Assessment of coding region variants in Kuwaiti population: implications for medical genetics and population genomics.

Sci Rep. 2018 Nov 08;8(1):16583

Authors: John SE, Antony D, Eaaswarkhanth M, Hebbar P, Channanath AM, Thomas D, Devarajan S, Tuomilehto J, Al-Mulla F, Alsmadi O, Thanaraj TA

Abstract
Consanguineous populations of the Arabian Peninsula have been underrepresented in global efforts that catalogue human exome variability. We sequenced 291 whole exomes of unrelated, healthy native Arab individuals from Kuwait to a median coverage of 45X and characterised 170,508 single-nucleotide variants (SNVs), of which 21.7% were 'personal'. Up to 12% of the SNVs were novel and 36% were population-specific. Half of the SNVs were rare and 54% were missense variants. The study complemented the Greater Middle East Variome by way of reporting many additional Arabian exome variants. The study corroborated Kuwaiti population genetic substructures previously derived using genome-wide genotype data and illustrated the genetic relatedness among Kuwaiti population subgroups, Middle Eastern, European and Ashkenazi Jewish populations. The study mapped 112 rare and frequent functional variants relating to pharmacogenomics and disorders (recessive and common) to the phenotypic characteristics of Arab population. Comparative allele frequency data and carrier distributions of known Arab mutations for 23 disorders seen among Arabs, of putative OMIM-listed causal mutations for 12 disorders observed among Arabs but not yet characterized for genetic basis in Arabs, and of 17 additional putative mutations for disorders characterized for genetic basis in Arab populations are presented for testing in future Arab studies.

PMID: 30409984 [PubMed - in process]

Community pharmacists and their role in pharmacogenomics testing: an Australian perspective drawing on international evidence.

Aust J Prim Health. 2018 Nov 09;:

Authors: Suppiah V, Lim CX, Hotham E

Abstract
Patients obtaining a prescription from a pharmacy expect that the drug will be effective and have minimal side-effects. Unfortunately, drugs exhibit the desired effect in ~25-60% of people prescribed any medication. Adverse effects occur at a rate of 10% in patients taking a medication, and this rate increases during and after hospitalisation, with the transition of care back to the ambulatory setting posing a particular risk. Pharmacogenomics testing has been shown to optimise pharmacotherapy by increasing medication effectiveness and reducing drug-related toxicity, thus curtailing overall healthcare costs. Evidence from international studies have shown that community pharmacists would be able to offer this highly relevant professional service to their clients, given suitable training. This specific training complements pharmacists' existing skills and expertise by educating them in an emerging scientific area of pharmacogenomics. However, in an increasingly tight financial climate, the provision of pharmacogenomics testing by Australian community pharmacists will only be viable with an appropriate reimbursement through the Medicare Benefits Schedule, currently accessible by other allied health practitioners but not by pharmacists.

PMID: 30409245 [PubMed - as supplied by publisher]

The measurement of drug-induced interferon γ-releasing cells and lymphocyte proliferation in severe cutaneous adverse reactions.

J Eur Acad Dermatol Venereol. 2018 Jun;32(6):992-998

Authors: Suthumchai N, Srinoulprasert Y, Thantiworasit P, Rerknimitr P, Tuchinda P, Chularojanamontri L, Rerkpattanapipat T, Chanprapaph K, Disphanurat W, Chakkavittumrong P, Tovanabutra N, Srisuttiyakorn C, Sukasem C, Klaewsongkram J, ThaiSCAR study group

Abstract
BACKGROUND: The lymphocyte transformation test (LTT) is a standard laboratory method to identify culprit drugs in patients with a history of drug-induced non-immediate hypersensitivity and is mainly performed during the recovery phase. The measurement of drug-specific interferon γ (IFN-γ)-releasing cells has been introduced to confirm culprit drugs, even during the acute phase of drug allergy.
OBJECTIVES: This study aimed to evaluate the capability of the enzyme-linked immunospot assay (ELISpot) to detect drug-specific IFN-γ-releasing cells during the acute phase and the capability of LTT to identify culprit drugs during the recovery phase in patients presenting with severe cutaneous adverse reactions (SCARs).
METHODS: Peripheral blood mononuclear cells (PBMCs) from 23 SCAR patients were collected during the acute and recovery phases and assayed for drug-specific IFN-γ-releasing cells and lymphocyte proliferation, respectively.
RESULTS: Drug-specific IFN-γ-releasing cells were detectable in 73.9% of SCAR subjects (55.6% and 85.7% in patients who were and were not taking systemic steroids, respectively), whereas LTT results were positive in 52.2% of SCAR subjects. The frequencies of drug-specific IFN-γ-releasing cells were significantly higher in patients with positive LTT than in those with negative LTT (260.1 ± 110.0 and 46.6 ± 20.7 cells/106 PBMCs, P = 0.01). A significant correlation between the results of the IFN-γ ELISpot assay and LTT was demonstrated (r = 0.65, P value <0.01).
CONCLUSION: The IFN-γ ELISpot assay could be a useful tool to identify culprit drugs in SCAR patients when culprit drug identification is urgently needed during the acute phase of drug allergy.

PMID: 29478292 [PubMed - indexed for MEDLINE]

Connecting genetic risk to disease end points through the human blood plasma proteome.

Nat Commun. 2017 02 27;8:14357

Authors: Suhre K, Arnold M, Bhagwat AM, Cotton RJ, Engelke R, Raffler J, Sarwath H, Thareja G, Wahl A, DeLisle RK, Gold L, Pezer M, Lauc G, El-Din Selim MA, Mook-Kanamori DO, Al-Dous EK, Mohamoud YA, Malek J, Strauch K, Grallert H, Peters A, Kastenmüller G, Gieger C, Graumann J

Abstract
Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into clinical applications. However, although hundreds of genetic variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits are key in establishing functional links between GWAS-identified risk-variants and disease end points. Here we describe a GWAS using a highly multiplexed aptamer-based affinity proteomics platform. We quantify 539 associations between protein levels and gene variants (pQTLs) in a German cohort and replicate over half of them in an Arab and Asian cohort. Fifty-five of the replicated pQTLs are located in trans. Our associations overlap with 57 genetic risk loci for 42 unique disease end points. We integrate this information into a genome-proteome network and provide an interactive web-tool for interrogations. Our results provide a basis for novel approaches to pharmaceutical and diagnostic applications.

PMID: 28240269 [PubMed - indexed for MEDLINE]

Essential characteristics of pharmacogenomics study publications.

Clin Pharmacol Ther. 2018 Nov 08;:

Authors: Thorn CF, Whirl-Carrillo M, Hachad H, Johnson JA, McDonagh EM, Ratain MJ, Relling MV, Scott SA, Altman RB, Klein TE

Abstract
Pharmacogenomics (PGx) can be seen as a model for biomedical studies: it includes all disease areas of interest, spans in vitro studies to clinical trials, while focusing on the relationships between genes and drugs and the resulting phenotypes. This review will examine different characteristics of PGx study publications and provide examples of excellence in framing PGx questions and reporting their resulting data in a way that maximizes the knowledge that can be built upon them. This article is protected by copyright. All rights reserved.

PMID: 30406943 [PubMed - as supplied by publisher]

Could polymorphisms of some hormonal receptor genes, involved in folliculogenesis help in predicting patient response to controlled ovarian stimulation?

J Assist Reprod Genet. 2018 Nov 08;:

Authors: Čuš M, Vlaisavljević V, Repnik K, Potočnik U, Kovačič B

Abstract
PURPOSE: The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in selected genes, responsible for hormonal regulation of folliculogenesis, are associated with response to controlled ovarian hyperstimulation (COH) and clinical characteristics of women enrolled in in vitro fertilization (IVF) programs.
METHODS: In a cross-sectional study, 60 (IVF) patients underwent COH by using gonadotropin-releasing hormone (GnRH) antagonist and recombinant follicle-stimulating hormone (rFSH) protocol. Patients were classified into three groups: poor-responders (according to Bologna criteria), normo-responders (≤ 15 oocytes), and hyper-responders (> 15 oocytes). Genotyping of SNPs AMH rs10407022, AMHR rs3741664, FSHR rs1394205 and rs6166, and ESR1 rs2234693 was performed using high-resolution melting analysis (HRMA). Basal FSH (bFSH), estradiol (E2), and anti-Müllerian hormone (AMH) were measured by enzyme-linked immunosorbent assay (ELISA).
RESULTS: Patients with GG genotype of FSHR rs1394205 had significantly lower AMH level (P = 0.016) and required higher rFSH dose per oocyte compared to women with AA or AG genotype (P = 0.036). We also found higher frequency of GG genotype of FSHR rs1394205 in poor- (76.5%) than in hyper-responders (37.5%, P = 0.002). Patients with AA genotype of FSHR rs6166 had higher level of measured bFSH compared to those with AG or GG genotypes (P = 0.043). Women with GG genotype of AMHR rs3741664 required higher rFSH dose in comparison with patients carrying genotypes AA or AG (P = 0.028).
CONCLUSIONS: The GG genotype at position rs1394205 is associated with poor ovarian response to COH. Patients with this genotype may require higher doses of rFSH for ovulation induction.

PMID: 30406448 [PubMed - as supplied by publisher]

Genome-wide association analysis identifies SNPs predictive of in vitro leukemic cell sensitivity to cytarabine in pediatric AML.

Oncotarget. 2018 Oct 09;9(79):34859-34875

Authors: Bargal SA, Rafiee R, Crews KR, Wu H, Cao X, Rubnitz JE, Ribeiro RC, Downing JR, Pounds SB, Lamba JK

Abstract
Cytarabine has been an integral part of acute myeloid leukemia (AML) chemotherapy for over four decades. However, development of resistance and high rates of relapse is a significant impediment in successfully treating AML. We performed a genome-wide association analysis (GWAS) and identified 113 (83 after adjusting for Linkage Disequilibrium) SNPs associated with in vitro cytarabine chemosensitivity of diagnostic leukemic cells from a cohort of 50 pediatric AML patients (p<10-4). Further evaluation of diagnostic leukemic cell gene-expression identified 19 SNP-gene pairs with a concordant triad of associations: i)SNP genotype with cytarabine sensitivity (p<0.0001), ii) gene-expression with cytarabine sensitivity (p<0.05), and iii) genotype with gene-expression (p<0.1). Two genes from SNP-gene pairs, rs1376041-GPR56 and rs75400242-IGF1R, were functionally validated by siRNA knockdown in AML cell lines. Consistent with association of rs1376041 and gene-expression in AML patients siRNA mediated knock-down of GPR56 increased cytarabine sensitivity of AML cell lines. Similarly for IGF1R, knockdown increased the cytarabine sensitivity of AML cell lines consistent with results in AML patients. Given both IGF1R and GPR56 are promising drug-targets in AML, our results on SNPs driving the expression/function of these genes will not only enhance our understanding of cytarabine resistance but also hold promise in personalizing AML for targeted therapies.

PMID: 30405880 [PubMed]

Tenofovir disoproxil fumarate discontinuation for renal outcomes: any room for treatment personalization?

Pharmacogenomics J. 2018 Nov 08;:

Authors: Calcagno A, Fiumanò M, Zugna D, Cusato J, Montrucchio C, Marinaro L, Trentini L, Ferrara M, D'Avolio A, Pizzi C, Di Perri G, Bonora S

Abstract
Tenofovir disoproxil fumarate (TDF) is a very effective antiviral drug that has been associated with tubular dysfunction. The aim of this study was to analyze the demographic, pharmacokinetic, and pharmacogenetic variables associated with TDF discontinuation for renal outcomes in stable HIV-positive patients using multivariable analyses. Three hundred and four patients were included (73% male, with median age and eCrCl of 45.3 years and 90.9 mL/min, respectively). After a median follow-up of 28.3 months, 27 patients discontinued TDF for renal adverse events [persistent urinary abnormalities (n = 21) or eCrCl < 60 mL/min (n = 6)] providing an incidence of 3.77 events per 100 patient-year. The probability of TDF discontinuation was higher with several features (male gender, older age, not Caucasians ancestry, absence of intravenous drug abuse, protease inhibitors, previous indinavir, HCV-positivity, lower CD4 cell count, detectable HIV-RNA, lower eCrCl, spot-urine proteinuria) and higher tenofovir concentrations but not genetic variants. Tenofovir plasma concentrations were prognostic of TDF discontinuation for renal adverse events suggesting that dose-adjustment may be warranted for long-term safety.

PMID: 30405212 [PubMed - as supplied by publisher]

CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta-analysis of randomized clinical trials.

Catheter Cardiovasc Interv. 2018 Nov 07;:

Authors: Kheiri B, Osman M, Abdalla A, Haykal T, Pandrangi PV, Chahine A, Ahmed S, Osman K, Bachuwa G, Hassan M, Bhatt DL

Abstract
OBJECTIVES: This study aimed to evaluate the efficacy and safety of personalized genotype-guided selection of antiplatelet therapy versus standard of care in patients undergoing percutaneous coronary intervention (PCI).
BACKGROUND: Clopidogrel is the most frequently used P2Y12 receptor antagonist in patients with coronary artery disease. However, genetic variations of clopidogrel are associated with inter-individual response variability which could limit its efficacy.
METHODS: Electronic databases were searched for all randomized clinical trials (RCTs) evaluating genotype-guided therapy versus standard of care in patients undergoing stent implantation. Aggregated risk ratios (RRs) and 95% CIs were calculated using a random-effects model.
RESULTS: We included 6 RCTs with a total of 2,371 patients. When compared with standard of care, the use of genotype-guided therapy did not significantly reduce major adverse cardiovascular events (MACE) (RR 0.67; 95% CI: 0.35-1.27; P = 0.22). However, MACE was significantly reduced in the subset of trials which enrolled only acute coronary syndromes (ACS) (P < 0.01). In addition, there was a significant reduction in myocardial infarction in the genotype-guided group (RR 0.44; 95% CI: 0.28-0.70; P < 0.01; I2 = 0%). Other clinical outcomes were not significantly different: cardiovascular mortality (RR 0.68; 95% CI: 0.27-1.74; P = 0.42), stroke (RR 0.62; 95% CI: 0.23-1.65; P = 0.34), stent thrombosis (RR 0.37; 95% CI: 0.13-1.06; P = 0.06), and bleeding (RR 0.68; 95% CI: 0.43-1.06; P = 0.09).
CONCLUSION: In patients undergoing stent implantation, MACE with genotype-guided therapy was not significantly reduced; however, there was a signal towards reduction of MACE in ACS patients, as well as a lower rate of MI, though this will require further confirmation in adequately powered trials.

PMID: 30403317 [PubMed - as supplied by publisher]

High prevalence of a hotspot of non-coding somatic mutations in intron 6 of GPR126 in bladder cancer.

Mol Cancer Res. 2018 Nov 06;:

Authors: Garinet S, Pignot G, Vacher S, Le Goux C, Schnitzler A, Chemlali W, Nanor S, Delongchamps NB, Zerbib M, Sibony M, Allory Y, Damotte D, Bieche I

Abstract
Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, non-coding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 non-muscle invasive bladder cancers (NMIBC) and 59 muscle invasive bladder cancers (MIBC). GPR126 mutations were analyzed by HRM and Sanger sequencing and GPR126 expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic GPR126 non-coding mutations occurred in 47.7% of samples and were negatively associated with GPR126 mRNA levels. GPR126 mutations had higher frequencies in non-smoker patients and were associated with a prior history of NMIBC. GPR126 overexpression was detected in 70.5% of samples. GPR126 mutation and overexpression status were not associated with outcome. In MIBC, somatic GPR126 mutations occurred in 44.1% of samples. Mutations were more frequent in females. GPR126 overexpression was detected in 27.1% of the sample. A trend towards significance was observed between GPR126 overexpression and better outcome. We identified the second most frequent mutational hotspot after TERT promoter (~70%) in bladder cancer, with a mutation rate of ~50%. Implications: The GPR126 intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer.

PMID: 30401719 [PubMed - as supplied by publisher]

Associations between the LEP -2548G/A Promoter and Baseline Weight and between LEPR Gln223Arg and Lys656Asn Variants and Change in BMI z Scores in Arab Children and Adolescents Treated with Risperidone.

Mol Neuropsychiatry. 2018 Oct;4(2):111-117

Authors: Almandil NB, Lodhi RJ, Ren H, Besag FMC, Rossolatos D, Ohlsen R, Slomp C, Lapetina DL, Plazzotta G, Murray ML, Al-Sulaiman AA, Gringras P, Wong ICK, Aitchison KJ

Abstract
Data on baseline (antipsychotics-naïve) age, weight, and height, and change in these at 3 subsequent follow-up time points up to 313.6 days (95% CI 303.5-323.7) were collected from 181 risperidone-treated children and adolescents (mean age 12.58 years, SD 4.99, range 2.17-17.7) attending a pediatric neurology clinic in Saudi Arabia. Owing to differences in genotypic distributions in the subsamples, results are reported for the white Arab population (n = 144). Age- and gender-normed body mass index (BMI)-standardized z scores (BMI z) were calculated (LMSgrowth program). Linear regression was performed for baseline weight and BMI z, while change in BMI z was assessed using random effects ordered logistic regression. The following single nucleotide polymorphisms (SNPs) were analyzed: rs7799039 in the LEP promoter, rs1805094 (previously rs8179183), rs1137100 and rs1137101 in the LEPR, and rs1414334 in HTR2C. We found a nominally significant association between rs7799309 and baseline weight, adjusting for height, age, gender, and diagnosis (A/G, p = 0.035, β = -3.62 vs. G/G). The rs1137101 (G/G, p = 0.018, odds ratio [OR] = 4.13 vs. A/A) and rs1805094 C allele carriers (p = 0.019, OR = 0.51) showed nominally significant associations with change in BMI z categories. Our data support and replicate previous relevant associations for these variants (including with weight gain when on risperidone), whilst being the first report of such associations in patients of Arab ethnicity.

PMID: 30397599 [PubMed]

The use of pharmacogenetic testing in patients with schizophrenia or bipolar disorder: A systematic review.

Ment Health Clin. 2018 Nov;8(6):294-302

Authors: Routhieaux M, Keels J, Tillery EE

Abstract
Introduction: Pharmacogenetic testing may assist in identifying an individual's risk of developing a mental illness as well as predict an individual's response to treatment. The objective of this study is to report published outcomes of pharmacogenetic testing in patients with schizophrenia or bipolar disorder.
Methods: A systematic review using PubMed and EBSCOhost through April 2017 was performed to identify articles that reported pharmacogenetic testing in adult patients with either bipolar disorder or schizophrenia using the keywords pharmacy, pharmacogenomics, pharmacogenetics, psychiatry, bipolar disorder, schizophrenia, mood stabilizer, and antipsychotic.
Results: A total of 18 articles were included in the final literature review. A wide variety of genes amongst adult patients with varying ethnicities were found to be correlated with the development of schizophrenia or bipolar disorder as well as response to antipsychotics and mood stabilizers.
Discussion: While current studies show a correlation between genetic variations and medication response or disease predisposition for patients with schizophrenia and bipolar disorder, research is unclear on the type of therapeutic recommendations that should occur based on the results of the pharmacogenetic testing. Hopefully interpreting pharmacogenetic results will one day assist with optimizing medication recommendations for individuals with schizophrenia and bipolar disorder.

PMID: 30397571 [PubMed]

Pharmacogenetics to prevent heparin-induced thrombocytopenia: what do we know?

Pharmacogenomics. 2018 Nov 06;:

Authors: Karnes JH

Abstract
Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated adverse reaction to heparin anticoagulants. The inability to predict HIT represents a considerable liability associated with heparin administration. Genetic studies of HIT are challenging due to the scarcity of true HIT cases, potential for misclassification, and many environmental risk factors. Genetic studies have not consistently identified risk alleles for HIT, the production of platelet factor 4/heparin antibodies or the thromboembolic complications of HIT. Genes implicated in HIT and platelet factor 4/heparin antibody levels include FCGR2A, TDAG8, HLA-DR and others. Compelling evidence also suggests that the FCGR2A H131R polymorphism is associated with HIT-related thrombosis. There is a need for well-powered, multiethnic studies with laboratory confirmation of HIT, detailed patient- and drug-specific data, and inclusion of both serologic and thromboembolic outcomes. Genomic biomarkers identified from such studies offer the possibility of shifting current clinical practice paradigms from early detection and treatment to prevention.

PMID: 30398086 [PubMed - as supplied by publisher]

Pharmacogenetic relevance of endothelial nitric oxide synthase polymorphisms and gene interactions.

Pharmacogenomics. 2018 Nov 06;:

Authors: Luizon MR, Pereira DA, Tanus-Santos JE

Abstract
Endothelial nitric oxide synthase (NOS3) is a key enzyme responsible for nitric oxide (NO) generation in the vascular endothelium. Endothelial dysfunction is characterized by reduced NO production, and is a hallmark of cardiovascular diseases. Drugs with cardiovascular action may activate NOS3 and result in NO release and vasodilation. Moreover, genetic variations affect NOS3 expression and activity, and may partially explain the variability in the responses to cardiovascular drugs. We reviewed NO signaling and genetic effects on NO formation, and the effects of NOS3 polymorphisms, haplotypes and gene-gene interactions within NO signaling pathways on the responses to cardiovascular drugs. We discuss the role of rare NOS3 variants and further gene-gene interactions analysis for the development of novel therapies for cardiovascular diseases.

PMID: 30398085 [PubMed - as supplied by publisher]

Analysis of outpatient HER2 testing in New York state using the statewide planning and research cooperative system.

Pharmacogenomics. 2018 Nov 06;:

Authors: Hefti E, Jacobs DM, Rana K, Blanco JG

Abstract
AIM: HER2 testing is necessary in the context of therapy with trastuzumab, pertuzumab, lapatinib and neratinib. There is a paucity of reports describing the utilization rates of HER2 testing in large outpatient populations.
METHODS: The Statewide Planning and Research Cooperative System (SPARCS) was used to examine HER2 testing across the state of New York (USA) during the 2012-2016 period.
RESULTS: There was a linear increase in HER2 testing (r = 0.91, p = 0.030). There were increases in HER2 testing observed among minorities, including 0.5-fold and 3.5-fold increases in individuals identified as black and Asian, respectively. Major state population centers showed the highest HER2 testing.
CONCLUSION: This study establishes a platform to further evaluate clinical utility, outcomes and equity of access for 'precision oncology' testing.

PMID: 30398082 [PubMed - as supplied by publisher]

Integrating metabolomics with genomics.

Pharmacogenomics. 2018 Nov 06;:

Authors: Telenti A

PMID: 30398072 [PubMed - as supplied by publisher]

Rosuvastatin pharmacogenetics in African populations.

Pharmacogenomics. 2018 Nov 06;:

Authors: Soko ND, Masimirembwa C, Dandara C

PMID: 30398065 [PubMed - as supplied by publisher]

The amount of activating EGFR mutations in circulating cell-free DNA is a marker to monitor osimertinib response.

Br J Cancer. 2018 Nov 06;:

Authors: Del Re M, Bordi P, Rofi E, Restante G, Valleggi S, Minari R, Crucitta S, Arrigoni E, Chella A, Morganti R, Tiseo M, Petrini I, Danesi R

Abstract
BACKGROUND: Circulating cell-free DNA (cfDNA) may help understand the molecular response to pharmacologic treatment and provide information on dynamics of clonal heterogeneity. Therefore, this study evaluated the correlation between treatment outcome and activating EGFR mutations (act-EGFR) and T790M in cfDNA in patients with advanced NSCLC given osimertinib.
METHODS: Thirty-four NSCLC patients resistant to first/second-generation EGFR-TKIs, positive for both act-EGFR and T790M in cfDNA at the time of progression were enrolled in this study. Plasma samples were obtained at osimertinib baseline and after 3 months of therapy; cfDNA was analyzed by droplet digital PCR and results were expressed as mutant allele frequency (MAF).
RESULTS: At baseline, act-EGFR MAF was significantly higher than T790M (p < 0.0001). act-EGFR MAF and T790M/act-EGFR MAF ratio were significantly correlated with disease response (p = 0.02). Cut-off values of act-EGFR MAF and T790M/act-EGFR ratio of 2.6% and 0.22 were found, respectively. The PFS of patients with act-EGFR MAF of > 2.6% and < 2.6%, were 10 months vs. not reached, respectively (p = 0.03), whereas patients with T790M/act-EGFR ≤ 0.22 had poorer PFS than patients with a value of > 0.22 (6 months vs. not reached, respectively, p = 0.01).
CONCLUSION: act-EGFR MAF and T790M/act-EGFR MAF ratio are potential markers of outcome in patients treated with osimertinib.

PMID: 30397287 [PubMed - as supplied by publisher]

The era of immunogenomics/immunopharmacogenomics.

J Hum Genet. 2018 Jul;63(8):865-875

Authors: Zewde M, Kiyotani K, Park JH, Fang H, Yap KL, Yew PY, Alachkar H, Kato T, Mai TH, Ikeda Y, Matsuda T, Liu X, Ren L, Deng B, Harada M, Nakamura Y

Abstract
Although germline alterations and somatic mutations in disease cells have been extensively analyzed, molecular changes in immune cells associated with disease conditions have not been characterized in depth. It is clear that our immune system has a critical role in various biological and pathological conditions, such as infectious diseases, autoimmune diseases, drug-induced skin and liver toxicity, food allergy, and rejection of transplanted organs. The recent development of cancer immunotherapies, particularly drugs modulating the immune checkpoint molecules, has clearly demonstrated the importance of host immune cells in cancer treatments. However, the molecular mechanisms by which these new therapies kill tumor cells are still not fully understood. In this regard, we have begun to explore the role of newly developed tools such as next-generation sequencing in the genetic characterization of both cancer cells and host immune cells, a field that is called immunogenomics/ immunopharmacogenomics. This new field has enormous potential to help us better understand changes in our immune system during the course of various disease conditions. Here we report the potential of deep sequencing of T-cell and B-cell receptors in capturing the molecular contribution of the immune system, which we believe plays critical roles in the pathogenesis of various human diseases.

PMID: 29785006 [PubMed - indexed for MEDLINE]

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