Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun. 2020 May 11;11(1):2220

Authors: Ji X, Mukherjee S, Landi MT, Bosse Y, Joubert P, Zhu D, Gorlov I, Xiao X, Han Y, Gorlova O, Hung RJ, Brhane Y, Carreras-Torres R, Christiani DC, Caporaso N, Johansson M, Liu G, Bojesen SE, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Chen C, Byun J, Dragnev KH, Field JK, Kiemeney LF, Lazarus P, Zienolddiny S, Lam S, Schabath MB, Andrew AS, Bertazzi PA, Pesatori AC, Diao N, Su L, Song L, Zhang R, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman C, Wilkens L, Fernandez-Somoano A, Fernandez-Tardon G, Heijden EHFMV, Kim JH, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Goodman GE, Cox A, Taylor F, Woll P, Wichmann E, Muley T, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd F, Tsao MS, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Butler LM, Offit K, Srinivasan P, Bandlamudi C, Hellmann MD, Solit DB, Robson ME, Rudin CM, Stadler ZK, Taylor BS, Berger MF, Houlston R, McLaughlin J, Stevens V, Nickle DC, Obeidat M, Timens W, Artigas MS, Shete S, Brenner H, Chanock S, Brennan P, McKay JD, Amos CI

Abstract
Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

PMID: 32393777 [PubMed - in process]

Tamoxifen Metabolism and Breast Cancer Recurrence: A Question Unanswered by CYPTAM.

J Clin Oncol. 2019 08 01;37(22):1982-1983

Authors: Goetz MP, Suman VJ, Nakamura Y, Kiyotani K, Jordan VC, Ingle JN

PMID: 31211604 [PubMed - indexed for MEDLINE]

CYP2D6 genotype and adverse events to risperidone in children and adolescents.

Pediatr Res. 2019 04;85(5):602-606

Authors: Oshikoya KA, Neely KM, Carroll RJ, Aka IT, Maxwell-Horn AC, Roden DM, Van Driest SL

Abstract
BACKGROUND: There are few and conflicting data on the role of cytochrome P450 2D6 (CYP2D6) polymorphisms in relation to risperidone adverse events (AEs) in children. This study assessed the association between CYP2D6 metabolizer status and risk for risperidone AEs in children.
METHODS: Children ≤18 years with at least 4 weeks of risperidone exposure were identified using BioVU, a de-identified DNA biobank linked to electronic health record data. The primary outcome of this study was AEs. After DNA sequencing, individuals were classified as CYP2D6 poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers.
RESULTS: For analysis, the 257 individuals were grouped as poor/intermediate metabolizers (n = 33, 13%) and normal/ultrarapid metabolizers (n = 224, 87%). AEs were more common in poor/intermediate vs. normal/ultrarapid metabolizers (15/33, 46% vs. 61/224, 27%, P = 0.04). In multivariate analysis adjusting for age, sex, race, and initial dose, poor/intermediate metabolizers had increased AE risk (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.1, P = 0.03).
CONCLUSION: Children with CYP2D6 poor or intermediate metabolizer phenotypes are at greater risk for risperidone AEs. Pre-prescription genotyping could identify this high-risk subset for an alternate therapy, risperidone dose reduction, and/or increased monitoring for AEs.

PMID: 30661084 [PubMed - indexed for MEDLINE]

Genetic variation in CRHR1 is associated with short-term respiratory response to corticosteroids in preterm infants at risk for bronchopulmonary dysplasia.

Pediatr Res. 2019 04;85(5):625-633

Authors: Lewis T, Truog W, Norberg M, Ballard PL, Torgerson D, TOLSURF Study Group

Abstract
BACKGROUND: Bronchopulmonary dysplasia (BPD) is an orphan disease and advances in prevention and treatment are lacking. The clinical efficacy of systemic corticosteroid therapy to reduce the severity of lung disease and BPD is highly variable. Our objective was to assess whether candidate SNPs in corticosteroid metabolism and response genes are associated with short-term phenotypic response to systemic corticosteroids in infants at high risk for BPD.
METHODS: Pharmacogenetic analysis of data from a large randomized controlled trial (TOLSURF) in infants treated with dexamethasone or hydrocortisone using multivariate linear regression. The primary outcome was a change in respiratory severity score (RSS, mean airway pressure x FiO2) at day 7 of corticosteroid treatment.
RESULTS: rs7225082 in the intron of CRHR1 is significantly associated with the magnitude of decrease in RSS 7 days after starting treatment with systemic corticosteroid (meta-analysis P = 2.8 × 10-4). Each T allele at rs7225082 is associated with a smaller absolute change in RSS at day 7, i.e., less response to systemic corticosteroids.
CONCLUSIONS: Genetic variability is associated with corticosteroid responsiveness with regard to respiratory status in preterm infants. Identification of genetic markers of corticosteroid responsiveness may allow for therapeutic individualization, with the goal of optimizing the risk-to-benefit ratio for an individual child.

PMID: 30467342 [PubMed - indexed for MEDLINE]

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Use of Real-World Evidence in US Payer Coverage Decision-Making for Next-Generation Sequencing-Based Tests: Challenges, Opportunities, and Potential Solutions.

Value Health. 2020 May;23(5):540-550

Authors: Deverka PA, Douglas MP, Phillips KA

Abstract
OBJECTIVES: Given the potential of real-world evidence (RWE) to inform understanding of the risk-benefit profile of next-generation sequencing (NGS)-based testing, we undertook a study to describe the current landscape of whether and how payers use RWE as part of their coverage decision making and potential solutions for overcoming barriers.
METHODS: We performed a scoping literature review of existing RWE evidentiary frameworks for evaluating new technologies and identified barriers to clinical integration and evidence gaps for NGS. We synthesized findings as potential solutions for improving the relevance and utility of RWE for payer decision-making.
RESULTS: Payers require evidence of clinical utility to inform coverage decisions, yet we found a relatively small number of published RWE studies, and these are predominately focused on oncology, pharmacogenomics, and perinatal/pediatric testing. We identified 3 categories of innovation that may help address the current undersupply of RWE studies for NGS: (1) increasing use of RWE to inform outcomes-based contracting for new technologies, (2) precision medicine initiatives that integrate clinical and genomic data and enable data sharing, and (3) Food and Drug Administration reforms to encourage the use of RWE. Potential solutions include development of data and evidence review standards, payer engagement in RWE study design, use of incentives and partnerships to lower the barriers to RWE generation, education of payers and providers concerning the use of RWE and NGS, and frameworks for conducting outcomes-based contracting for NGS.
CONCLUSIONS: We provide numerous suggestions to overcome the data, methodologic, infrastructure, and policy challenges constraining greater integration of RWE in assessments of NGS.

PMID: 32389218 [PubMed - in process]

Democratizing Precision Medicine Through Community Engagement.

Clin Pharmacol Ther. 2019 09;106(3):488-490

Authors: Fohner AE, Volk KG, Woodahl EL

PMID: 31206610 [PubMed - indexed for MEDLINE]

Emerging Applications of Metabolomics in Clinical Pharmacology.

Clin Pharmacol Ther. 2019 09;106(3):544-556

Authors: Pang H, Jia W, Hu Z

Abstract
Metabolic disturbances have been associated with many human diseases, including cancer, diabetes, and cardiovascular disease. Metabolomics, a rapidly growing member of the -omics family, investigates cellular metabolism by quantifying metabolites on a large scale and provides a link between metabolic pathways and the upstream genome that governs them. With the advances in analytical technologies, metabolomics is becoming a powerful tool for identifying diagnostic biomarkers of diseases, elucidating the pathological mechanisms, discovering novel drug targets, predicting drug responses, interpreting the mechanisms of drug action, as well as enabling precision treatment of patients. In this review, we highlight the recent advances of technologies and methodologies in metabolomics and their applications to the field of clinical pharmacology. Recent publications from 2013 to 2018 are covered in the review, and current challenges and potential future directions in the field are also discussed.

PMID: 31173340 [PubMed - indexed for MEDLINE]

Evolving Concepts of Mitochondrial Dynamics.

Annu Rev Physiol. 2019 02 10;81:1-17

Authors: Dorn GW

Abstract
The concept that mitochondria are highly dynamic is as widely accepted as it is untrue for a number of important contexts. Healthy mitochondria of the most energy-dependent and mitochondrial-rich mammalian organ, the heart, only rarely undergo fusion or fission and are seemingly static within cardiac myocytes. Here, we revisit mitochondrial dynamism with a fresh perspective developed from the recently discovered multifunctionality of mitochondrial fusion proteins and newly defined mechanisms for direct cross talk between mitochondrial dynamics, biogenesis, quality control, and trafficking pathways. Insights gained from comparing static mitochondrial biology in cardiac myocytes and dynamic mitochondrial biology in neurons are reviewed with the goal of understanding contextual fallacies of overly generalized characterizations of these essential and intriguing organelles.

PMID: 30256725 [PubMed - indexed for MEDLINE]

Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity.

Breast Cancer Res Treat. 2020 May 08;:

Authors: Umamaheswaran G, Kadambari D, Muthuvel SK, Kalaivani S, Devi J, Damodaran SE, Pradhan SC, Dubashi B, Dkhar SA, Adithan C

Abstract
PURPOSE: Musculoskeletal adverse events (MS-AEs) and vasomotor symptoms (VMSs) are the major side-effects of newer generation non-steroidal aromatase inhibitor (AI), letrozole. Single-nucleotide polymorphisms (SNPs) in CYP19A1 gene coding for the enzyme aromatase are related to AI treatment-associated adverse drug reactions. Therefore, we aimed to determine whether SNPs in the CYP19A1 gene are associated with adjuvant letrozole-induced 'specific' AEs in postmenopausal hormone receptor-positive (HR+) breast cancer patients.
METHODS: Genomic DNA was isolated from 198 HR+ breast cancer patients by the phenol-chloroform method, and eleven SNPs in the CYP19A1 gene were genotyped by TaqMan genotyping assays on the qRT-PCR system. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, and the data were analyzed using SPSS v19.0 and Haploview v4.2 statistical software.
RESULTS: Subjects carrying the genetic variants of CYP19A1 gene SNP rs700519 had significantly higher odds (OR 2.33; 95% CI [1.29-4.20], P = 0.0057) of MS-AEs under dominant statistical effect. The frequency of the two distinct haplotypes that include the variant allele 'T' at rs700519 locus, H5-GCTATCTGGCG (P = 0.042) and H11-GCTATTGCACG (P = 0.013) were significantly higher in patients with musculoskeletal toxicity than in those without MS-AEs and thus predisposing to MS-AEs. Similarly, H6-GCCAGCTGGCG (P = 0.037) haplotype exhibited higher frequencies in patients presented with VMSs. However, no such association was observed between CYP19A1 genotypes and VMSs.
CONCLUSIONS: To the best of our knowledge, this is the first study assessing the impact of CYP19A1 genetic variations with adjuvant letrozole treatment-associated AEs in Indian women. Genetic variations in the CYP19A1 gene is associated with letrozole-induced AEs and warrants further investigation in larger cohorts to validate this finding.

PMID: 32385792 [PubMed - as supplied by publisher]

The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.

Nat Commun. 2020 May 08;11(1):2306

Authors: Fischer K, Fenzl A, Liu D, Dyar KA, Kleinert M, Brielmeier M, Clemmensen C, Fedl A, Finan B, Gessner A, Jastroch M, Huang J, Keipert S, Klingenspor M, Brüning JC, Kneilling M, Maier FC, Othman AE, Pichler BJ, Pramme-Steinwachs I, Sachs S, Scheideler A, Thaiss WM, Uhlenhaut H, Ussar S, Woods SC, Zorn J, Stemmer K, Collins S, Diaz-Meco M, Moscat J, Tschöp MH, Müller TD

Abstract
During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62-/- and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.

PMID: 32385399 [PubMed - as supplied by publisher]

Pharmacokinetic and pharmacodynamic analyses of cocaine and its metabolites in behaviorally divergent inbred mouse strains.

Genes Brain Behav. 2020 May 08;:e12666

Authors: Zhu J, Beechinor RJ, Thompson T, Schorzman AN, Zamboni W, Crona DJ, Weiner DL, Tarantino LM

Abstract
Cocaine is a psychostimulant with a high potential for abuse and addiction. Risk for cocaine use disorder is driven, in part, by genetic factors. Animal models of addiction-relevant behaviors have proven useful for studying both genetic and non-genetic contributions to drug response. In a previous study, we examined initial locomotor sensitivity to cocaine in genetically diverse inbred mouse strains. That work highlighted the relevance of pharmacokinetics in initial locomotor response to cocaine but was limited by a single dose and two sampling points. The objective of the present study was to characterize the pharmacokinetics and pharmacodynamics of cocaine and its metabolites (norcocaine and benzoylecgonine) in 6 inbred mouse strains (I/LnJ, C57BL/6J, FVB/NJ, BTBR T+ tf/J, LG/J, LP/J) that exhibit extreme locomotor responses to cocaine. Mice were administered cocaine at one of 4 doses and concentrations of cocaine, norcocaine, and benzoylecgonine were analyzed in both plasma and brain tissue at 5 different time points. Initial locomotor sensitivity to cocaine was used as a pharmacodynamic endpoint. We developed an empirical population PK model that simultaneously characterizes cocaine, norcocaine, and benzoylecgonine in plasma and brain tissues. We observed interstrain variability occurring in the brain compartment that may contribute to pharmacodynamic differences amongst select strains. Our current work paves the way for future studies to explore strain-specific pharmacokinetic differences and identify factors other than pharmacokinetics that are responsible for the diverse behavioral response to cocaine across these inbred mouse strains.

PMID: 32383297 [PubMed - as supplied by publisher]

Identifying key transcription factors for pharmacogenetic studies of antipsychotics induced extrapyramidal symptoms.

Psychopharmacology (Berl). 2020 May 07;:

Authors: Boloc D, Rodríguez N, Torres T, García-Cerro S, Parellada M, Saiz-Ruiz J, Cuesta MJ, Bernardo M, Gassó P, Lafuente A, Mas S, Arnaiz JA

Abstract
INTRODUCTION: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies.
METHODS: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP.
RESULTS: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1.
CONCLUSION: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.

PMID: 32382784 [PubMed - as supplied by publisher]

Family medicine clinic finds success with pharmacogenomics.

Am J Health Syst Pharm. 2020 May 08;:

Authors: Traynor K

PMID: 32382730 [PubMed - as supplied by publisher]

African Pharmacogenomics Consortium: Consolidating pharmacogenomics knowledge, capacity development and translation in Africa: Consolidating pharmacogenomics knowledge, capacity development and translation in Africa.

AAS Open Res. 2019;2:19

Authors: Dandara C, Masimirembwa C, Haffani YZ, Ogutu B, Mabuka J, Aklillu E, Bolaji O, H3Africa

Abstract
The African Pharmacogenomics Consortium (APC) was formally launched on the 6th September 2018. This white paper outlines its vision, and objectives towards addressing challenges of conducting and applying pharmacogenomics in Africa and identifies opportunities for advancement of individualized drugs use on the continent.  Africa, especially south of the Sahara, is beset with a huge burden of infectious diseases with much co-morbidity whose multiplicity and intersection are major challenges in achieving the sustainable development goals (SDG), SDG3, on health and wellness. The profile of drugs commonly used in African populations lead to a different spectrum of adverse drug reactions (ADRs) when compared to other parts of the world. Coupled with the genetic diversity among Africans, the APC is established to promote pharmacogenomics research and its clinical implementation for safe and effective use of medicine in the continent.  Variation in the way patients respond to treatment is mainly due to differences in activity of enzymes and transporters involved in pathways associated with each drug's disposition.  Knowledge of pharmacogenomics, therefore, helps in identifying genetic variants in these proteins and their functional effects. Africa needs to consolidate its pharmacogenomics expertise and technological platforms to bring pharmacogenomics to use.

PMID: 32382701 [PubMed]

QKI deficiency leads to osteoporosis by promoting RANKL-induced osteoclastogenesis and disrupting bone metabolism.

Cell Death Dis. 2020 May 07;11(5):330

Authors: Du T, Yan Z, Zhu S, Chen G, Wang L, Ye Z, Wang W, Zhu Q, Lu Z, Cao X

Abstract
Quaking (QKI), an RNA-binding protein, has been reported to exhibit numerous biological functions, such as mRNA regulation, cancer suppression, and anti-inflammation. However, little known about the effects of QKI on bone metabolism. In this study, we used a monocyte/macrophage-specific QKI knockout transgenic mouse model to investigate the effects of QKI deficiency on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. The loss of QKI promoted the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) from bone marrow macrophages, and upregulated the expression of OC-specific markers, including TRAP (Acp5) and cathepsin K (Ctsk). The pro-osteoclastogenesis effect of QKI deficiency was achieved by amplifying the signaling cascades of the NF-κB and mitogen-activated protein kinase (MAPK) pathways; then, signaling upregulated the activation of nuclear factor of activated T cells c1 (NFATc1), which is considered to be the core transcription factor that regulates OC differentiation. In addition, QKI deficiency could inhibit osteoblast (OB) formation through the inflammatory microenvironment. Taken together, our data suggest that QKI deficiency promoted OC differentiation and disrupted bone metabolic balance, and eventually led to osteopenia under physiological conditions and aggravated the degree of osteoporosis under pathological conditions.

PMID: 32382069 [PubMed - in process]

Rat brain CYP2D activity alters in vivo central oxycodone metabolism, levels and resulting analgesia.

Addict Biol. 2019 03;24(2):228-238

Authors: McMillan DM, Miksys S, Tyndale RF

Abstract
Oxycodone is metabolized by CYP2D to oxymorphone. Despite oxymorphone being a more potent opioid-receptor agonist, its contribution to oxycodone analgesia may be minor because of low peripheral production, low blood-brain barrier permeability and central nervous system efflux. CYP2D metabolism within the brain may contribute to variation in central oxycodone and oxymorphone levels, thereby affecting analgesia. Brain CYP2D expression and activity are subject to exogenous regulation; nicotine induces rat brain, but not liver, CYP2D consistent with higher brain CYP2D in smokers. We assessed the role of rat brain CYP2D in orally administered oxycodone metabolism (in vivo brain microdialysis) and analgesia (tail-flick test) by inhibiting brain CYP2D selectively with intracerebroventricular propranolol (mechanism-based inhibitor) and inducing brain CYP2D with nicotine. Inhibiting brain CYP2D increased brain oxycodone levels (1.8-fold; P < 0.03) and analgesia (1.5-fold AUC0-60 ; P < 0.001) after oxycodone, while inducing brain CYP2D increased brain oxymorphone levels (4.6-fold; P < 0.001) and decreased analgesia (0.8-fold; P < 0.02). Inhibiting the induced brain CYP2D reversed the change in oxycodone levels (1.2-fold; P > 0.1) and analgesia (1.1-fold; P > 0.3). Brain, but not plasma, metabolic ratios were affected by pre-treatments. Peak analgesia was inversely correlated with ex vivo brain (P < 0.003), but not hepatic (P > 0.9), CYP2D activity. Altering brain CYP2D did not affect analgesia from oral oxymorphone (P > 0.9 for AUC0-60 across all groups), which is not a CYP2D substrate. Thus, brain CYP2D metabolism alters local oxycodone levels and response, suggesting that people with increased brain CYP2D activity may have reduced oxycodone response. Factors that alter individual oxycodone response may be useful for optimizing treatment and minimizing abuse liability.

PMID: 29266563 [PubMed - indexed for MEDLINE]

The COVID-19 pandemic: consideration for brain infection.

Neuroscience. 2020 May 04;:

Authors: Mao XY, Jin WL

PMID: 32380269 [PubMed - as supplied by publisher]

Recommendations for Clinical Warfarin Sensitivity Genotyping Allele Selection: A Report of the Association for Molecular Pathology and College of American Pathologists.

J Mol Diagn. 2020 May 04;:

Authors: Pratt VM, Cavallari LH, Del Tredici AL, Hachad H, Ji Y, Kalman LV, Ly RC, Moyer AM, Scott SA, Whirl-Carrillo M, Weck KE

Abstract
The goals of the Association for Molecular Pathology (AMP) Clinical Practice Committee's AMP Pharmacogenomics (PGx) Working Group are to define the key attributes of pharmacogenetic (PGx) alleles recommended for clinical testing and a minimum set of variants that should be included in clinical PGx genotyping assays. This document series provide recommendations for a minimum panel of variant alleles ("Tier 1") and an extended panel of variant alleles ("Tier 2") that will aid clinical laboratories when designing assays for PGx testing. The AMP PGx Working Group considered functional impact of the variants, allele frequencies in multiethnic populations, the availability of reference materials (RMs), as well as other technical considerations for PGx testing when developing these recommendations. Our ultimate goal is to promote standardization of PGx gene/allele testing across clinical laboratories. These recommendations are not to be interpreted as prescriptive but to provide a reference guide. Of note, a separate article with recommendations for CYP2C9 allele selection was previously developed by the PGx Working Group that can be applied broadly to CYP2C9-related medications. The warfarin sensitivity allele recommendations in this report incorporate the previous CYP2C9 allele recommendations and additional genes and alleles that are specific to warfarin sensitivity testing.

PMID: 32380173 [PubMed - as supplied by publisher]

Implementation of a pharmacogenomic program in a Brazilian Public Institution.

Pharmacogenomics. 2020 May 07;:

Authors: Suarez-Kurtz G, Kovaleski G, Elias AB, Motta V, Wolch K, Emerenciano M, Mansur MB, Palladino AM, Accioly MT, Ferreira M, Gonçalves AA, de Melo AC

Abstract
This narrative review describes implementation, current status and perspectives of a pharmacogenomic (PGx) program at the Brazilian National Cancer Institute (INCA), targeting the cancer chemotherapeutic drugs - fluoropyrimidines, irinotecan and thiopurines. This initiative, designed as a research project, was supported by a grant from the Brazilian Ministry of Health. A dedicated task force developed standard operational procedures from recruitment of patients to creating PGx reports with dosing recommendations, which were successfully applied to test 100 gastrointestinal cancer INCA outpatients and 162 acute lymphoblastic leukemia pediatric patients from INCA and seven other hospitals. The program has been subsequently expanded to include gastrointestinal cancer patients from three additional cancer treatment centers. We anticipate implementation of routine pre-emptive PGx testing at INCA but acknowledge challenges associated with this transition, such as continuous financing support, availability of trained personnel, adoption of the PGx-informed prescription by the clinical staff and, ultimately, evidence of cost-effectiveness.

PMID: 32378980 [PubMed - as supplied by publisher]