Further evidence for association of GAL, GALR1 and NPY1R variants with opioid dependence.

Pharmacogenomics. 2020 Aug 06;:

Authors: Randesi M, Levran O, den Brink WV, Blanken P, van Ree JM, Ott J, Kreek MJ

Abstract
Aim: Heroin addiction is a chronic, relapsing disease that has genetic and environmental, including drug-induced, contributions. Stress influences the development of addictions. This study was conducted to determine if variants in stress-related genes are associated with opioid dependence (OD). Patients & methods: One hundred and twenty variants in 26 genes were analyzed in 597 Dutch subjects. Patients included 281 OD in methadone maintenance with or without heroin-assisted treatment and 316 controls. Results: Twelve SNPs in seven genes showed a nominally significant association with OD. Experiment-wise significant associations (p < 0.05) were found for three SNP pairs, through an interaction effect: NPY1R/GAL rs4691910/rs1893679, NPY1R/GAL rs4691910/rs3136541 and GALR1/GAL rs9807208/rs3136541. Conclusion: This study lends more evidence to previous reports of association of stress-related variants with heroin dependence.

PMID: 32757697 [PubMed - as supplied by publisher]

Regulatory CDH4 genetic variants associate with risk to develop capecitabine-induced hand-foot syndrome.

Clin Pharmacol Ther. 2020 Aug 05;:

Authors: Ruiz-Pinto S, Pita G, Martín M, Nunez-Torres R, Cuadrado A, Shahbazi MN, Caronia D, Kojic A, Moreno LT, de JC, la Torre-Montero, Lozano M, López-Fernández LA, Ribelles N, García-Saenz JA, Alba E, Milne RL, Losada A, Pérez-Moreno M, Benítez J, González-Neira A

Abstract
Capecitabine-Induced Hand-Foot Syndrome (CiHFS) is a common dermatological adverse reaction affecting around 30% of capecitabine-treated cancer patients, and the main cause of dose reductions and chemotherapy delays. To identify novel genetic factors associated with CiHFS in cancer patients, we carried out an extreme-phenotype genome-wide association study (GWAS) in 166 breast and colorectal capecitabine-treated cancer patients with replication in a second cohort of 85 patients. We discovered and replicated a cluster of four highly correlated SNPs associated with susceptibility to CiHFS at 20q13.33 locus (top hit=rs6129058, HR=2.40, 95%CI =1.78-3.20; P=1.2x10-8 ). Using circular chromosome conformation capture sequencing, we identified a chromatin contact between the locus containing the risk alleles and the promoter of CDH4, located 90 kilobases away. The risk haplotype was associated with decreased levels of CDH4 mRNA and the protein it encodes, R-cadherin (RCAD), which mainly localizes in the granular layer of the epidermis. In human keratinocytes, CDH4 downregulation resulted in reduced expression of involucrin, a protein of the cornified envelope, an essential structure for skin barrier function. Immunohistochemical analyses revealed that skin from patients with severe CiHFS exhibited low levels of RCAD and involucrin before capecitabine treatment. Our results uncover a novel mechanism underlying individual genetic susceptibility to CiHFS with implications for clinically relevant risk prediction.

PMID: 32757270 [PubMed - as supplied by publisher]

"LRF/ZBTB7A conservation accentuates its potential as a therapeutic target for the hematopoietic disorders".

Gene. 2020 Aug 02;:145020

Authors: Chondrou V, Markopoulos GS, Patrinos GP, Kouraklis-Symeonidis A, Symeonidis A, Papachatzopoulou A, Sgourou A

Abstract
Conserved sequences across species have always provided valuable insights to improve our understanding on the human genome's entity and the interplay among different loci. Lymphoma/leukemia related factor (LRF) is encoded by ZBTB7A gene and belongs to an evolutionarily conserved family of transcription factors, implicated in vital cellular functions. The present data, demonstrating the wide-spread and the high overlap of the LRF/ZBTB7A recognition sites with genomic segments identified as CpG islands in the human genome, suggest that its binding capacity strongly depends on a specific sequence-encoded feature within CpGs. We have previously shown that de-methylation of the CpG island 326 lying in the ZBTB7A gene promoter is associated with impaired pharmacological induction of fetal hemoglobin in β-type hemoglobinopathies patients. Within this context we aimed to investigate the extent of the LRF/ZBTB7A conservation among primates and mouse genome, focusing our interest also on the CpG island flanking the gene's promoter region, in an effort to further establish its epigenetic regulatory role in human hematopoiesis and pharmacological involvement in hematopoietic disorders. Comparative analysis of the human ZBTB7A nucleotide and amino acid sequences and orthologous sequences among non-human primates and mouse, exhibited high conservation scores. Pathway analysis, clearly indicated that LRF/ZBTB7A influences conserved cellular processes. These data in conjunction with the high levels of expression foremost in hematopoietic tissues, highlighted LRF/ZBTB7A as an essential factor operating indisputably during hematopoiesis.

PMID: 32755656 [PubMed - as supplied by publisher]

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the (Modern) Treatment of Melanoma.

Clin Pharmacokinet. 2019 08;58(8):1029-1043

Authors: Kim HY, Upadhyay PJ, Fahmy A, Liu X, Duong JK, Boddy AV

Abstract
Targeted therapies, based on identification of common oncogenic mutations such as BRAF V600E/K and monoclonal antibody immunotherapies, have transformed the treatment of melanoma. Dual mitogen-activated protein kinase (MAPK) pathway inhibition of BRAF V600E/K and MEK 1/2 kinases with BRAF-MEK inhibitors using dabrafenib-trametinib, vemurafenib-cobimetinib and encorafenib-binimetinib is now the standard of care for BRAF V600E/K tumours. Monoclonal antibodies, such as pembrolizumab and nivolumab, against programmed cell death protein (PD-1) on T cells, as well as ipilimumab against cytotoxic T lymphocyte antigen-4 (CTLA-4), enable restoration of suppressed T-cell antitumour response, and have also shown improved clinical benefit compared with traditional chemotherapy. Exploration of different combination therapies, sequence of treatment, and dosing strategies is ongoing, and the understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of these new agents is fundamental in devising the optimal regimen. Preclinical and clinical studies, as well as population PK modelling, provide essential data in terms of PK parameters, metabolism, interpatient variability, drug interactions and PD effects at the target. This review gathers the current evidence and understanding of the clinical PK and PD of drugs used in the modern treatment of melanoma, and the factors determining drug disposition, exposure and clinical response, and also highlighting areas of further research.

PMID: 30868471 [PubMed - indexed for MEDLINE]

Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial.

Ann Oncol. 2019 06 01;30(6):945-952

Authors: Hrebien S, Citi V, Garcia-Murillas I, Cutts R, Fenwick K, Kozarewa I, McEwen R, Ratnayake J, Maudsley R, Carr TH, de Bruin EC, Schiavon G, Oliveira M, Turner N

Abstract
BACKGROUND: Dynamic changes in circulating tumour DNA (ctDNA) levels may predict long-term outcome. We utilised samples from a phase I/II randomised trial (BEECH) to assess ctDNA dynamics as a surrogate for progression-free survival (PFS) and early predictor of drug efficacy.
PATIENTS AND METHODS: Patients with estrogen receptor-positive advanced metastatic breast cancer (ER+ mBC) in the BEECH study, paclitaxel plus placebo versus paclitaxel plus AKT inhibitor capivasertib, had plasma samples collected for ctDNA analysis at baseline and at multiple time points in the development cohort (safety run-in, part A) and validation cohort (randomised, part B). Baseline sample ctDNA sequencing identified mutations for longitudinal analysis and mutation-specific digital droplet PCR (ddPCR) assays were utilised to assess change in ctDNA abundance (allele fraction) between baseline and 872 on-treatment samples. Primary objective was to assess whether early suppression of ctDNA, based on pre-defined criteria from the development cohort, independently predicted outcome in the validation cohort.
RESULTS: In the development cohort, suppression of ctDNA was apparent after 8 days of treatment (P = 0.014), with cycle 2 day 1 (4 weeks) identified as the optimal time point to predict PFS from early ctDNA dynamics. In the validation cohort, median PFS was 11.1 months in patients with suppressed ctDNA at 4 weeks and 6.4 months in patients with high ctDNA (hazard ratio = 0.20, 95% confidence interval 0.083-0.50, P < 0.0001). There was no difference in the level of ctDNA suppression between patients randomised to capivasertib or placebo overall (P = 0.904) nor in the PIK3CA mutant subpopulation (P = 0.071). Clonal haematopoiesis of indeterminate potential (CHIP) was evident in 30% (18/59) baseline samples, although CHIP had no effect on tolerance of chemotherapy nor on PFS.
CONCLUSION: Early on-treatment ctDNA dynamics are a surrogate for PFS. Dynamic ctDNA assessment has the potential to substantially enhance early drug development.
CLINICAL REGISTRATION NUMBER: NCT01625286.

PMID: 30860573 [PubMed - indexed for MEDLINE]

A Rare Complex BRAF Mutation Involving Codon V600 and K601 in Primary Cutaneous Melanoma: Case Report.

Front Oncol. 2020;10:1056

Authors: Consoli F, Barbieri G, Picciolini M, Medicina D, Bugatti M, Tovazzi V, Liserre B, Zambelli C, Zorzi F, Berruti A, Giurisato E, Vermi W

Abstract
BRAF is one of the most common mutated kinases detected in human cancer, particularly in cases of primary cutaneous melanomas (PCM). Mutations of the BRAF proto-oncogene, at the p.V600 codon, has been detected in more than 50% of primary and metastatic melanoma cells in clinical samples. In addition to the most frequent BRAF p.V600E mutation, corresponding to the single base pair substitution c.1799T>A, rarer mutations, within and outside the V600 codon, have been described. Expectedly, BRAF and MEK inhibitors (or their combination) have been poorly explored as potential therapeutic strategies in metastatic melanomas harboring this rare mutation. By using a set of sequencing techniques and immunohistochemistry, this work reports the genomic and clinical features of two melanoma patients showing a rare complex mutation affecting codon V600 and K601 of the BRAF gene, leading to a V600E2; K601I change. Specifically, these two patients show a distinct clinical behavior and significantly differ in their responses to BRAF and MEK inhibitors. Indeed, although this treatment has proven to be effective and safe in both cases, the observed variability between the two patients resulted as a direct consequence of the baseline extent of brain involvement, intracranial treatment failure as well as on the PTEN status.

PMID: 32754440 [PubMed]

Pharmacogenetic-Guided Algorithm to Improve Daily Dose of Warfarin in Elder Han-Chinese Population.

Front Pharmacol. 2020;11:1014

Authors: Ren Y, Yang C, Chen H, Dai D, Wang Y, Zhu H, Wang F

Abstract
Objectives: To verify the accuracy of the International Warfarin Pharmacogenetics Consortium (IWPC) algorithm, identify the effects of genetic and clinical factors on warfarin stable dose, and to establish a new warfarin stable dose prediction algorithm for the elderly Han-Chinese population under the guidance of pharmacogenetics.
Methods: According to the inclusion criteria, 544 non-valvular atrial fibrillation patients taking warfarin for anticoagulation treatment were enrolled. Data information of three groups including the whole population, people under 65 years old and over 65 years old were substituted into the IWPC algorithm respectively to verify its accuracy. The basic data and clinical information of 360 elderly people were collected for statistical analysis and the genotypes of VKORC1-G1639A and CYP2C9 were detected by Sanger sequencing. The new algorithm of the elder pharmacogenetics warfarin dosing was obtained by stepwise multiple regression. The determination coefficient (R2), root mean squared error (RMSE), and the proportion of the predicted value within the true value range of ±20%(20%-p) were used to evaluate the accuracy of the IWPC algorithm and the new algorithm.
Results: Among the three different age groups, the warfarin stable dose predictive accuracy of IWPC algorithm was the lowest in the elderly patients above 65-year-old. In this study, the important factors influencing the stable dose of warfarin in the elderly Han-Chinese were height, weight, body surface area, serum creatinine level, amiodarone usage, CYP2C9 (*1*2, *1*3), and VKORC1 (GG/GA) genotypes. By means of stepwise multiple regression analysis, we established a new elder warfarin dosing algorithm (R2=0.3714) containing height, creatinine, amiodarone usage, CYP2C9 (*1*2 or *1*3), and VKORC1 (GA or GG) genotypes. The prediction accuracy and clinical availability of the Elderly algorithm was significantly better than that of IWPC algorithm verified by RMSE, R2, and (20%-p) methods.
Conclusions: The IWPC model may not be suitable for the elder Han-Chinese population. Polymorphism of CYP2C9 and VKORC1 obviously affected warfarin stable dose of the elder Han-Chinese. Combination of genetic data with demographic and clinical factors could help to better improve warfarin doses in the elder Han-Chinese population.

PMID: 32754031 [PubMed]

Sequential Whole Exome Sequencing Reveals Somatic Mutations Associated with Platinum Response in NSCLC.

Onco Targets Ther. 2020;13:6485-6496

Authors: Guo AX, Xiao F, Shao WH, Zhan Y, Zhang L, Xiong J, Gao Y, Yin JY

Abstract
Purpose: Resistance is one of the main limitations of successful platinum treatment in non-small-cell lung cancer (NSCLC) patients. In this study, we aimed to identify somatic mutations associated with platinum response.
Patients and Methods: A total of 57 patients who received platinum-based chemotherapy only and 13 patients who received neoadjuvant chemotherapy (NAC) were enrolled. Somatic mutations were obtained from targeted and whole exome sequencing (WES).
Results: Somatic mutations in a total of 225 genes were observed. Nonsynonymous variants in EGFR, TTN, TP53 and KRAS, and copy number variations (SCNVs) in chromosome 8q24.3 and 22q11.21 were identified to be associated with platinum response. Based on these mutations, the mutational signature associated with the failure of DNA double-strand break and calcium signaling pathways were identified to be associated with platinum response. Besides, we observed a decrease in tumor mutational burden after chemotherapy. We also evaluated the mutation spectrum consistency between cell-free DNA (cfDNA) and tissue DNA. Somatic mutations detected in cfDNA were consistent with that in tDNA, which indicated that plasma might be used for somatic mutation detection.
Conclusion: These results support that somatic mutations can affect platinum drug response and provide potential clinical biomarkers for NSCLC treatment.

PMID: 32753889 [PubMed]

Does the Caesarean Section Impact on 11β HSD2 and Fetal Cortisol?

Int J Environ Res Public Health. 2020 Aug 01;17(15):

Authors: Słabuszewska-Jóżwiak A, Włodarczyk M, Kilian K, Rogulski Z, Ciebiera M, Szymańska-Majchrzak J, Zaręba K, Szymański JK, Raczkiewicz D, Nowicka G, Jakiel G

Abstract
PURPOSE: Comparison of the activity of 11beta-hydroxysteroid dehydrogenase type 2 in the placenta and the umbilical cord blood cortisol level between caesarean sections with or without uterine contraction and vaginal delivery groups. Cortisol is the main stress hormone responsible for the normal adaptation of the neonate to extrauterine life. The disorders resulting from a dysfunction of the 11β-HSD 2-cortisol system can explain the higher risk of developing diseases in children born by caesarean section.
METHODS: 111 healthy, pregnant women in singular pregnancy at term of delivery were included into the study. The study comprised 11β-HSD 2 in placental tissue from 49 pregnant women delivering by elective caesarean section and 46 pregnant women delivering by vagina. In 16 cases of the elective caesarean section, regular uterine contractions were declared. Cortisol level was estimated in umbilical cord blood directly after delivery.
RESULTS: We found no statistically significant differences in the activity of 11β-HSD 2 in placentas delivered via caesarean sections (29.61 on average in elective caesarean sections and 26.65 on average in intrapartum caesarean sections) compared to vaginal deliveries (31.94 on average, p = 0.381), while umbilical cord blood cortisol in the elective caesarean sections group was significantly lower (29.86 on average) compared to the vaginal deliveries (55.50 on average, p < 0.001) and intrapartum caesarean sections (52.27 on average, p < 0.001).
CONCLUSIONS: The model of placental 11β-HSD 2 activity and umbilical cord blood cortisol concentration seems to be significant in conditions of stress associated with natural uterine contractions in labour.

PMID: 32752242 [PubMed - in process]

Drug Use among Nursing Home Residents in Denmark for Drugs Having Pharmacogenomics Based (PGx) Dosing Guidelines: Potential for Preemptive PGx Testing.

J Pers Med. 2020 Jul 31;10(3):

Authors: Vermehren C, Søgaard Nielsen R, Jørgensen S, Drastrup AM, Westergaard N

Abstract
BACKGROUND: Polypharmacy is most prevalent among the elderly population and in particular among nursing home residents. The frequency of the use of drugs with pharmacogenomics (PGx)-based dosing guidelines for CYP2D6, CYP2C9, CYP2C19 and SLCO1B1 were measured among nursing home residents in the Capital Region of Denmark as well as drug-drug interactions. The aim was to evaluate the potential of applying PGx-test as a supportive tool in medication reviews.
METHODS: Drug use among nursing home residents during 2017-2018 in the Capital Region of Copenhagen, for drugs with PGx-based dosing guidelines available through the PharmGKB website, were measured. Drug-drug interactions were scored in severity by using drug interaction checkers.
RESULTS: The number of residents using drugs with PGx-based actionable dosing guidelines (AG) were 119 out of 141 residents (84.3%). Of these 119 residents, 87 residents used drugs with AG for CYP2C19, 47 residents for CYP2D6, and 42 residents for SLCO1B1. In addition, 30 residents used two drugs with an AG for CYP2C19, and for CYP2D6, it was only seven residents. The most used drugs with AG were clopidogrel (42), pantoprazole (32), simvastatin (30), metoprolol (25), and citalopram (24). The most frequent drug interactions found with warnings were combinations of proton pump inhibitors and clopidogrel underscoring the potential for phenoconversion.
CONCLUSION: this study clearly showed that the majority of the nursing home residents were exposed to drugs or drug combinations for which there exist PGx-based AG. This indeed supports the notion of accessing and accounting for not only drug-gene but also drug-drug-gene interactions as a supplement to medication review.

PMID: 32752034 [PubMed]

Review on chemogenomic approaches towards hepatitis C viral targets.

J Cell Biochem. 2019 08;120(8):12167-12181

Authors: Venkatesan A, Prabhu Dass J F

Abstract
Hepatitis C virus (HCV) is the most prevalent viral pathogen that infects more than 185 million people worldwide. HCV infection leads to chronic liver diseases such as liver cirrhosis and hepatocellular carcinoma. Direct-acting antivirals (DAAs) are the recent combination therapy for HCV infection with reduced side effects than prior therapies. Sustained virological response (SVR) acts as a gold standard marker to monitor the success of antiviral treatment. Older treatment therapies attain 50-55% of SVR compared with DAAs which attain around 90-95%. The current review emphasizes the recent chemogenomic updates that have been unfolded through structure-based drug design of HCV drug target proteins (NS3/4A, NS5A, and NS5B) and ligand-based drug design of DAAs in achieving a stable HCV viral treatment strategies.

PMID: 30887580 [PubMed - indexed for MEDLINE]

Plasmodium falciparum K13 expression associated with parasite clearance during artemisinin-based combination therapy.

J Antimicrob Chemother. 2019 07 01;74(7):1890-1893

Authors: Silva M, Ferreira PE, Otienoburu SD, Calçada C, Ngasala B, Björkman A, Mårtensson A, Gil JP, Veiga MI

Abstract
BACKGROUND: Delayed parasite clearance and, consequently, reduced efficacy of artemisinin-based combination therapies have been linked with Plasmodium falciparum K13 gene SNPs in Southeast Asia. In Africa, significantly prolonged clearance has not yet been observed and the presently restricted variation in parasite clearance cannot be explained by K13 polymorphisms.
OBJECTIVES: Our aim was to study the in vivo pfK13 transcriptional response in patients treated with artemether-lumefantrine and explore whether the pfk13 transcripts can explain the patients' parasite clearance outcomes.
PATIENTS AND METHODS: A total of 47 Tanzanian children with microscopically confirmed uncomplicated P. falciparum malaria were hospitalized and received artemether-lumefantrine treatment (clinical trial ID: NCT00336375). RNA was extracted from venous blood samples collected before treatment initiation and at five more timepoints after treatment. cDNA was synthesized and pfk13 transcripts measured by real-time PCR.
RESULTS: A wide range of pfk13 transcript variation was observed throughout all timepoints after artemether-lumefantrine treatment. Taking parasite clearance data together with the pfk13 transcripts profile, we observed a negative correlation inferring that pfk13 down-regulation is associated with longer parasite clearance time.
CONCLUSIONS: The findings suggest that a reduced PfK13 transcriptional response may represent a first step towards artemisinin tolerance/resistance.

PMID: 30869127 [PubMed - indexed for MEDLINE]

A comprehensive rat transcriptome built from large scale RNA-seq-based annotation.

Nucleic Acids Res. 2020 Aug 04;:

Authors: Ji X, Li P, Fuscoe JC, Chen G, Xiao W, Shi L, Ning B, Liu Z, Hong H, Wu J, Liu J, Guo L, Kreil DP, Łabaj PP, Zhong L, Bao W, Huang Y, He J, Zhao Y, Tong W, Shi T

Abstract
The rat is an important model organism in biomedical research for studying human disease mechanisms and treatments, but its annotated transcriptome is far from complete. We constructed a Rat Transcriptome Re-annotation named RTR using RNA-seq data from 320 samples in 11 different organs generated by the SEQC consortium. Totally, there are 52 807 genes and 114 152 transcripts in RTR. Transcribed regions and exons in RTR account for ∼42% and ∼6.5% of the genome, respectively. Of all 73 074 newly annotated transcripts in RTR, 34 213 were annotated as high confident coding transcripts and 24 728 as high confident long noncoding transcripts. Different tissues rather than different stages have a significant influence on the expression patterns of transcripts. We also found that 11 715 genes and 15 852 transcripts were expressed in all 11 tissues and that 849 house-keeping genes expressed different isoforms among tissues. This comprehensive transcriptome is freely available at http://www.unimd.org/rtr/. Our new rat transcriptome provides essential reference for genetics and gene expression studies in rat disease and toxicity models.

PMID: 32749457 [PubMed - as supplied by publisher]

PARC report: a health-systems focus on reimbursement and patient access to pharmacogenomics testing.

Pharmacogenomics. 2020 Aug 04;:

Authors: L Rogers S, Keeling NJ, Giri J, Gonzaludo N, Jones JS, Glogowski E, Formea CM

Abstract
Pharmacogenomics test coverage and reimbursement are major obstacles to clinical uptake. Several early adopter programs have been successfully initiated through dedicated investments by federal and institutional research funding. As a result of research endeavors, evidence has grown sufficiently to support development of pharmacogenomics guidelines. However, clinical uptake is still limited. Third-party payer support plays an important role in increasing adoption, which to date has been limited to reactive single-gene testing. Access to and interest in direct-to-consumer genetic testing are driving demand for increasing healthcare providers and third-party awareness of this burgeoning field. Pharmacogenomics implementation models developed by early adopters promise to expand patient access and options, as testing continues to increase due to growing consumer interest and falling test prices.

PMID: 32748688 [PubMed - as supplied by publisher]

Correction: Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

Genet Med. 2020 Aug 03;:

Authors: Beitelshees AL, Stevenson JM, El Rouby N, Dillon C, Empey PE, Fielstein EM, Johnson JA, Limdi NA, Ong HH, Franchi F, Angiolillo DJ, Peterson JF, Rosenman MB, Skaar TC, Tuteja S, Cavallari LH, IGNITE Pharmacogenetics Working Group

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 32747766 [PubMed - as supplied by publisher]

Clinically relevant endothelial nitric oxide synthase polymorphisms and their impact on drug response.

Expert Opin Drug Metab Toxicol. 2020 Aug 04;:

Authors: Cotta Filho CK, Oliveira-Paula GH, Rondon Pereira VC, Lacchini R

Abstract
INTRODUCTION: Nitric Oxide (NO) is a molecule with multiple functions. Several drugs involve the modulation of NO levels in their mechanism of action. NO is mainly produced in vessels by endothelial NO synthase, which is encoded by NOS3 gene. This gene shows genetic polymorphisms associated with hypertension and other cardiovascular diseases, inflammation, psychiatric disorders, cancer, and others.
AREAS COVERED: Four functional polymorphisms of NOS3 were selected: rs2070744, rs3918226, rs61722009 and rs1799983 and their association with differential drug responses was explored. This review explores beyond the cardiovascular area, including drugs regardless of their clinical indications.
EXPERT OPINION: While there is good evidence of the clinical importance of NOS3 single nucleotide polymorphisms, the current knowledge is superficial in most clinical settings and further studies are needed. Basic science advances are also needed to help to interpret genetic association data. While there are controversies, most data from chronic treatment studies show a trend for loss-of-function alleles, that predispose to higher risk for disease, associating with better clinical response across different drug classes and clinical settings. Acute pharmacological responses were poorly explored, although there seem to be a trend where gain-of-function alleles associate with better clinical responses when observed in the scale of minutes to hours.

PMID: 32746648 [PubMed - as supplied by publisher]

Genetic Variants in DNA Mismatch Repair Pathway predict prognosis of Lung Cancer patients with receiving Platinum-Based Chemotherapy.

J Cancer. 2020;11(18):5281-5288

Authors: Liu JY, Zou T, Yin JY, Wang Z, Wang Y, Liu ZQ, Chen J, Chen ZW

Abstract
Objective: To investigate the relationships between genetic variants in DNA mismatch repair pathway genes and the prognosis of platinum-based chemotherapy in lung cancer patients. Methods: 346 lung cancer patients who received at least two cycles of platinum-based chemotherapy were recruited in this study. A total of 35 single nucleotide polymorphisms in 7 DNA mismatch repair genes were genotyped to investigate their associations with platinum-based chemotherapy prognosis. Result: The results revealed that patients carried MSH2 rs4608577 TT genotype had a significantly shorter progression free survival than patients with GG or GT genotypes (Additive model: P=0.003, OR =0.94, 95% CI =0.33-1.57). Patients with SAPCD1 rs707937 TT genotype had a significantly longer overall survival than patients with GG or GT genotypes (Additive model: P=0.0003, OR=0.75, 95% CI =0.35-1.14). Eight SNPs and fourteen SNPs were related to progression free survival and overall survival in subgroup analyses, respectively. Conclusion: Our findings suggest that the MSH2 rs4608577 and SAPCD1 rs707937 may be potential clinical biomarkers for predicting platinum-based chemotherapy prognosis in lung cancer patients.

PMID: 32742474 [PubMed]

KRAS inhibition in non-small cell lung cancer: Past failures, new findings and upcoming challenges.

Eur J Cancer. 2020 Jul 31;137:57-68

Authors: Passiglia F, Malapelle U, Del Re M, Righi L, Pagni F, Furlan D, Danesi R, Troncone G, Novello S

Abstract
Despite the high prevalence of Kirsten rat sarcoma (KRAS) mutations in non-small cell lung cancer (NSCLC), for a long time it has been defined as an 'undruggable target', with precision medicine not considered as an adequate approach to treat this subgroup of patients. After several years of efforts, preliminary data from early clinical trials have recently demonstrated that direct pharmacological inhibition of KRAS p.G12C mutation is possible, emerging as an effective targeted treatment for about 10-12% of patients with advanced NSCLC, with potential relevant impact on their long-term survival and quality of life. This review reports the current status of KRAS mutations detection in the Italian real-word scenario, summarises the biological basis of KRAS inhibition in NSCLC and provides an updated overview of therapeutic strategies, discussing the potential reasons for past failures and analysing the upcoming challenges related to the advent of new targeted agents in clinical practice.

PMID: 32745965 [PubMed - as supplied by publisher]

Patient perceptions of pharmacogenomic testing in the community pharmacy setting.

Res Social Adm Pharm. 2020 Jul 13;:

Authors: Bright D, Worley M, Porter BL

Abstract
BACKGROUND: In order to optimize community pharmacist roles and patient outcomes, a better understanding of patient perceptions of pharmacogenomic (PGx) testing may be helpful for successful integration into community pharmacy practice.
OBJECTIVE: The objective of this study was to identify patient perceptions related to PGx testing in the community pharmacy setting.
METHODS: Semi-structured, face-to-face interviews were conducted with adults ≥18 years of age to gather their perceptions of PGx testing. Interview participants were taking either an antiplatelet agent or a selective serotonin reuptake inhibitor listed in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and were patients at one of two community pharmacies in West Michigan. Interview questions were designed to follow the Theory of Planned Behavior and to take into account existing literature on patient perceptions of PGx. Interviews were recorded, transcribed by a third party transcription service, coded by a team of three researchers to identify themes, and analyzed using nVivo qualitative analysis software.
RESULTS: A total of 19 interviews were conducted over a period of 16 days in June 2016. Upon preliminary evaluation, four themes related to patient perceptions of PGx testing were consistently observed across multiple interviews: 1) trust, 2) experience, 3) risk/benefit, and 4) clarity.
CONCLUSIONS: Semi-structured patient interviews revealed four themes related to PGx testing in the community pharmacy setting. These themes may influence the desire to pursue PGx testing. Future research may seek to identify how community pharmacists can communicate with patients about PGx in the context of these themes to empower patients to make positive health care decisions.

PMID: 32741696 [PubMed - as supplied by publisher]

DNA repair gene polymorphisms, tumor control, and treatment toxicity in prostate cancer patients treated with permanent implant prostate brachytherapy.

Prostate. 2020 05;80(8):632-639

Authors: Carignan D, Lessard T, Villeneuve L, Desjardins S, Magnan S, Després P, Martin AG, Foster W, Guillemette C, Lévesque É, Vigneault E

Abstract
BACKGROUND: Radiotherapy and brachytherapy are common treatments for localized prostate cancer (PCa). However, very few studies evaluated the association of variations in DNA damage response genes and treatment outcomes and toxicity in brachytherapy-treated patients.
PURPOSE: To evaluate the association of inherited germline variations in DNA repair-associated genes with tumor control and treatment toxicity in patients treated with low-dose-rate prostate brachytherapy (LDRB).
MATERIAL AND METHODS: The cohort consists of 475 I-125 LDRB patients with a median follow-up of 51 months after seed implantation. Patients were genotyped for 215 haplotype tagging single nucleotide variations (htSNPs) in 29 candidate genes of DNA damage response and repair pathways. Their association with biochemical recurrence (BCR) was assessed using Cox regression models and Kaplan-Meier survival curves. Linear regressions and analysis of covariance (ANCOVA) between early and late International Prostate Symptom Score (IPSS) with htSNPs were used to evaluate the association with urinary toxicity.
RESULTS: After adjustment for the established risk factors, six htSNPs in five genes were found to be significantly associated with an altered risk of BCR, with adjusted hazard ratios (HRadj. ) ranging between 3.6 and 11.1 (P < .05). Compared to carriers of the ERCC3 rs4150499C allele, patients homozygous for the T allele (n = 22) had a significant higher risk of BCR with a HR of 11.13 (IC95  = 3.9-32.0; P < .0001; q < 0.001). The Kaplan-Meier survival curve revealed a mean BCR-free survival time reduced from 213 ± 7 to 99 ± 12 months (log-rank P < .0001) for homozygous T carriers compare to noncarriers. For late IPSS (>6 months after treatment), htSNP rs6544990 from MSH2 showed a statistically significant b-coefficient of 1.85 ± 0.52 (P < .001; q < 0.1). Homozygous carriers of the MSH2 rs6544990C allele (n = 62) had a mean late IPSS 3.6 points higher than patients homozygous for the A allele (n = 132). This difference was significant when tested by ANCOVA using pretreatment IPSS as a covariate (P < .01).
CONCLUSIONS: This study suggests an association of the intronic variants of the DNA nucleotide excision repair ERCC3 and DNA mismatch repair MSH2 genes with elevated risk of BCR and late urinary toxicity respectively after LDRB. Further validation is required before translational clinical advances.

PMID: 32201973 [PubMed - indexed for MEDLINE]