Interpretation Of Molecular Data Research Articles

A curated gene and biological system annotation of adverse outcome pathways related to human health

Adverse outcome pathways (AOPs) are emerging as a central framework in modern toxicology and other fields in biomedicine. They serve as an extension of pathway-based concepts by depicting biological mechanisms as causally linked sequences of key events (KEs) from a molecular initiating event (MIE) to an adverse outcome. AOPs guide the use and development of new approach methodologies (NAMs) aimed at reducing animal experimentation. While AOPs model the systemic mechanisms at various levels of biological organisation, toxicogenomics provides the means to study the molecular mechanisms of chemical exposures. Systematic integration of these two concepts would improve the application of AOP-based knowledge while also supporting the interpretation of complex omics data. Hence, we established this link through rigorous curation of molecular annotations for the KEs of human relevant AOPs. We further expanded and consolidated the annotations of the biological context of KEs. These curated annotations pave the way to embed AOPs in molecular data interpretation, facilitating the emergence of new knowledge in biomedicine.

INNV-08. LOW AND INTERMEDIATE GRADE GLIOMA UMBRELLA STUDY OF MOLECULAR GUIDED THERAPIES (LUMOS) STUDY

Abstract BACKGROUND Grade 2 and 3 (G2/3) gliomas are the second largest group of brain tumors in adults. Although the prognosis for G2/3 gliomas at the time of relapse mirror those of glioblastoma, there are few trials in this space. METHODS LUMOS was a national multi-center pilot study for patients with relapsed G2/3 gliomas designed to match contemporaneous tissue obtained at the time of disease progression with subsequent targeted therapies. The objective was to establish the feasibility of a precision oncology, umbrella approach to obtain and type tissue within a useful timeframe. As a key feature of LUMOS, a multidisciplinary Molecular Tumor Advisory Panel (MTAP) with subspecialty neuro-oncology expertise was formed to interpret the complex genomic information and provide a simplified recommendation to the treating physician. RESULTS Ten patients (median age 42: range 32-62; four G2 astrocytoma, one G3 astrocytoma, three G2 oligoendroglioma, one G3 oligodendroglioma, one mixed tumor) were enrolled in the study. Eight patients had biopsies within 6 months of study entry whilst two underwent a biopsy during the study. All patients had potentially targetable alterations (10 IDH, 3 FGFR, 2 PIK3K, CCND3, NRAS, CDK4, PRPRZ1-MET fusion and MET amplification). Matched therapies were delivered for two patients via compassionate access outside the study. The median turnaround time (TAT) of MTAP reports was 6.2 weeks (range 4.2-9.7 weeks) but 4.6 weeks when lag time for shipping was removed. CONCLUSION LUMOS confirmed that this design was feasible with good turnaround times. The MTAP facilitated education and support for treating physicians. Thes findings support moving to a larger study using contemporaneous and longitudinal tissue samples matched with targeted therapies as part of a comprehensive umbrella study design. Delivery and interpretation of molecular data is a challenge shared across oncology which may be mitigated with a neuro-oncology specific molecular tumor board.

The Pan African Vivax and Ovale Network (PAVON): Refocusing on Plasmodium vivax, ovale and asymptomatic malaria in sub-Saharan Africa.

The recent World Malaria report shows that progress in malaria elimination has stalled. Current data acquisition by NMCPs depend on passive case detection and clinical reports focused mainly on Plasmodium falciparum (Pf). In recent times, several countries in sub-Saharan Africa have reported cases of Plasmodium vivax (Pv) with a considerable number being Duffy negative. The burden of Pv and Plasmodium ovale (Po) appear to be more than acknowledged. Similarly, the contribution of asymptomatic malaria in transmission is hardly considered by NMCPs in Africa. Inclusion of these as targets in malaria elimination agenda is necessary to achieve elimination goal, as these harbor hypnozoites. The Pan African Vivax and Ovale Network (PAVON) is a new consortium of African Scientists working in Africa on the transmission profile of Pv and Po. The group collaborates with African NMCPs to train in Plasmodium molecular diagnostics, microscopy, and interpretation of molecular data from active surveys to translate into policy. Details of the mission, rational and modus operandi of the group are outlined.

Comparison of the clinical interpretation of high-dimensional molecular data by two molecular tumor boards.

3564 Background: The clinical interpretation of molecular data is a bottleneck of precision oncology. High-dimensional molecular data, such as RNA sequencing (RNA-seq) and whole-exome sequencing (WES), will likely increase the complexity of clinical interpretation. We compared the recommendations by two molecular tumor boards (MTBs) that independently interpreted the same high-dimensional molecular profiles. Methods: Patients with advanced solid tumors, no available standard therapy, an ECOG performance status of 0-1, and available fresh-frozen tissue underwent WES of tumor tissue and normal blood as well as RNA-seq of tumor tissue within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program of the German Cancer Consortium (DKTK). Data from 46 patients (WES and RNA-seq, n = 41; WES alone, n = 5) were independently discussed by two MTBs. Treatment recommendations were compared with regard to levels of evidence, therapeutic baskets, and types of biomarkers. Results: A total of 51,610 aberrations (median, 393 per patient) were considered for clinical interpretation (34,314 mutations/single-nucleotide variants, 7,115 mRNA expression changes, 6,144 DNA copy number variations, 4,037 gene fusions). 110 and 132 treatment options were identified by the two MTBs, respectively, with an overall agreement rate of 44.1%. The highest agreement rates were identified for treatment options based on clinical levels of evidence (Level 1, 60%; Level 2, 49.6%) and for poly(ADP-ribose)-polymerase inhibition (57.1%). The lowest agreement rates were identified when MTBs opted for traditional chemotherapy (0%), combination therapies (6.9%), therapies based on preclinical levels of evidence (Level 3, 35.9%; Level 4, 32%), and MAPK inhibition (35%). Similar agreement rates, ranging from 39% (gene fusions) to 54% (loss of heterozygosity), were observed for different types of biomarkers. Conclusions: Reproducible, evidence-based annotation of high-dimensional molecular data is feasible. Our experience provides a basis for ongoing harmonization and standardization efforts within the MTBs of the DKTK.

Case report: multiple UGT1A1 gene variants in a patient with Crigler-Najjar syndrome

BackgroundInherited unconjugated hyperbilirubinemia is caused by variants in the gene UGT1A1 leading to Gilbert’s syndrome and Crigler-Najjar syndrome types I and II. These syndromes are differentiated on the basis of UGT1A1 residual enzymatic activity and its affected bilirubin levels and responsiveness to phenobarbital treatment.Case presentationIn this report, we present a boy with Crigler-Najjar syndrome type II with high unconjugated bilirubin levels that decreased after phenobarbital treatment but increased in adolescence. Four different UGT1A1 gene variants have been identified for this patient, of which one is novel (g.11895_11898del) most likely confirming diagnose molecularly.ConclusionsThe presented case highlights the challenges encountered with the interpretation of molecular data upon identification of multiple variants in one gene that are causing different degree reducing effect on enzyme activity leading to several clinical conditions.

MARKER-ASSISTED REDUCTION OF REDUNDANCY IN GERMPLASM COLLECTIONS: GENETIC AND ECONOMIC ASPECTS

ISHS XXVI International Horticultural Congress: Plant Genetic Resources, The Fabric of Horticultures Future MARKER-ASSISTED REDUCTION OF REDUNDANCY IN GERMPLASM COLLECTIONS: GENETIC AND ECONOMIC ASPECTS

Further support for a Palaearctic origin of Leishmania.

The fossil record and systematics of murid rodents, reservoirs of zoonotic cutaneous leishmaniasis in the Palaearctic, Oriental, African, Nearctic and Neotropical, strongly support a Palaearctic origin of Leishmania. The fossil record and systematics of phlebotomine sand flies reinforce this idea. Interpretations of molecular data that place the origin of Leishmania in the Neotropical are inconsistent with the natural histories of reservoirs and vectors. The evolutionary pattern of New World rats (Sigmodontinae) indicates that they may be the most important reservoirs of zoonotic cutaneous leishmaniasis throughout their range.

Chapter 9 Electron Microscopic Imaging of Chromatin with Nucleosome Resolution

Nuclear DNA in eukaryotes has a nucleosomal organization. Specific assemblies of nucleosomes and nonhistone nuclear proteins play important roles in local transcriptional regulation and in large-scale regulatory events, such as silencing and heterochromatization. The three-dimensional conformation and spatial arrangement of these assemblies plays a crucial functional role, and a complete understanding of nuclear processes must include architectural and compositional aspects. Imaging methods provide reliable information at a level of resolution sufficient to complement and assist in the interpretation of molecular data. There are two principal modes of studying chromatin with conventional transmission electron microscopy, each having advantages and disadvantages. For both, it is important to recognize the various levels of uncertainty that accompany each preparative step and to take this into account in interpreting the final images. In situ studies employ sections of cells or nuclei that are subjected to chemical fixation or cryoimmobilization. These methods preserve intranuclear location and relationships among large-scale nuclear structures.

Marker‐assisted selection in cattle

Abstract Direct observation of genetic differences using molecular techniques has prompted investigation into the nature and amount of genetic variation in cattle. Utilization of molecular data will include parentage analysis, individual identification, sexing of embryos and clones and detection of genetic defects. Opportunities to utilize molecular data as markers for useful quantitative traits, especially genetic potential for performance, are being investigated. At present, many important questions about potential costs and benefits of implementation of these strategies remain unanswered. Interdisciplinary teams of scientists are needed to research these questions and significant educational efforts should be made to train students and industry personnel in appropriate use and interpretation of molecular data.

Molecular phylogeny

The avalanche of molecular sequence data from a wide variety of organisms and genes makes the construction and testing of evolutionary trees a widespread and demanding activity. We present the most recent advances in the interpretation of molecular data, as well as recent phylogenetic results affecting both molecular evolutionary biology and other areas of biological research.