OncoGEMINI: software for investigating tumor variants from multiple biopsies with integrated cancer annotations

Abstract Background DNA sequencing has unveiled extensive tumor heterogeneity in several different cancer types, with many exhibiting diverse subclonal populations. Identifying and tracing mutations throughout the expansion and progression of a tumor represents a significant challenge. Furthermore, prioritizing the subset of such mutations most likely to contribute to tumor evolution or that could serve as potential therapeutic targets represents an ongoing problem. Results Here, we describe OncoGEMINI, a new tool designed for exploring the complex patterns and trajectory of somatic and inherited variation observed in heterogeneous tumors biopsied over the course of treatment. This is accomplished by creating a searchable database of variants that includes tumor sampling time points and allows for filtering methods that reflect specific changes in variant allele frequencies over time. Additionally, by incorporating existing annotations and resources that facilitate the interpretation of cancer mutations (e.g., CIViC, DGIdb), OncoGEMINI enables rapid searches for, and potential identification of, mutations that may be driving subclonal evolution. Conclusions By combining relevant genomic annotations alongside specific filtering tools, OncoGEMINI provides powerful and customizable approaches that enable the quick identification of individual tumor variants that meet specified criteria. It can be applied to a wide range of tumor-derived sequence data, but is especially designed for studies with multiple samples, including longitudinal datasets. It is available under an MIT license at github.com/fakedrtom/oncogemini.

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OncoGEMINI: Software for Investigating Tumor Variants From Multiple Biopsies With Integrated Cancer Annotations

10.1101/2020.03.10.979591 ◽

2020 ◽

Cited By ~ 2

Author(s):

Thomas J. Nicholas ◽

Michael J. Cormier ◽

Xiaomeng Huang ◽

Yi Qiao ◽

Gabor T. Marth ◽

...

Keyword(s):

Dna Sequencing ◽

Tumor Heterogeneity ◽

Tumor Evolution ◽

Searchable Database ◽

Significant Challenge ◽

Multiple Biopsies ◽

Cancer Mutations ◽

Cancer Types ◽

Tumor Sampling ◽

Over Time

AbstractDNA sequencing has unveiled extensive tumor heterogeneity in several different cancer types, with many exhibiting diverse subclonal populations. Identifying and tracing mutations throughout the expansion and progression of a tumor represents a significant challenge. Furthermore, prioritizing the subset of such mutations most likely to contribute to tumor evolution or that could serve as potential therapeutic targets represents an ongoing problem. Here we describe OncoGEMINI, a new tool designed for exploring the complex patterns and trajectory of somatic and inherited variation observed in heterogeneous tumors biopsied over the course of treatment. This is accomplished by creating a searchable database of variants that includes tumor sampling timepoints and allows for filtering methods that reflect specific changes in variant allele frequencies over time. Additionally, by incorporating existing annotations and resources that facilitate the interpretation of cancer mutations (e.g., CIViC, DGIdb), OncoGEMINI enables rapid searches for, and potential identification of, mutations that may be driving subclonal evolution.

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Proteomic and Genomic Signatures of Repeat-instability in Cancer and Adjacent Normal Tissues

10.1101/491423 ◽

2018 ◽

Author(s):

Erez Persi ◽

Davide Prandi ◽

Yuri I. Wolf ◽

Yair Pozniak ◽

Christopher Barbieri ◽

...

Keyword(s):

Cancer Progression ◽

Sequence Data ◽

Repetitive Sequences ◽

Tumor Evolution ◽

Repeat Instability ◽

Primary Tumors ◽

Normal Tissues ◽

Genomic Signatures ◽

Repeat Content ◽

Wide Range

SummaryRepetitive sequences are hotspots of evolution at multiple levels. However, due to technical difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content of proteomes and genomes, directly from proteomic and genomic raw sequence data, and applied it to analyze a wide range of tumors and normal tissues. We identify high similarity between the repeat-instability in tumors and their patient-matched normal tissues, but also tumor-specific signatures, both in protein expression and in the genome, that strongly correlate with cancer progression and robustly predict the tumorigenic state. In a patient, the hierarchy of genomic repeat instability signatures accurately reconstructs tumor evolution, with primary tumors differentiated from metastases. We find an inverse relationship between repeat-instability and point mutation load, within and across patients, and independently of other somatic aberrations. Thus, repeat-instability is a distinct, transient and compensatory adaptive mechanism in tumor evolution.

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mtDNAcombine: tools to combine sequences from multiple studies

BMC Bioinformatics ◽

10.1186/s12859-021-04048-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Eleanor F. Miller ◽

Andrea Manica

Keyword(s):

Sequence Data ◽

Data Extraction ◽

Bayesian Skyline Plot ◽

Model Organisms ◽

Data Sets ◽

Data Handling ◽

Online Database ◽

Genetic Studies ◽

Wide Range ◽

Existing Data

Abstract Background Today an unprecedented amount of genetic sequence data is stored in publicly available repositories. For decades now, mitochondrial DNA (mtDNA) has been the workhorse of genetic studies, and as a result, there is a large volume of mtDNA data available in these repositories for a wide range of species. Indeed, whilst whole genome sequencing is an exciting prospect for the future, for most non-model organisms’ classical markers such as mtDNA remain widely used. By compiling existing data from multiple original studies, it is possible to build powerful new datasets capable of exploring many questions in ecology, evolution and conservation biology. One key question that these data can help inform is what happened in a species’ demographic past. However, compiling data in this manner is not trivial, there are many complexities associated with data extraction, data quality and data handling. Results Here we present the mtDNAcombine package, a collection of tools developed to manage some of the major decisions associated with handling multi-study sequence data with a particular focus on preparing sequence data for Bayesian skyline plot demographic reconstructions. Conclusions There is now more genetic information available than ever before and large meta-data sets offer great opportunities to explore new and exciting avenues of research. However, compiling multi-study datasets still remains a technically challenging prospect. The mtDNAcombine package provides a pipeline to streamline the process of downloading, curating, and analysing sequence data, guiding the process of compiling data sets from the online database GenBank.

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Emerging Molecular Receptors for the Specific-Target Delivery of Ruthenium and Gold Complexes into Cancer Cells

Molecules ◽

10.3390/molecules26113153 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3153

Author(s):

João Franco Machado ◽

João D. G. Correia ◽

Tânia S. Morais

Keyword(s):

Progesterone Receptors ◽

Biological Evaluation ◽

Cell Organelles ◽

Gold Complexes ◽

Main Research ◽

Wide Range ◽

Cancer Types ◽

Organometallic Molecules ◽

G Protein Coupled

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.

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Genome diversity in Ukraine

GigaScience ◽

10.1093/gigascience/giaa159 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Taras K Oleksyk ◽

Walter W Wolfsberger ◽

Alexandra M Weber ◽

Khrystyna Shchubelka ◽

Olga T Oleksyk ◽

...

Keyword(s):

Sequence Data ◽

Copy Number Variations ◽

Genomic Variation ◽

High Coverage ◽

Genome Data ◽

New Information ◽

Genome Wide ◽

Public Data ◽

Genome Wide Data ◽

Multiple Samples

Abstract Background The main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. Results The genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population. Conclusions Our results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.

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Sequence data from isolated lichen-associated melanized fungi enhance delimitation of two new lineages within Chaetothyriomycetidae

Mycological Progress ◽

10.1007/s11557-021-01706-8 ◽

2021 ◽

Vol 20 (7) ◽

pp. 911-927

Author(s):

Lucia Muggia ◽

Yu Quan ◽

Cécile Gueidan ◽

Abdullah M. S. Al-Hatmi ◽

Martin Grube ◽

...

Keyword(s):

Sequence Data ◽

Single Species ◽

Sister Group ◽

Asexual Propagation ◽

Dna Sequence Data ◽

Wide Range ◽

The Family ◽

Rock Inhabiting Fungi ◽

Stable Habitat

AbstractLichen thalli provide a long-lived and stable habitat for colonization by a wide range of microorganisms. Increased interest in these lichen-associated microbial communities has revealed an impressive diversity of fungi, including several novel lineages which still await formal taxonomic recognition. Among these, members of the Eurotiomycetes and Dothideomycetes usually occur asymptomatically in the lichen thalli, even if they share ancestry with fungi that may be parasitic on their host. Mycelia of the isolates are characterized by melanized cell walls and the fungi display exclusively asexual propagation. Their taxonomic placement requires, therefore, the use of DNA sequence data. Here, we consider recently published sequence data from lichen-associated fungi and characterize and formally describe two new, individually monophyletic lineages at family, genus, and species levels. The Pleostigmataceae fam. nov. and Melanina gen. nov. both comprise rock-inhabiting fungi that associate with epilithic, crust-forming lichens in subalpine habitats. The phylogenetic placement and the monophyly of Pleostigmataceae lack statistical support, but the family was resolved as sister to the order Verrucariales. This family comprises the species Pleostigma alpinum sp. nov., P. frigidum sp. nov., P. jungermannicola, and P. lichenophilum sp. nov. The placement of the genus Melanina is supported as a lineage within the Chaetothyriales. To date, this genus comprises the single species M. gunde-cimermaniae sp. nov. and forms a sister group to a large lineage including Herpotrichiellaceae, Chaetothyriaceae, Cyphellophoraceae, and Trichomeriaceae. The new phylogenetic analysis of the subclass Chaetothyiomycetidae provides new insight into genus and family level delimitation and classification of this ecologically diverse group of fungi.

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Congenital adrenal hyperplasia: molecular mechanisms resulting in 21-hydroxylase deficiency

Acta Endocrinologica ◽

10.1530/acta.0.112s315 ◽

1986 ◽

Vol 113 (4_Suppl) ◽

pp. S315-S320 ◽

Cited By ~ 7

Author(s):

Patricia A. Donohoue ◽

Cornelis Van Dop ◽

Nicholas Jospe ◽

Claude J. Migeon

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Molecular Mechanisms ◽

Sequence Data ◽

Phenotypic Expression ◽

Restriction Pattern ◽

Class Iii ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Wide Range ◽

21 Hydroxylase Deficiency

Abstract 21-Hydroxylase deficiency resulting in congenital adrenal hyperplasia (CAH) is a HLA-linked autosomal recessive disorder that has a wide range of phenotypic expression. Two homologous 21-hydroxylase genes (21-OHA and 21-OHB) occur within the Class III region of the major histocompatibility complex, but only one (21-OHB) appears to function in adrenal steroidogenesis. Our restriction maps, and initial sequence data from White et al. (Pediatr Res 20:274A (1986)) for the two human 21-OH genes reveal a high degree of homology between these genes and a reading frame shift mutation in the 21-OHA gene respectively. Among fourteen control subjects, the intragenic restriction patterns of the 21-OHA and 21-OHB genes are invariant. The few restriction fragment length polymorphisms (RFLPs) found in some controls result from polymorphic restriction sites outside the 21-OH genes. In patients with CAH, several different mechanisms for mutation of the 21-OHB gene have been described: 1) deletion of the unique sequences of the 21-OHB gene, 2) conversion of the unique sequences of the 21-OHB gene to those of 21-OHA, and 3) mutations of 21-OHB which do not result in a detectable alteration of restriction pattern (e.g., point mutations). Duplication of the 21-OHA gene has been found in some patients with attenuated CAH; however, the significance of this finding remains unclear.

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A50 Whole-genome sequencing of African swine fever isolates from Sardinia

Virus Evolution ◽

10.1093/ve/vez002.049 ◽

2019 ◽

Vol 5 (Supplement_1) ◽

Author(s):

C Torresi ◽

F Granberg ◽

L Bertolotti ◽

A Oggiano ◽

B Colitti ◽

...

Keyword(s):

Amino Acid ◽

Sequence Data ◽

Temporal Distribution ◽

African Swine Fever ◽

Amino Acid Identity ◽

Genotype I ◽

Acid Identity ◽

Wide Range ◽

Intergenic Sequences ◽

Genes Encoding

Abstract In order to assess the molecular epidemiology of African swine fever (ASF) in Sardinia, we analyzed a wide range of isolates from wild and domestic pigs over a 31-year period (1978–2009) by genotyping sequence data from the genes encoding the p54 and the p72 proteins and the CVR. On this basis, the analysis of the B602L gene revealed a minor difference, placing the Sardinian isolates into two clusters according to their temporal distribution. As an extension of this study, in order to achieve a higher level of discrimination, three further variable genome regions, namely p30, CD2v, and I73R/I329L, of a large number of isolates collected from outbreaks in the years 2002–14 have been investigated. Sequence analysis of the CD2v region revealed a temporal subdivision of the viruses into two subgroups. These data, together with those from the B602L gene analysis, demonstrated that the viruses circulating in Sardinia belong to p72/genotype I, but since 1990 have undergone minor genetic variations in respect to its ancestor, thus making it impossible to trace isolates, enabling a more accurate assessment of the origin of outbreaks, and extending knowledge of virus evolution. To solve this problem, we have sequenced and annotated the complete genome of nine ASF isolates collected in Sardinia between 1978 and 2012. This was achieved using sequence data determined by next-generation sequencing. The results showed a very high identity with range of nucleotide similarity among isolates of 99.5 per cent to 99.9 per cent. The ASF virus (ASFV) genomes were composed of terminal inverted repeats and conserved and non-conserved ORFs. Among the conserved ORFs, B385R, H339R, and O61R-p12 showed 100 per cent amino acid identity. The same was true for the hypervariable ORFs, with regard to X69R, DP96R, DP60R, EP153R, B407L, I10L, and L60L genes. The EP402R and B602L genes showed, as expected, an amino acid identity range of 98.5 per cent to 100 per cent and 91 per cent to 100 per cent, respectively. In addition, all of the isolates displayed variable intergenic sequences. As a whole, the results from our studies confirmed a remarkable genetic stability of the ASFV/p72 genotype I viruses circulating in Sardinia.

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Psychosocial status of Hungarian cancer patients. A descriptive study

Orvosi Hetilap ◽

10.1556/oh.2014.29849 ◽

2014 ◽

Vol 155 (26) ◽

pp. 1024-1032

Author(s):

Magda Rohánszky ◽

Rózsa Katonai ◽

Barna Konkolÿ Thege

Keyword(s):

Cancer Patients ◽

Social Life ◽

Normal Population ◽

Group Method ◽

Psychosocial Status ◽

Wide Range ◽

Psychosocial Difficulties ◽

Cancer Types ◽

Population Standards ◽

After Cancer

Introduction: Psychosocial status of cancer patients is still understudied in Hungary. Aim: The aim of the authors was to obtain current information on the mental and social status of this patient group. Method: Altogether, 1070 cancer patients with a wide range of cancer types were included in the study (30.0% male; age: 55.9±11.0 years). Results: A large part of the patients had serious financial difficulties and 41.3% of them were struggling with at least one more comorbid chronic disease. Further, 52.2% of the patients reported at least moderate anxiety or depression, while the occurrence of suicidal thoughts was almost three times higher among them than in the Hungarian normal population (13.0% vs. 4.6%). Level of perceived social support was also lower than the population standards and 61.6% of the patients reported willingness to benefit from professional psychological support. Quality of social life of the patients deteriorated with time after cancer diagnosis. A positive phenomenon, however, was that the primary coping style reported was active problem solving. Conclusions: The authors conclude that it is necessary to screen cancer patients for psychosocial difficulties and to establish conditions for their adequate mental and social care in Hungary. Orv. Hetil., 2014, 155(26), 1024–1032.

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Criticality in tumor evolution and clinical outcome

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1807256115 ◽

2018 ◽

Vol 115 (47) ◽

pp. E11101-E11110 ◽

Cited By ~ 11

Author(s):

Erez Persi ◽

Yuri I. Wolf ◽

Mark D. M. Leiserson ◽

Eugene V. Koonin ◽

Eytan Ruppin

Keyword(s):

Clinical Outcome ◽

Cancer Biology ◽

Patient Survival ◽

Fitness Landscape ◽

Purifying Selection ◽

Nonlinear Effects ◽

Tumor Evolution ◽

Evolutionary Trajectories ◽

Cancer Types ◽

Selection Phase

How mutation and selection determine the fitness landscape of tumors and hence clinical outcome is an open fundamental question in cancer biology, crucial for the assessment of therapeutic strategies and resistance to treatment. Here we explore the mutation-selection phase diagram of 6,721 tumors representing 23 cancer types by quantifying the overall somatic point mutation load (ML) and selection (dN/dS) in the entire proteome of each tumor. We show that ML strongly correlates with patient survival, revealing two opposing regimes around a critical point. In low-ML cancers, a high number of mutations indicates poor prognosis, whereas high-ML cancers show the opposite trend, presumably due to mutational meltdown. Although the majority of cancers evolve near neutrality, deviations are observed at extreme MLs. Melanoma, with the highest ML, evolves under purifying selection, whereas in low-ML cancers, signatures of positive selection are observed, demonstrating how selection affects tumor fitness. Moreover, different cancers occupy specific positions on the ML–dN/dS plane, revealing a diversity of evolutionary trajectories. These results support and expand the theory of tumor evolution and its nonlinear effects on survival.

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