Pharma Perspective on Drug Repurposing.

Br J Pharmacol. 2017 Mar 29;:

Authors: Cha Y, Erez T, Reynolds IJ, Kumar D, Ross J, Koytiger G, Kusko R, Zeskind B, Risso S, Kagan E, Papapetropoulos S, Grossman I, Laifenfeld D

Abstract
Drug repurposing holds the potential to bring medications with known safety profiles to new patient populations. Numerous examples exist for the identification of new indications for existing molecules, most stemming from serendipitous findings or focused recent efforts specifically limited to the mode of action of a specific drug. In recent years, the need for new approaches to drug R&D, combined with the advent of big-data repositories and associated analytics has generated interest in developing systematic approaches to drug repurposing. A variety of innovative computational methods to enable systematic repurposing screens, experimental as well as through in-silico approaches, have emerged. An efficient drug repurposing pipeline requires the combination of access to molecule data, appropriate analytical expertise to enable robust insights, expertise and experimental set up for validation, and clinical development know-how. In this review we describe some of the main approaches to systematic repurposing, discuss the various players in this field and the need for strategic collaborations to increase likelihood of success in bringing existing molecules to new indications, as well as the current advantages, considerations and challenges in repurposing as a drug-development strategy pursued by pharmaceutical companies.

PMID: 28369768 [PubMed - as supplied by publisher]

Age and Semantic Inhibition Measured by the Hayling Task: A Meta-Analysis.

Arch Clin Neuropsychol. 2017 Mar 01;32(2):198-214

Authors: Cervera-Crespo T, González-Alvarez J

Abstract
Objective: Cognitive aging is commonly associated with a decrease in executive functioning (EF). A specific component of EF, semantic inhibition, is addressed in the present study, which presents a meta-analytic review of the literature that has evaluated the performance on the Hayling Sentence Completion test in young and older groups of individuals in order to assess the magnitude of the age effect.
Method: A systematic search involving Web of Science, PsyINFO, PsychARTICLE, and MedLine databases and Google Scholar was performed. A total of 11 studies were included in this meta-analysis, encompassing a total of 887 participants; 440 young and 447 older adults. The effect sizes for group differences on four measures of the Hayling test, latency responses and error scores on the Automatic and Inhibition sections of the test were calculated using the Comprehensive Meta-Analysis software package.
Results: The results revealed large age effects for response latencies in both the Automatic (Hedges' g = 0.81) and Inhibitory conditions (Hedges' g = 0.98), though the latter two effect sizes did not differ from each other. In contrast, analysis of errors revealed a significant difference between the small effect seen in the Automatic condition (Hedges' g = 0.13) relative to the moderate effect seen in the Inhibition condition (Hedges' g = 0.55).
Conclusions: These results may be important for a better understanding of the inhibitory functioning in elderly individuals, although they should be interpreted with caution because of the limited number of studies in the literature to date.

PMID: 28365747 [PubMed - in process]

Actionable, long-term stable and semantic web compatible identifiers for access to biological collection objects.

Database (Oxford). 2017 Jan 01;2017(1):

Authors: Güntsch A, Hyam R, Hagedorn G, Chagnoux S, Röpert D, Casino A, Droege G, Glöckler F, Gödderz K, Groom Q, Hoffmann J, Holleman A, Kempa M, Koivula H, Marhold K, Nicolson N, Smith VS, Triebel D

Abstract
With biodiversity research activities being increasingly shifted to the web, the need for a system of persistent and stable identifiers for physical collection objects becomes increasingly pressing. The Consortium of European Taxonomic Facilities agreed on a common system of HTTP-URI-based stable identifiers which is now rolled out to its member organizations. The system follows Linked Open Data principles and implements redirection mechanisms to human-readable and machine-readable representations of specimens facilitating seamless integration into the growing semantic web. The implementation of stable identifiers across collection organizations is supported with open source provider software scripts, best practices documentations and recommendations for RDF metadata elements facilitating harmonized access to collection information in web portals.
Database URL: : http://cetaf.org/cetaf-stable-identifiers.

PMID: 28365724 [PubMed - in process]

A Simulation Study to Compare the Treatment Effect of Tamoxifen by CYP2D6 Genotypes and Third-Generation Aromatase Inhibitors.

J Clin Pharmacol. 2017 Apr 03;:

Authors: Park GC, Jung JA, Bae KS, Lim HS

Abstract
Some prospective, randomized clinical trials, including ATAC and BIG 1-98, demonstrated superior treatment effect of third-generation aromatase inhibitors (AIs) versus tamoxifen in postoperative therapy for patients with breast cancer. In retrospective genotyping analyses of the 2 studies using tumor samples, no difference in the treatment effect of tamoxifen was observed by CYP2D6 genotypes. However, those analyses did not consider loss of heterozygosity that could have occurred when genotyping using tumor tissue. The present simulation study aimed to comparatively evaluate the treatment effect of tamoxifen versus AIs of anastrozole and letrozole by CYP2D6 genotypes. A meta-analysis was conducted to estimate disease-free survival (DFS) hazard ratios of CYP2D6 genotypes representing extensive metabolizers (EMs), HRW/W,TAM , versus intermediate metabolizers (IMs)/poor metabolizers (PMs), HRV/W,TAM , using previous study results in which genotypes were determined using blood samples. Based on known allele frequencies, the CYP2D6 genotype distribution of participants in ATAC and BIG 1-98 trials were simulated. Subseqyuently, DFS HRs of AIs versus tamoxifen by CYP2D6 genotypes (HRAI/TAM,W for EMs, HRAI/TAM,V for IMs/PMs) were estimated via regression analyses using NONMEM, based on the simulated genotype distributions, HRV/W,TAM , and HRs, of AIs versus tamoxifen (HRAI/TAM ) reported in the ATAC and BIG 1-98 trials. Median HRAI/TAM,V (95% prediction interval [PI]) was 0.43 (0.23-0.79) and 0.40 (0.22-0.73) for the ATAC and BIG 1-98 trials, respectively. However, the corresponding HRAI/TAM,W values were 0.97 (0.84-1.11) and 0.91 (0.77-1.08), respectively. These results suggest that in patients with the CYP2D6 genotype representing EMs, the treatment effect of tamoxifen is comparable to that of AIs.

PMID: 28369967 [PubMed - as supplied by publisher]

System pharmacogenomics application in infectious diseases.

Brief Funct Genomics. 2017 Mar 21;:

Authors: Mandlik V, Kabra R, Singh S

Abstract
The new era in systems pharmacology has revolutionized the human biology. Its applicability, precise treatment, adequate response and safety measures fit into all the paradigm of medical/clinical practice. The importance of mathematical models in understanding the disease pathology and epideomology is now being realized. The advent of high-throughput technologies and the emergence of systems biology have resulted in the creation of systems pharmacogenomics and the focus is now on personalized medicine. However, there are some regulatory issues that need to be addresssed; are we ready for this universal adoption? This article details some of the infectious disease pharmacogenomics to the developments in this area.

PMID: 28369182 [PubMed - as supplied by publisher]

Classics in Chemical Neuroscience: Aripiprazole.

ACS Chem Neurosci. 2017 Apr 03;:

Authors: Casey AB, Canal CE

Abstract
Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D2 receptor binding kinetics, have significantly lower risk of movement side effects, but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology-characterized by its unique agonist activity at dopamine D2, D3 and serotonin 5-HT1A receptors as well as antagonist activity at serotonin 5-HT2A receptors-translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.

PMID: 28368577 [PubMed - as supplied by publisher]

Do polymorphisms in MDR1 and CYP3A5 genes influence the risk of cytogenetic relapse in patients with chronic myeloid leukemia on imatinib therapy?

Leuk Lymphoma. 2017 Apr 03;:1-9

Authors: Harivenkatesh N, Kumar L, Bakhshi S, Sharma A, Kabra M, Velpandian T, Gogia A, Shastri SS, Gupta YK

Abstract
Influence of polymorphisms in the genes coding for imatinib transporters and metabolizing enzymes on cytogenetic relapse in patients with chronic myeloid leukemia (CML) is not known. One hundred and four patients (52 cases with cytogenetic relapse and 52 controls without relapse) with chronic-phase CML on imatinib therapy and have completed 5 years of follow-up were enrolled. The following single nucleotide polymorphisms (SNPs) were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene, using PCR-RFLP method and validated by direct gene sequencing. Imatinib trough levels were measured using LC-MS/MS. Patients with CC genotype for MDR1-C1236T polymorphism were at significantly higher risk for cytogenetic relapse [OR =4.382, 95% CI (1.145, 16.774), p = .022], while those with TT genotype for MDR1-C3435T polymorphism had significantly lower risk of relapse [OR =0.309, 95% CI (0.134, 0.708), p = .005]. Imatinib trough levels were lower in patients with relapse compared to those without relapse (1551.4 ± 1324.1 vs. 2154.2 ± 1358.3 ng/mL; p = .041). MDR1-C3435T genotype [adjusted-OR: 0.266; 95% CI (0.111, 0.636); p = .003] and trough levels (p = .014) were independent predictors of relapse in multivariate analysis. To conclude, C1236T and C3435T polymorphisms in MDR1 gene and trough levels significantly influence the risk of cytogenetic relapse. MDR1-C3435T genotype might emerge as a potential biomarker to predict the risk of cytogenetic relapse in patients with CML.

PMID: 28367681 [PubMed - as supplied by publisher]

Potential protective function of the sterol regulatory element binding factor 1-fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration.

Heliyon. 2017 Mar;3(3):e00266

Authors: Ashikawa Y, Nishimura Y, Okabe S, Sato Y, Yuge M, Tada T, Miyao H, Murakami S, Kawaguchi K, Sasagawa S, Shimada Y, Tanaka T

Abstract
Age-related macular degeneration (AMD) is the most common cause of vision loss in elderly individuals throughout the developed world. Inhibitors of vascular endothelial growth factor have been successfully used to treat choroidal neovascularization in late-stage AMD. The pathogenesis of early-stage AMD, however, remains largely unknown, impairing efforts to develop effective therapies that prevent progression to late-stage AMD. To address this, we performed comparative transcriptomics of macular and extramacular retinal pigmented epithelium-choroid (RPE-choroid) tissue from early-stage AMD patients. We found that expression of fatty acid desaturase 1 (FADS1), FADS2, and acetyl-CoA acetyltransferase 2 (ACAT2) is increased in macular but not extramacular tissue, possibly through activation of sterol regulatory element binding factor 1 (SREBF1). Consistent with this, we also found that expression of Fads1 is increased in RPE-choroid in a mouse model of early-stage AMD. In zebrafish, deletion of fads2, which encodes a protein that functions as both Fads1 and Fads2 in other species, enhanced apoptosis in the retina upon exposure to intense light. Similarly, pharmacological inhibition of Srebf1 enhanced apoptosis and reduced fads2 expression in zebrafish exposed to intense light. These results suggest that the SREBF1-FADS1/2 axis may be activated in macular RPE-choroid as a protective response during early-stage AMD and could thus be a therapeutic target for early-stage AMD.

PMID: 28367511 [PubMed - in process]

Medication Risk Mitigation: Coordinating and Collaborating with Health Care Systems, Universities, and Researchers to Facilitate the Design and Execution of Practice-Based Research.

Clin Geriatr Med. 2017 May;33(2):257-281

Authors: Bain KT, Knowlton CH, Turgeon J

Abstract
The high prevalence of inappropriate polypharmacy in geriatric populations is unacceptable. Traditional medication risk mitigation (MRM) strategies have proven to be effective at improving polypharmacy, but these strategies have not consistently translated into positive health outcomes. Enhanced MRM strategies, such as using pharmacogenomics information, are needed, and these strategies need to be tested. A formidable challenge is successfully integrating pharmacogenomic information into clinical practice. As the medication experts on health care teams, pharmacists have a clear role to play in developing, integrating, and assessing enhanced MRM strategies to improve therapeutic outcomes for geriatric patients.

PMID: 28364995 [PubMed - in process]

Development and Validation of Liquid Chromatography/Tandem Mass Spectrometry Analysis for Therapeutic Drug Monitoring of Risperidone and 9-Hydroxyrisperidone in Pediatric Patients with Autism Spectrum Disorders.

J Clin Lab Anal. 2016 Nov;30(6):1236-1246

Authors: Vanwong N, Prommas S, Puangpetch A, Hongkaew Y, Nuntamool N, Nakorn CN, Ngamsamut N, Limsila P, Sukasem C

Abstract
BACKGROUND: Risperidone (RIS) is a widely used atypical antipsychotic drug. We developed and validated a sensitive and accurate LC-MS/MS method, which requires a small-volume of plasma and small-volume injection for measurement of RIS levels in ASD pediatric patients. We also investigated the relationship between RIS levels and RIS dosages, including prolactin levels.
METHOD: Blood samples were processed by protein precipitation extraction. Only 1 μl of sample was injected. Plasma samples were separated on a C18 column (4.6 cm × 50 mm; 1.8 μm particle size). Detection was by MS-MS with an analytical run time of 6 min.
RESULTS: The inter-day accuracy of RIS was 101.33-107.68% and 95.24-103.67% for 9-OH-RIS. The inter-day precision of RIS was ≤7.27% CV and ≤7.41% CV for 9-OH-RIS. The extraction recovery of RIS and 9-OH-RIS were 95.01 ± 7.31-112.62 ± 7.50% and 90.27 ± 11.15-114.00 ± 10.35%, respectively. This method was applied in the therapeutic drug monitoring of ASD pediatric patients. Higher RIS dosage has a tendency to produce higher RIS plasma levels. The high RIS plasma levels have a tendency to produce hyperprolactinemia.
CONCLUSION: The determination of RIS in individual patients might be clinically useful for monitoring and prediction of treatment response.

PMID: 27346210 [PubMed - indexed for MEDLINE]

Pseudomonas eradication and clinical effectivness of Ivacaftor in four Hispanic patients with S549N.

Pediatr Pulmonol. 2017 Apr 03;:

Authors: Strang A, Fischer AJ, Chidekel A

Abstract
Ivacaftor was approved for rarer class-III CFTR mutations including S549N in 2014. Since these mutations are uncommon, ongoing reports of patient experiences with Ivacaftor and these mutations are important. This case series describes the clinical effectiveness (including airway infection status, lung function, and growth) of Ivacaftor therapy in four pediatric Hispanic patients with S549N and F508del over 24 months. In these patients, Ivacaftor was highly efficacious with no further Pseudomonas-positive cultures despite prior chronic colonization in three patients as well as notable improvements in lung function and growth. The remarkable improvements in lung function and growth were similar to G551D patients with more striking changes in airway infection status. Pediatr Pulmonol. © 2016 Wiley Periodicals, Inc.

PMID: 28371569 [PubMed - as supplied by publisher]

Patient and Provider Perspectives on Communication About Body Image With Adolescents and Young Adults With Cystic Fibrosis.

J Pediatr Psychol. 2017 Mar 24;:

Authors: Helms SW, Christon LM, Dellon EP, Prinstein MJ

Abstract
Objective : This mixed-methods study examined perspectives of adolescents and young adults (AYAs) with cystic fibrosis (CF) and health care providers on body image communication. Interviews and questionnaires were completed by 20 AYAs and 28 providers. Although 85% of patients reported they had never had a body image conversation with a health care provider, 74% of providers reported discussing this topic with patients. Patients and providers described body image as an important issue, which should be discussed comfortably and supportively. However, patients often preferred to discuss body image as a distinct topic, separate from physical health, whereas providers preferred integrating body image conversations within weight- and health-based discussions.  Body image is an important topic for AYAs with CF that often goes unaddressed or addressed in ways that are less preferred by patients. Providers should reduce barriers to effective communication about this important topic, particularly through increased awareness of AYA preferences.

PMID: 28369522 [PubMed - as supplied by publisher]

Nonsense Suppression as an Approach to Treat Lysosomal Storage Diseases.

Diseases. 2016 Dec;4(4):

Authors: Keeling KM

Abstract
In-frame premature termination codons (PTCs) (also referred to as nonsense mutations) comprise ~10% of all disease-associated gene lesions. PTCs reduce gene expression in two ways. First, PTCs prematurely terminate translation of an mRNA, leading to the production of a truncated polypeptide that often lacks normal function and/or is unstable. Second, PTCs trigger degradation of an mRNA by activating nonsense-mediated mRNA decay (NMD), a cellular pathway that recognizes and degrades mRNAs containing a PTC. Thus, translation termination and NMD are putative therapeutic targets for the development of treatments for genetic diseases caused by PTCs. Over the past decade, significant progress has been made in the identification of compounds with the ability to suppress translation termination of PTCs (also referred to as readthrough). More recently, NMD inhibitors have also been explored as a way to enhance the efficiency of PTC suppression. Due to their relatively low threshold for correction, lysosomal storage diseases are a particularly relevant group of diseases to investigate the feasibility of nonsense suppression as a therapeutic approach. In this review, the current status of PTC suppression and NMD inhibition as potential treatments for lysosomal storage diseases will be discussed.

PMID: 28367323 [PubMed - in process]

Corrector VX-809 Promotes Interactions Between Cytoplasmic Loop One and the First Nucleotide-Binding Domain of CFTR.

Biochem Pharmacol. 2017 Mar 30;:

Authors: Loo TW, Clarke DM

Abstract
A large number of correctors have been identified that can partially repair defects in folding, stability and trafficking of CFTR processing mutants that cause cystic fibrosis (CF). The best corrector, VX-809 (Lumacaftor), has shown some promise when used in combination with a potentiator (Ivacaftor). Understanding the mechanism of VX-809 is essential for development of better correctors. Here, we tested our prediction that VX-809 repairs folding and processing defects of CFTR by promoting interactions between the first cytoplasmic loop (CL1) of transmembrane domain 1 (TMD1) and the first nucleotide-binding domain (NBD1). To investigate whether VX-809 promoted CL1/NBD1 interactions, we performed cysteine mutagenesis and disulfide cross-linking analysis of Cys-less TMD1 (residues 1-436) and ΔTMD1 (residues 437-1480; NBD1-R-TMD2-NBD2) truncation mutants. It was found that VX-809, but not bithiazole correctors, promoted maturation (exited endoplasmic reticulum for addition of complex carbohydrate in the Golgi) of the ΔTMD1 truncation mutant only when it was co-expressed in the presence of TMD1. Expression in the presence of VX-809 also promoted cross-linking between R170C (in CL1 of TMD1 protein) and L475C (in NBD1 of the ΔTMD1 truncation protein). Expression of the ΔTMD1 truncation mutant in the presence of TMD1 and VX-809 also increased the half-life of the mature protein in cells. The results suggest that the mechanism by which VX-809 promotes maturation and stability of CFTR is by promoting CL1/NBD1 interactions.

PMID: 28366727 [PubMed - as supplied by publisher]

Indications for lung resection surgery and lung transplant in South American children with cystic fibrosis.

Paediatr Respir Rev. 2017 Feb 16;:

Authors: Villac Adde F, Vidal Campos S, de Oliveira Braga Teixeira RH, Rodrigues JC

Abstract
The current available literature evaluating lung resection surgery and lung transplantation in children with cystic fibrosis (CF) was reviewed through a PubMed search and references from selected studies were additionally included. Pulmonary resections, i.e. lobectomy, segmentectomy, and pneumonectomy, are seldom performed in CF. The main indications, in patients with a forced expiratory volume in 1second (FEV1) that is greater than 30% predicted, are localized bronchiectasis/atelectasis, severe hemoptysis, and bronchopleural fistula refractory to medical management. The potential benefits are decreased symptoms and pulmonary exacerbations, and an improved quality of life. Pre and postoperative intensive care is mandatory for surgical candidates. The risk of death should be taken into account when the procedure is considered. Selection for lung transplantation (LTx) candidates in children with CF in South America follows the International Society for Heart and Lung Transplantation (ISHLT) criteria. When compared to adults with CF, a poorer survival rate after LTx in children with CF has been observed in the literature, as well as in our LTx center in Brazil, reasons for which are still unknown. The main complications after LTx in children are early and late acute rejection, and infections. LTx is a therapeutic option for eligible children with CF, fulfilling the lung transplant candidacy criteria, as post-transplant survival rates are increasingly improving due to better management of the transplanted patient.

PMID: 28366682 [PubMed - as supplied by publisher]

Telemedicine is the way forward for the management of Cystic Fibrosis- The case against.

Paediatr Respir Rev. 2017 Mar 14;:

Authors: Lenney W

Abstract
It is reasonable to suggest that Telemedicine could help in the management of chronic diseases by giving patients more flexibility to remain at home with opportunities to forward electronic data to healthcare professionals, reduce hospital emergency attendances and reduce overall costs. The reality, particularly in cystic fibrosis care, is this has not happened. There is concern that home-generated lung function data is of poor quality and virtually no studies show improved outcomes. The UK has a poor record in developing novel IT programmes and we need many more well designed clinical studies in Telemedicine before wading in with ill-conceived expensive plans just because the idea seems interesting.

PMID: 28366680 [PubMed - as supplied by publisher]

Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling.

Cell Stem Cell. 2017 Mar 22;:

Authors: McCauley KB, Hawkins F, Serra M, Thomas DC, Jacob A, Kotton DN

Abstract
Effective derivation of functional airway organoids from induced pluripotent stem cells (iPSCs) would provide valuable models of lung disease and facilitate precision therapies for airway disorders such as cystic fibrosis. However, limited understanding of human airway patterning has made this goal challenging. Here, we show that cyclical modulation of the canonical Wnt signaling pathway enables rapid directed differentiation of human iPSCs via an NKX2-1(+) progenitor intermediate into functional proximal airway organoids. We find that human NKX2-1(+) progenitors have high levels of Wnt activation but respond intrinsically to decreases in Wnt signaling by rapidly patterning into proximal airway lineages at the expense of distal fates. Using this directed approach, we were able to generate cystic fibrosis patient-specific iPSC-derived airway organoids with a defect in forskolin-induced swelling that is rescued by gene editing to correct the disease mutation. Our approach has many potential applications in modeling and drug screening for airway diseases.

PMID: 28366587 [PubMed - as supplied by publisher]

Current characteristics, challenges and coping strategies of young people with cystic fibrosis as they transition to adulthood.

Clin Med (Lond). 2017 Apr;17(2):121-125

Authors: Askew K, Bamford J, Hudson N, Moratelli J, Miller R, Anderson A, Doe S, Bourke SJ

Abstract
This study provides detailed data on the current characteristics, perceptions and outcomes of 45 young people with cystic fibrosis (CF) as they transition into adulthood. Although many had severe disease, they generally coped well, found attendance at a transition clinic helpful and welcomed the increased independence of an adult healthcare environment. Levels of psychological distress were low with only 15.6% having anxiety and 6.7% depression. The main psychological coping strategy used was optimistic acceptance. Overall, most remained stable after transfer but 33% had some decline in lung function and 9% in nutritional status, requiring intensification of treatment. They had high levels of satisfaction with their relationships and life situations and 76% were in employment or education. These results are encouraging and as life expectancy improves, young adults with CF are coping well with transition into adulthood.

PMID: 28365620 [PubMed - in process]

Cousins not twins: intra and inter-tumoral heterogeneity in syndromic neuroendocrine tumours.

J Pathol. 2017 Mar 31;:

Authors: Flynn A, Dwight T, Benn D, Deb S, Colebatch AJ, Fox S, Harris J, Duncan EL, Robinson B, Hogg A, Ellul J, To H, Duong C, Miller JA, Yates C, James P, Trainer A, Gill AJ, Clifton-Bligh R, Hicks RJ, Tothill RW

Abstract
Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common co-operative changes required for tumorigenesis, while controlling for the genetic background of the individual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET and MAX. Using whole exome sequencing and high-density SNP arrays, we analyzed two to four primary tumours from each patient. We also applied multi-regional sampling, to assess intra-tumoral heterogeneity and clonal evolution, in two cases involving phaeochromocytoma/paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary phaeochromocytoma/paraganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour.

PMID: 28369925 [PubMed - as supplied by publisher]

Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.

Clin Genet. 2017 Mar 30;:

Authors: Khan AO, Budde BS, Nürnberg P, Kawalia A, Lenzner S, Bolz HJ

Abstract
To uncover the genotype underlying early-onset cone-rod dystrophy and central nummular macular atrophic lesion in two siblings from an endogamous Arab family, we performed targeted next-generation sequencing (NGS) of 44 retinal dystrophy genes, whole-exome sequencing (WES) and genome-wide linkage analysis. Targeted NGS and WES in the index patient highlighted two homozygous variants, a CCDC66 frameshift deletion and a novel missense NMNAT1 variant, c.500G>A (p.Asn167Ser). Linkage and segregation analysis excluded the CCDC66 variant and confirmed the NMNAT1 mutation. Biallelic NMNAT1 mutations cause Leber congenital amaurosis with a central nummular macular atrophic lesion (LCA9). The NMNAT1 mutation reported here underlied cone-rod dystrophy rather than LCA but the fundus lesion was compatible with that of LCA9 patients, highlighting that such a fundus appearance should raise suspicion for biallelic mutations in NMNAT1 when in the context of any retinal dystrophy. Although Ccdc66 mutations have been proposed to cause retinal disease in dogs, our results and public databases challenge CCDC66 as a candidate gene for human retinal dystrophy.

PMID: 28369829 [PubMed - as supplied by publisher]