the degradation pathway of endogenous pyrimidine and fluoropyrimidine drugs such as 5-fluorouracil (5-FU). DPD catalyzes the reduction of uracil, thymine, and 5-FU. In Caucasians, DPYD mutations, including DPYD*2A, DPYD*13, c.2846A>T, and 1129-5923C>G/hapB3, are known to contribute to interindividual variations in the toxicity of 5-FU. However, none of these DPYD polymorphisms have been identified in the Asian population. Recently, 21 DPYD allelic variants, including some novel-single nucleotide variants (SNVs), were identified in 1,070 healthy Japanese individuals by analyzing their whole-genome sequences (WGS), but the functional alterations caused by these variants remain unknown. In this study, in vitro analysis was performed on 22 DPD allelic variants by transiently expressing wild-type DPD and 21 DPD variants in 293FT cells and characterizing their enzymatic activities, using 5-FU as a substrate. DPD expression levels and dimeric forms were determined using immunoblotting and blue native-PAGE, respectively. Additionally, the values of three kinetic parameters, the Michaelis constant (Km), maximum velocity (Vmax), and intrinsic clearance (CLint = Vmax/Km), were determined for the reduction of 5-FU. We found that 10 variants exhibited significantly decreased intrinsic clearance in comparison to wild-type DPD. Moreover, the band patterns observed in the immunoblots of blue native gels indicated that DPD dimerization is required for enzymatic activity in DPD. Thus, the detection of rare DPYD variants might facilitate severe adverse effect prediction of 5-FU-based chemotherapy in the Japanese population.

PMID: 29769267 [PubMed - as supplied by publisher]

Allergy to chlorpromazine and valproic acid following carbamazepine hypersensitivity in a patient with an HLA-B*4601 allele.

Neuropsychiatr Dis Treat. 2018;14:1139-1142

Authors: Sakurada K, Kozaru T, Yamada K, Nibuya M, Nagata K, Suzuki E

Abstract
A 73-year-old man, exhibiting psychomotor excitement after traumatic brain injury, developed allergic cutaneous eruptions and hepatic inflammation that did not resolve after the cessation of carbamazepine (CBZ). Fusing maculopapular erythema was observed in the face, neck, presternal region, and bilaterally in the forearms and feet. A drug-induced lymphocyte stimulation test revealed hypersensitivity to chlorpromazine (CPZ) and valproic acid (VPA), as well as to CBZ. The allergic reaction with eosinophilia to CPZ and VPA was suspected to have emerged following CBZ hypersensitivity, since previous treatment with CPZ and VPA prior to the introduction of CBZ had not been associated with adverse reactions earlier in the course of treatment. Recent studies have indicated linkages between severe CBZ hypersensitivity - but not mild CBZ hypersensitivity - and specific leukocyte antigens, HLA-B*1502 and HLA-A*3101, in Asian and European populations. The present case exhibited the HLA-B*4601 allele, which is associated with a high relative risk for the development of CBZ-induced maculopapular eruptions in Japanese and Han Chinese populations. Although cross-hypersensitivity among aromatic compounds, including CBZ and CPZ, is well-established, data regarding CBZ allergy-associated hypersensitivity to VPA are limited. In the present case, a cutaneous allergy to mianserin (a tetracyclic antidepressant) was also observed later in the course of treatment, suggesting additional cross-reactivity exists among aromatic psychotropic drugs. Thus, the association between the HLA-B*4601 allele and allergic reactions to VPA, aromatic psychotropic drugs, and CBZ should be further examined in future studies.

PMID: 29765217 [PubMed]

Pharmacogenomics in Papua New Guineans: unique profiles and implications for enhancing drug efficacy while improving drug safety.

Pharmacogenet Genomics. 2018 Jun;28(6):153-164

Authors: Tucci JD, Pumuye PP, Helsby NA, Barratt DT, Pokeya PP, Hombhanje F, Somogyi AA

Abstract
Papua New Guinea (PNG) can be roughly divided into highland, coastal and island peoples with significant mitochondrial DNA differentiation reflecting early and recent distinct migrations from Africa and East Asia, respectively. Infectious diseases such as tuberculosis, malaria and HIV severely impact on the health of its peoples for which drug therapy is the major treatment and pharmacogenetics has clinical relevance for many of these drugs. Although there is generally little information about known single nucleotide polymorphisms in the population, in some instances, their frequencies have been shown to be higher than anywhere worldwide. For example, CYP2B6*6 is over 50%, and CYP2C19*2 and *3 are over 40 and 25%, respectively. Conversely, CYP2A6*9, 2B6*2, *3, *4 and *18, and 2C8*3 appear to be much lower than in Whites. CYP2D6 known variants are unclear, and for phase II enzymes, only UGT2B7 and UGT1A9 data are available, with variant frequencies either slightly lower than or similar to Whites. Although almost all PNG people tested are rapid acetylators, but which variant(s) define this phenotype is not known. For HLA-B*13:01, HLA-B*35:05 and HLA-C*04:01, the frequencies show some regioselectivity, but the clinical implications with respect to adverse drug reactions are not known. There are minimal phenotype data for the CYPs and nothing is known about drug transporter or receptor genetics. Determination of genetic variants that are rare in Whites or Asians but common in PNG people is a topic of both scientific and clinical importance, and further research needs to be carried out. Optimizing the safety and efficacy of infectious disease drug therapy through pharmacogenetic studies that have translation potential is a priority.

PMID: 29768302 [PubMed - in process]

Digesting a Path Forward: The Utility of Collagenase Tumor Treatment for Improved Drug Delivery.

Mol Pharm. 2018 May 16;:

Authors: Dolor A, Szoka FC

Abstract
Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment. Although collagen synthesis inhibitors are in clinical development, the use of collagenases is contentious and clinically untested in cancer patients. Pretreatment of murine tumors with collagenases increased drug uptake and diffusion 2-10-fold. This modest improvement resulted in decreased tumor growth, but the benefits of collagenase treatment are confounded by risks of toxicity from collagen breakdown in healthy tissues. In this review, we evaluate the published in vitro and in vivo benefits and limitations of collagenase treatment to improve drug delivery.

PMID: 29767984 [PubMed - as supplied by publisher]

Avoidable drug-gene conflicts and polypharmacy interactions in patients participating in a personalized medicine program.

Per Med. 2017 May;14(3):221-233

Authors: Reynolds KK, Pierce DL, Weitendorf F, Linder MW

Abstract
AIM: Determine the ability of a pharmacogenetic service, PRIMER, to identify drug-gene (DGI) and drug-drug interactions (DDI) in patients across multiple conditions. PRIMER consists of patient selection criteria, a gene panel and actionable guidance for DGIs and DDIs.
RESULTS: The average patient was prescribed 12 medications. PRIMER identified significant DGIs in 73% of patients tested, with 43% having more than one DGI. DDIs were found in 87% of patients. The most common actionable DGIs were for opioid, psychotropic and cardiovascular medications.
CONCLUSION: The pairing of patient selection criteria, a multigene panel with evidence-based interpretation and review of DDIs maximizes the patients tested who have actionable benefit and alerts physicians to potentially critical adjustments needed for the patient's medication regimen.

PMID: 29767587 [PubMed - in process]

Lethal hepatotoxicity following 5-fluorouracil/cisplatin chemotherapy: a relevant case report.

Per Med. 2017 May;14(3):197-201

Authors: Hajj A, Ghosn M, Mourad D, Hojaiban K, Mousallem P, Khabbaz LR

Abstract
Some articles have reported severe toxicities induced by cisplatin/5-fluorouracil regimens, nevertheless, severe and lethal liver toxicity has not been previously reported. In this article, we report the case of a 72-year-old woman, who developed fulminant hepatitis, hypoglycemia and hypotension with atrial fibrillation not responding to treatment. After ruling out all other possible causes of hepatitis, the toxicity was more likely attributed to 5-fluorouracil. Genotyping was performed and the patient was found to be a homozygote carrier of the T variant of the MTHFR gene. The patient died two days later. Several factors, including genetic factors, could explain this severe toxicity. The present case discusses the importance of personalized medicine in oncology based on pharmacogenetic analysis of polymorphisms.

PMID: 29767581 [PubMed - in process]

Pharmacogenetics of novel oral anticoagulants: a review of identified gene variants & future perspectives.

Per Med. 2018 May 16;:

Authors: Ašić A, Marjanović D, Mirat J, Primorac D

Abstract
Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants.

PMID: 29767545 [PubMed - as supplied by publisher]

The impact of real-world cardiovascular-related pharmacogenetic testing in an insured population.

Int J Clin Pract. 2018 May 16;:e13088

Authors: Billings J, Racsa PN, Bordenave K, Long CL, Ellis JJ

Abstract
BACKGROUND: Pharmacogenomics is intended to help clinicians provide the right drug to the right patient at an appropriate dose. However, limited evidence of clinical utility has slowed uptake of pharmacogenomic testing (PGT).
OBJECTIVE: To evaluate the impact of real-world cardiovascular (CV)-related PGT on clinical outcomes, healthcare resource utilisation (HCRU) and cost in a large, heterogeneous population.
METHODS: Individuals with Medicare Advantage Prescription Drug, Medicaid, or commercial coverage between 1/1/2011 and 9/30/2015 and ≥1 atherosclerotic CV-related diagnosis were identified. Those with ≥1 claim for CV-related PGT were included in the test group (index date = 1st PGT claim) and matched 1:2 to controls without PGT. Individuals aged <22 or ≥90 years old on the index date, with <12 months continuous enrollment before and after the index date, or without an ASCVD-related diagnosis in the 12-month pre-index period were excluded. The primary outcome was occurrence of a major CV event during the 12-month post-index period.
RESULTS: After adjustment, the PGT group was significantly more likely to experience ischaemic stroke, pulmonary embolism, deep vein thrombosis or a composite event compared with controls. Adjusting for baseline characteristics, HCRU was significantly higher for the test group across all measured outcomes except all-cause and ASCVD-related inpatient admissions. Median all-cause and ASCVD-related healthcare costs were significantly higher for the test group.
CONCLUSIONS: Real world PGT in a large population did not improve outcomes. Tailoring medication therapy to each patient holds great promise for providing quality care but a deeper understanding of how widespread utilisation of PGT might impact objective health outcomes is needed.

PMID: 29767472 [PubMed - as supplied by publisher]

Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A.

Blood. 2018 May 15;:

Authors: Buscarlet M, Provost S, Feroz Zada Y, Bourgoin V, Mollica L, Dubé MP, Busque L

Abstract
We analyzed DNA from PMN (granulocytes), CD14+ (monocytes), CD19+ (B-cells) and CD3+ (T-cells) of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Individuals were aged 55 to 96 (mean age: 70.0). Three lineage categories were defined: myeloid (PMN±monocytes), myelolympho-B (myeloid and B-cells), multipotent (myeloid, B and T-cells). Six individuals with aberrant patterns were excluded from analysis. Fifty-six had a single DNMT3A mutation, 24 had a single TET2 mutation, 7 had a single mutation in other genes (JAK2, ASXL1, CBL or TP53), and 14 had multiple mutations. The lineage restriction patterns of single DNMT3A or TET2 mutated individuals were different. The proportion of myeloid restricted mutations was higher for TET2 (54.2%, 13/24) than for DNMT3A (23.2%, 13/56) (P<.05). It was similar for myelolympho-B but with a 1.5 fold greater proportion of myeloid cells for TET2 individuals (P<.05). Importantly, there was 0% (0/24) individuals with TET2 mutation in the multipotent category in contrast to 35.7% (20/56) for DNMT3A (P<.01). The clone size predicted multipotent pattern for DNMT3A suggesting a time delay for extensive lineage clonal dominance. These distinctive features may be important in deciphering the transformation mechanisms of these frequent mutations.

PMID: 29764839 [PubMed - as supplied by publisher]

Impact of ethnicity on the natural history of Parkinson disease.

Med J Aust. 2018 May 21;208(9):410-414

Authors: Sauerbier A, Aris A, Lim EW, Bhattacharya K, Ray Chaudhuri K

Abstract
Parkinson disease (PD) affects people of all races and ethnicity worldwide. PD is a multineurotransmitter and multisystem disorder and our current concept of the natural history of PD has changed considerably over the past decades. Many aspects of this heterogeneous condition still remain unexplained; one aspect that is poorly studied is the role of ethnicity and manifest motor and non-motor PD. Some preliminary data suggest that the prodromal risk of developing PD, clinical symptom expression and the experience of living with the condition may vary between different ethnic groups. Several factors might play a role in the influence of ethnicity on PD, such as pharmacogenetics, sociocultural aspects and environmental exposures. Increased knowledge on the role of ethnicity in PD may help shed light on the symptom expression and treatment response of PD, address inequalities in health care delivery worldwide and improve the delivery of personalised medicine.

PMID: 29764354 [PubMed - in process]

Multiplexed Nanopore Sequencing of HLA-B Locus in Māori and Pacific Island Samples.

Front Genet. 2018;9:152

Authors: Ton KNT, Cree SL, Gronert-Sum SJ, Merriman TR, Stamp LK, Kennedy MA

Abstract
The human leukocyte antigen (HLA) system encodes the human major histocompatibility complex (MHC). HLA-B is the most polymorphic gene in the MHC class I region and many HLA-B alleles have been associated with adverse drug reactions (ADRs) and disease susceptibility. The frequency of such HLA-B alleles varies by ethnicity, and therefore it is important to understand the prevalence of such alleles in different population groups. Research into HLA involvement in ADRs would be facilitated by improved methods for genotyping key HLA-B alleles. Here, we describe an approach to HLA-B typing using next generation sequencing (NGS) on the MinION™ nanopore sequencer, combined with data analysis with the SeqNext-HLA software package. The nanopore sequencer offers the advantages of long-read capability and single molecule reads, which can facilitate effective haplotyping. We developed this method using reference samples as well as individuals of New Zealand Māori or Pacific Island descent, because HLA-B diversity in these populations is not well understood. We demonstrate here that nanopore sequencing of barcoded, pooled, 943 bp polymerase chain reaction (PCR) amplicons of 49 DNA samples generated ample read depth for all samples. HLA-B alleles were assigned to all samples at high-resolution with very little ambiguity. Our method is a scaleable and efficient approach for genotyping HLA-B and potentially any other HLA locus. Finally, we report our findings on HLA-B genotypes of this cohort, which adds to our understanding of HLA-B allele frequencies among Māori and Pacific Island people.

PMID: 29760718 [PubMed]

An Updated Taxonomy and a Graphical Summary Tool for Optimal Classification and Comprehension of Omics Research.

OMICS. 2018 May;22(5):337-353

Authors: Pirih N, Kunej T

Abstract
The volume of publications and the type of research approaches used in omics system sciences are vast and continue to expand rapidly. This increased complexity and heterogeneity of omics data are challenging data extraction, sensemaking, analyses, knowledge translation, and interpretation. An extended and dynamic taxonomy for the classification and summary of omics studies are essential. We present an updated taxonomy for classification of omics research studies based on four criteria: (1) type and number of genomic loci in a research study, (2) number of species and biological samples, (3) the type of omics technology (e.g., genomics, transcriptomics, and proteomics) and omics technology application type (e.g., pharmacogenomics and nutrigenomics), and (4) phenotypes. In addition, we present a graphical summary approach that enables the researchers to define the main characteristics of their study in a single figure, and offers the readers to rapidly grasp the published study and omics data. We searched the PubMed and the Web of Science from 09/2002 to 02/2018, including research and review articles, and identified 90 scientific publications. We propose a call toward omics studies' standardization for reporting in scientific literature. We anticipate the proposed classification scheme will usefully contribute to improved classification of published reports in genomics and other omics fields, and help data extraction from publications for future multiomics data integration.

PMID: 29762088 [PubMed - in process]

Genomics and pharmacogenomics of pediatric acute lymphoblastic leukemia.

Crit Rev Oncol Hematol. 2018 Jun;126:100-111

Authors: Wu C, Li W

Abstract
Acute lymphoblastic leukaemia (ALL) is a prevalent form of pediatric cancer that accounts for 70-80% of all leukemias. Genome-based analysis, exome sequencing, transcriptomics and proteomics have provided insight into genetic classification of ALL and helped identify novel subtypes of the disease. B and T cell-based ALL are two well-characterized genomic subtypes, significantly marked by bone marrow disorders, along with mutations in trisomy 21 and T53. The other ALLs include Early T-cell precursor ALL, Philadelphia chromosome-like ALL, Down syndrome-associated ALL and Relapsed ALL. Chromosomal number forms a basis of classification, such as, hypodiploid ALL, near-haploid, low-hypodiploid, high-hypodiploid and hypodiploid-ALL. Advances in therapies targeting ALL have been noteworthy, with significant pre-clinical and clinical studies on drug pharmacokinetics and pharmacodynamics. Methotrexate and 6-mercaptopurine are leading drugs with best demonstrated efficacies against childhood ALL. The drugs in combination, following dose titration, have also been used for maintenance therapy. Methotrexate-polyglutamate is a key metabolite that specifically targets the disease pathogenesis, and 6-thioguanine nucleotides, derived from 6-mercaptopurine, impede replication and transcription processes, inducing cytotoxicity. Additionally, glucocorticoids, asparaginase, anthracycline, vincristine and cytarabine that trans-repress gene expression, deprives cells of asparagine, triggers cell cycle arrest, influences cytochrome-P450 polymorphism and inhibits DNA polymerase, respectively, have been used in chemotherapy in ALL patients. Overall, this review covers the progress in genome technology related to different sub-types of ALL and pharmacokinetics and pharmacodynamics of its medications. It also enlightens adverse effects of current drugs, and emphasizes the necessity of genome-wide association studies for restricting childhood ALL.

PMID: 29759551 [PubMed - in process]

First French Pilot Quality Assessment of the EndoPredict Test for Early Luminal Breast Carcinoma.

Anticancer Res. 2018 05;38(5):2909-2914

Authors: Lehmann-Che J, Miquel C, Wong J, Callens C, Rouleau E, Quillien V, Lozano N, Cayre A, Lacroix L, Bieche I, Bertheau P, Teixeira L, Llorca FP, Lamy PJ, DE Cremoux P, GFCO GROUP

Abstract
BACKGROUND/AIM: Genomic signatures are needed for the determination of prognosis in patients with early stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. EndoPredict test is a RNA-based multigene assay that assesses the risk of 10-year relapse in this context. Quality assessment is a mandatory requirement for a laboratory to address the analytical quality of these molecular analyses. The aim of the study was to demonstrate the robustness of this prognostic test, its usefulness for the patient's treatment strategy, at the national level.
MATERIALS AND METHODS: This study presents a pilot quality assessment (QA) of the EndoPredict test using composite design, including the follow-up of internal control values (qREF) of the 12 genes of the assay for 151 independent tests and one formalin-fixed paraffin embedded (FFPE) breast cancer sample. The evaluation of the test was performed by comparing the results of six independent medical laboratories.
RESULTS: All measures were highly reproducible and quantification of the qREF showed a standard deviation of less than 0.50 and a coefficient of variation always of <2%. All laboratories found concordant results for the breast cancer samples. The mean EndoPredict (EP) score for the breast cancer sample was 4.97±0.24. The mean of EPclin score was 3.07±0.05.
CONCLUSION: This first French independent reported QA assessed the robustness and reproducibility of the EndoPredict test. Such a simple composite design could represent an adapted QA for an expensive diagnostic test.

PMID: 29715116 [PubMed - indexed for MEDLINE]

Combined Influence of Genetic Polymorphism and DNA Methylation on ABCB1 Expression and Function in Healthy Chinese Males.

Eur J Drug Metab Pharmacokinet. 2017 Aug;42(4):627-634

Authors: Wu LX, Zhao HB, Wen CJ, Li Y, Shao YY, Yang Z, Zhou HH

Abstract
BACKGROUND AND OBJECTIVES: It is well known that the expression and function of ATP-binding cassette transporter B1 (ABCB1) show high interindividual variability, but the reasons have not yet been fully elucidated. In this study, combined influence of genetic polymorphism and DNA methylation on ABCB1 mRNA expression and digoxin pharmacokinetics in healthy Chinese males was analyzed.
METHODS: A total of 93 subjects who were homozygous for the ABCB1 1236-2677-3435 TTT or CGC haplotype were enrolled in this study. DNA methylation status of the ABCB1 promoter and ABCB1 mRNA expression level in exfoliated intestinal epithelial cells were analyzed using bisulfite sequencing PCR and real-time PCR. The pharmacokinetics of digoxin in subjects were investigated after administration of a single oral dose of digoxin 0.5 mg.
RESULTS: The DNA methylation levels of ABCB1 promoter showed no significant difference between TTT/TTT and CGC/CGC carriers (P = 0.54). Subjects with TTT/TTT haplotype pair and high methylation status (TTT/TTT-HM) showed a significantly lower ABCB1 mRNA level compared to other subjects. Compared with TTT/TTT-HM subgroup, the area under the plasma concentration-time curve from time zero to 72 h (AUC0-72) of digoxin was decreased by 26.9 %, the maximum plasma concentration (C max) was decreased by 25 % and the apparent oral clearance (CL/F) was increased by 21.2 % in CGC/CGC-LM subgroup. The values of time to maximum concentration (t max) and terminal elimination half-life (t 1/2) showed no significant difference.
CONCLUSIONS: Both genetic polymorphism and DNA methylation variation should be taken into consideration to explain the interindividual variability in ABCB1 expression and function more clearly.

PMID: 27683186 [PubMed - indexed for MEDLINE]