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Nucleic acid based therapies: developing frontier for precision medicine.

BMJ. 2018 01 23;360:k223

Authors: Pirmohamed M

PMID: 29363539 [PubMed - indexed for MEDLINE]

Novel Genetic Variants of Sporadic Atrial Septal Defect (ASD) in a Chinese Population Identified by Whole-Exome Sequencing (WES).

Med Sci Monit. 2018 Mar 05;24:1340-1358

Authors: Liu Y, Cao Y, Li Y, Lei D, Li L, Hou ZL, Han S, Meng M, Shi J, Zhang Y, Wang Y, Niu Z, Xie Y, Xiao B, Wang Y, Li X, Yang L, Wang W, Jiang L

Abstract
BACKGROUND Recently, mutations in several genes have been described to be associated with sporadic ASD, but some genetic variants remain to be identified. The aim of this study was to use whole-exome sequencing (WES) combined with bioinformatics analysis to identify novel genetic variants in cases of sporadic congenital ASD, followed by validation by Sanger sequencing. MATERIAL AND METHODS Five Han patients with secundum ASD were recruited, and their tissue samples were analyzed by WES, followed by verification by Sanger sequencing of tissue and blood samples. Further evaluation using blood samples included 452 additional patients with sporadic secundum ASD (212 male and 240 female patients) and 519 healthy subjects (252 male and 267 female subjects) for further verification by a multiplexed MassARRAY system. Bioinformatic analyses were performed to identify novel genetic variants associated with sporadic ASD. RESULTS From five patients with sporadic ASD, a total of 181,762 genomic variants in 33 exon loci, validated by Sanger sequencing, were selected and underwent MassARRAY analysis in 452 patients with ASD and 519 healthy subjects. Three loci with high mutation frequencies, the 138665410 FOXL2 gene variant, the 23862952 MYH6 gene variant, and the 71098693 HYDIN gene variant were found to be significantly associated with sporadic ASD (P<0.05); variants in FOXL2 and MYH6 were found in patients with isolated, sporadic ASD (P<5×10^-4). CONCLUSIONS This was the first study that demonstrated variants in FOXL2 and HYDIN associated with sporadic ASD, and supported the use of WES and bioinformatics analysis to identify disease-associated mutations.

PMID: 29505555 [PubMed - in process]

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Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing.

Nat Commun. 2018 01 15;9(1):216

Authors: Nahar R, Zhai W, Zhang T, Takano A, Khng AJ, Lee YY, Liu X, Lim CH, Koh TPT, Aung ZW, Lim TKH, Veeravalli L, Yuan J, Teo ASM, Chan CX, Poh HM, Chua IML, Liew AA, Lau DPX, Kwang XL, Toh CK, Lim WT, Lim B, Tam WL, Tan EH, Hillmer AM, Tan DSW

Abstract
EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.

PMID: 29335443 [PubMed - indexed for MEDLINE]

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Clinical implications of genomic profiles in metastatic breast cancer with a focus on TP53 and PIK3CA, the most frequently mutated genes.

Oncotarget. 2017 Apr 25;8(17):27997-28007

Authors: Kim JY, Lee E, Park K, Park WY, Jung HH, Ahn JS, Im YH, Park YH

Abstract
Breast cancer (BC) has been genetically profiled through large-scale genome analyses. However, the role and clinical implications of genetic alterations in metastatic BC (MBC) have not been evaluated. Therefore, we conducted whole-exome sequencing (WES) and RNA-Seq of 37 MBC samples and targeted deep sequencing of another 29 MBCs. We evaluated somatic mutations from WES and targeted sequencing and assessed gene expression and performed pathway analysis from RNA-Seq. In this analysis, PIK3CA was the most commonly mutated gene in estrogen receptor (ER)-positive BC, while in ER-negative BC, TP53 was the most commonly mutated gene (p = 0.018 and p < 0.001, respectively). TP53 stopgain/loss and frameshift mutation was related to low expression of TP53 in contrast nonsynonymous mutation was related to high expression. The impact of TP53 mutation on clinical outcome varied with regard to ER status. In ER-positive BCs, wild type TP53 had a better prognosis than mutated TP53 (median overall survival (OS) (wild type vs. mutated): 88.5 ± 54.4 vs. 32.6 ± 10.7 (months), p = 0.002). In contrast, mutated TP53 had a protective effect in ER-negative BCs (median OS: 0.10 vs. 32.6 ± 8.2, p = 0.026). However, PIK3CA mutation did not affect patient survival. In gene expression analysis, CALM1, a potential regulator of AKT, was highly expressed in PIK3CA-mutated BCs. In conclusion, mutation of TP53 was associated with expression status and affect clinical outcome according to ER status in MBC. Although mutation of PIK3CA was not related to survival in this study, mutation of PIK3CA altered the expression of other genes and pathways including CALM1 and may be a potential predictive marker of PI3K inhibitor effectiveness.

PMID: 28427202 [PubMed - indexed for MEDLINE]

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Experience with precision genomics and tumor board, indicates frequent target identification, but barriers to delivery.

Oncotarget. 2017 Apr 18;8(16):27145-27154

Authors: Bryce AH, Egan JB, Borad MJ, Stewart AK, Nowakowski GS, Chanan-Khan A, Patnaik MM, Ansell SM, Banck MS, Robinson SI, Mansfield AS, Klee EW, Oliver GR, McCormick JB, Huneke NE, Tagtow CM, Jenkins RB, Rumilla KM, Kerr SE, Kocher JA, Beck SA, Fernandez-Zapico ME, Farrugia G, Lazaridis KN, McWilliams RR

Abstract
BACKGROUND: The ability to analyze the genomics of malignancies has opened up new possibilities for off-label targeted therapy in cancers that are refractory to standard therapy. At Mayo Clinic these efforts are organized through the Center for Individualized Medicine (CIM).
RESULTS: Prior to GTB, datasets were analyzed and integrated by a team of bioinformaticians and cancer biologists. Therapeutically actionable mutations were identified in 65% (92/141) of the patients tested with 32% (29/92) receiving genomically targeted therapy with FDA approved drugs or in an independent clinical trial with 45% (13/29) responding. Standard of care (SOC) options were continued by 15% (14/92) of patients tested before exhausting SOC options, with 71% (10/14) responding to treatment. Over 35% (34/92) of patients with actionable targets were not treated with 65% (22/34) choosing comfort measures or passing away.
MATERIALS AND METHODS: Patients (N = 165) were referred to the CIM Clinic between October 2012 and December 2015. All patients received clinical genomic panel testing with selected subsets receiving array comparative genomic hybridization and clinical whole exome sequencing to complement and validate panel findings. A genomic tumor board (GTB) reviewed results and, when possible, developed treatment recommendations.
CONCLUSIONS: Treatment decisions driven by tumor genomic analysis can lead to significant clinical benefit in a minority of patients. The success of genomically driven therapy depends both on access to drugs and robustness of bioinformatics analysis. While novel clinical trial designs are increasing the utility of genomic testing, robust data sharing of outcomes is needed to optimize clinical benefit for all patients.

PMID: 28423702 [PubMed - indexed for MEDLINE]

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Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation.

Clin Cancer Res. 2017 Feb 01;23(3):735-745

Authors: Yu L, Kim HT, Kasar S, Benien P, Du W, Hoang K, Aw A, Tesar B, Improgo R, Fernandes S, Radhakrishnan S, Klitgaard J, Lee C, Getz G, Setlur SR, Brown JR

Abstract
PURPOSE: Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL.
EXPERIMENTAL DESIGN: We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity.
RESULTS: We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number.
CONCLUSIONS: We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. Clin Cancer Res; 23(3); 735-45. ©2016 AACR.

PMID: 27503198 [PubMed - indexed for MEDLINE]

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Quality Control for the Illumina HumanExome BeadChip.

Curr Protoc Hum Genet. 2016 Jul 01;90:2.14.1-2.14.16

Authors: Igo RP, Cooke Bailey JN, Romm J, Haines JL, Wiggs JL

Abstract
The Illumina HumanExome BeadChip and other exome-based genotyping arrays offer inexpensive genotyping of some 240,000 mostly nonsynonymous coding variants across the human genome. The HumanExome chip, with its highly non-uniform distribution of markers and emphasis on rare coding variants, presents some unique challenges for quality control (QC) and data cleaning. Here, we describe QC procedures for HumanExome data, with examples of challenges specific to exome arrays from our experience cleaning a data set of ∼7,500 samples from the NEIGHBORHOOD Consortium. We focus on standard procedures for QC of genome-wide array data including genotype calling, sex verification, sample identity verification, relationship checking, and population structure that are complicated by the HumanExome panel's enrichment in rare, exonic variation. © 2016 by John Wiley & Sons, Inc.

PMID: 27367164 [PubMed - indexed for MEDLINE]

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Non-adherence to medication regimens among older African-American adults.

BMC Geriatr. 2017 Jul 25;17(1):163

Authors: Bazargan M, Smith J, Yazdanshenas H, Movassaghi M, Martins D, Orum G

Abstract
BACKGROUND: Despite concerns about racial differences on adherence to prescribed medication rigimens among older adults, current information about nonadherence among underserved elderly African Americans with co-morbidities is limited. This study examines the association between adherence to drug regimens and an array of medication-related factors, including polypharmacy, medication regimen complexity, use of Potentially Inappropriate Medications (PIM), and knowledge about the therapeutic purpose and instructions of medication use.
METHODS: Four-hundred African Americans, aged 65 years and older, were recruited from South Los Angeles. Structured, face-to-face interviews and visual inspection of participants' medications were conducted. From the medication container labels, information including strength of the drug, expiration date, instructions, and special warnings were recorded. The Medication Regimen Complexity Index (MRCI) was measured to quantify multiple features of drug regimen complexity. The Beers Criteria was used to measure the PIM use.
RESULTS: Participants reported taking an average of 5.7 prescription drugs. Over 56% could not identify the purpose of at least one of their medications. Only two-thirds knew dosage regimen of their medications. Thirty-five percent of participants indicated that they purposely had skipped taking at least one of their medications within last three days. Only 8% of participants admitted that they forgot to take their medications. The results of multivariate analysis showed that co-payment for drugs, memory deficits, MRCI, and medication-related knowledge were all associated with adherence to dosage regimen of medications. Participants with a higher level of knowledge about therapeutic purpose and knowledge about dosage regimen of their medications were seven times (CI: 4.2-10.8) more likely to adhere to frequency and dose of medications. Participants with a low complexity index were two times (CI: 1.1-3.9) more likely to adhere to the dosage regimen of their medications, compared with participants with high drug regimen complexity index.
CONCLUSIONS: While other studies have documented that non-adherence remains an important issue among older adults, our study shows that for underserved elderly African Americans, these issues are particularly striking. A periodic comprehensive assessment of all medications that they use remains a critical initial step to identify medication related issues. Assessment of their disease and medication related knowledge (e.g., therapeutic purposes, side-effects, special instructions, etc.) and their ability to follow complicated medication regimens and modification of their drug regimens requires inter-professional collaboration.

PMID: 28743244 [PubMed - indexed for MEDLINE]

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Concurrent use of alcohol interactive medications and alcohol in older adults: a systematic review of prevalence and associated adverse outcomes.

BMC Geriatr. 2017 Jul 17;17(1):148

Authors: Holton AE, Gallagher P, Fahey T, Cousins G

Abstract
BACKGROUND: Older adults are susceptible to adverse effects from the concurrent use of medications and alcohol. The aim of this study was to systematically review the prevalence of concurrent use of alcohol and alcohol-interactive (AI) medicines in older adults and associated adverse outcomes.
METHODS: A systematic search was performed using MEDLINE (PubMed), Embase, Scopus and Web of Science (January 1990 to June 2016), and hand searching references of retrieved articles. Observational studies reporting on the concurrent use of alcohol and AI medicines in the same or overlapping recall periods in older adults were included. Two independent reviewers verified that studies met the inclusion criteria, critically appraised included studies and extracted relevant data. A narrative synthesis is provided.
RESULTS: Twenty studies, all cross-sectional, were included. Nine studies classified a wide range of medicines as AI using different medication compendia, thus resulting in heterogeneity across studies. Three studies investigated any medication use and eight focused on psychotropic medications. Based on the quality assessment of included studies, the most reliable estimate of concurrent use in older adults ranges between 21 and 35%. The most reliable estimate of concurrent use of psychotropic medications and alcohol ranges between 7.4 and 7.75%. No study examined longitudinal associations with adverse outcomes. Three cross-sectional studies reported on falls with mixed findings, while one study reported on the association between moderate alcohol consumption and adverse drug reactions at hospital admission.
CONCLUSIONS: While there appears to be a high propensity for alcohol-medication interactions in older adults, there is a lack of consensus regarding what constitutes an AI medication. An explicit list of AI medications needs to be derived and validated prospectively to quantify the magnitude of risk posed by the concurrent use of alcohol for adverse outcomes in older adults. This will allow for risk stratification of older adults at the point of prescribing, and prioritise alcohol screening and brief alcohol interventions in high-risk groups.

PMID: 28716004 [PubMed - indexed for MEDLINE]

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[Prevalence of potentially inappropriate drug prescription in the elderly].

Rev Calid Asist. 2016 Sep-Oct;31(5):279-84

Authors: Fajreldines A, Insua J, Schnitzler E

Abstract
INTRODUCTION: One of the causes of preventable adverse drug events (ADES) in older patients constitutes inappropriate prescription of drugs (PIM). The PIM is where risks exceed the clinical benefit. Several instruments can be use to measure this problem, the most used are: a) Beers criteria; b) Screening tool to Older People Potentially inappropriate Prescription (STOPP); c) Screening tool to Alert Doctors to Right Appropriate indicated Treatments (START); d) The Medication Appropriateness Index (MAI). This study aims to assess the prevalence of PIM, in a population of older adults in three clinical scopes of university hospital.
MATERIAL AND METHODS: cross sectional study of 300 cases from a random sample of fields: hospitalization (n=100), ambulatory (n=100) and emergency (n=100), all patients over 65 years old or more who where treated at our hospital.
RESULTS: 1355 prescription drugs were analized, finding patients hospitalized (PIM) of 57.7%, 55%, 26%, and 80% according to Beers, in ambulatory 36%, 36.5%, 5% and 52% with the same tools and in emergency 35%, 35%, 6% y 52% with the same tools. Was found significant association the PIM with polipharmacy with Beers, STOPP and MAI.
CONCLUSIONS: results can be compare to world literature (26-80% vs 11-73.1%). The STOPP-START used in an integrated manner would be best estimating the problem of PIM.

PMID: 26970837 [PubMed - indexed for MEDLINE]

Notice NOT-OD-18-145 from the NIH Guide for Grants and Contracts

Notice NOT-AR-18-017 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-707 from the NIH Guide for Grants and Contracts. The purpose of this FOA is the rapid and efficient translation of innovative laboratory research findings into therapies, devices or other resources for use by clinicians to treat visual system diseases or disorders. Multidisciplinary teams of scientists and clinicians will focus on generating preclinical data that will lead to the development of biological interventions, such as gene therapy, cell-based therapy, pharmacological approaches, and/or medical devices. The ultimate goal of this program is to make technological, biological and pharmacological resources available to clinicians and their patients.

Funding Opportunity PAR-18-706 from the NIH Guide for Grants and Contracts. The goal of this FOA is to define and characterize neural cell populations, neural circuits, and brain networks and regions that are vulnerable to brain aging and Alzheimers disease (AD). Understanding mechanisms underlying selective vulnerability from cells to networks in AD is critical to fully define the disease process and to develop effective therapies.

Funding Opportunity RFA-DA-19-005 from the NIH Guide for Grants and Contracts. This FOA solicits applications proposing phased research projects, with transition milestones, to develop and rigorously test the effects of strategies to improve opioid treatment quality measures, both on changes in the measures themselves and on patient outcomes. The overall goal is to advance the field of clinical quality measurement and management in opioid use disorder treatment by generating research better aligning quality measurement with quality improvement.

Notice NOT-MH-18-027 from the NIH Guide for Grants and Contracts

Funding Opportunity PAS-18-698 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) seeks to stimulate HIV/AIDS research within the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) that addresses high priority HIV/AIDS research priorities outlined by the NIH Office of AIDS Research (OAR). These priorities are described in NOT-OD-15-137: NIH HIV/AIDS Research Priorities and Guidelines for Determining AIDS Funding.

Notice NOT-MH-18-026 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-HD-19-001 from the NIH Guide for Grants and Contracts. A major objective of this funding opportunity announcement (FOA) is to invite SBIR applications to foster collaboration between clinical and bioengineering research communities to develop and test safe, accurate, and effective devices for use in neonatal, perinatal, and pediatric care settings. These can be new devices or improvements on existing devices. The studies may range from concept to developmental phases, with a clear commercialization plan to enable healthcare providers to use them in regular clinical care settings in the population, which is the focus of this FOA.

Notice NOT-NS-18-048 from the NIH Guide for Grants and Contracts