ORCID Profile
0000-0002-4840-1095
Current Organisations
Universidad de Las Palmas de Gran Canaria
,
Australian BioCommons
,
University of Melbourne
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Publisher: Springer New York
Date: 10-12-2017
DOI: 10.1007/978-1-4939-7514-3_5
Abstract: Hi-Plex is a suite of methods to enable simple, accurate, and cost-effective highly multiplex PCR-based targeted sequencing (Nguyen-Dumont et al., Biotechniques 58:33-36, 2015). At its core is the principle of using gene-specific primers (GSPs) to "seed" (or target) the reaction and universal primers to "drive" the majority of the reaction. In this manner, effects on lification efficiencies across the target licons can, to a large extent, be restricted to early seeding cycles. Product sizes are defined within a relatively narrow range to enable high-specificity size selection, replication uniformity across target sites (including in the context of fragmented input DNA such as that derived from fixed tumor specimens (Nguyen-Dumont et al., Biotechniques 55:69-74, 2013 Nguyen-Dumont et al., Anal Biochem 470:48-51, 2015), and application of high-specificity genetic variant calling algorithms (Pope et al., Source Code Biol Med 9:3, 2014 Park et al., BMC Bioinformatics 17:165, 2016). Hi-Plex offers a streamlined workflow that is suitable for testing large numbers of specimens without the need for automation.
Publisher: Springer Science and Business Media LLC
Date: 19-10-2017
Publisher: Springer Berlin Heidelberg
Date: 2005
DOI: 10.1007/11546382_7
Publisher: Oxford University Press (OUP)
Date: 09-2019
DOI: 10.1093/GIGASCIENCE/GIZ109
Abstract: Bioinformatics software tools are often created ad hoc, frequently by people without extensive training in software development. In particular, for beginners, the barrier to entry in bioinformatics software development is high, especially if they want to adopt good programming practices. Even experienced developers do not always follow best practices. This results in the proliferation of poorer-quality bioinformatics software, leading to limited scalability and inefficient use of resources lack of reproducibility, usability, adaptability, and interoperability and erroneous or inaccurate results. We have developed Bionitio, a tool that automates the process of starting new bioinformatics software projects following recommended best practices. With a single command, the user can create a new well-structured project in 1 of 12 programming languages. The resulting software is functional, carrying out a prototypical bioinformatics task, and thus serves as both a working ex le and a template for building new tools. Key features include command-line argument parsing, error handling, progress logging, defined exit status values, a test suite, a version number, standardized building and packaging, user documentation, code documentation, a standard open source software license, software revision control, and containerization. Bionitio serves as a learning aid for beginner-to-intermediate bioinformatics programmers and provides an excellent starting point for new projects. This helps developers adopt good programming practices from the beginning of a project and encourages high-quality tools to be developed more rapidly. This also benefits users because tools are more easily installed and consistent in their usage. Bionitio is released as open source software under the MIT License and is available at ionitio-team/bionitio.
Publisher: figshare
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 08-02-2018
Publisher: Oxford University Press (OUP)
Date: 09-2022
Abstract: Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA variants. Ultimately, the goal of many of these studies is to associate genetic variants to phenotypes or fitness. We introduce VIVID, an interactive, user-friendly web application that integrates a wide range of approaches for encoding genotypic to phenotypic information in any organism or disease, from an in idual or population, in three-dimensional (3D) space. It allows mutation mapping and annotation, calculation of interactions and conservation scores, prediction of harmful effects, analysis of ersity and selection, and 3D visualization of genotypic information encoded in Variant Call Format on AlphaFold2 protein models. VIVID enables the rapid assessment of genes of interest in the study of adaptive evolution and the genetic load, and it helps prioritizing targets for experimental validation. We demonstrate the utility of VIVID by exploring the evolutionary genetics of the parasitic protist Plasmodium falciparum, revealing geographic variation in the signature of balancing selection in potential targets of functional antibodies.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2017
DOI: 10.1007/S10689-016-9961-X
Abstract: An apparently balanced t(2 )(q37.3 q13.2) translocation that appears to segregate with renal cell carcinoma (RCC) has indicated potential areas to search for the elusive genetic basis of clear cell RCC. We applied Hi-Plex targeted sequencing to analyse germline DNA from 479 in iduals affected with clear cell RCC for this breakpoint translocation and genetic variants in neighbouring genes on chromosome 2, ACKR3 and COPS8. While only synonymous variants were found in COPS8, one of the missense variants in ACKR3:c.892C>T, observed in 4/479 in iduals screened (0.8%), was predicted likely to damage ACKR3 function. Identification of causal genes for RCC has potential clinical utility, where risk assessment and risk management can offer better outcomes, with surveillance for at-risk relatives and nephron sparing surgery through earlier intervention.
Publisher: Public Library of Science (PLoS)
Date: 14-09-2022
DOI: 10.1371/JOURNAL.PONE.0273783
Abstract: The question of whether it is appropriate to attribute authorship to deceased in iduals of original studies in the biomedical literature is contentious. Authorship guidelines utilized by journals do not provide a clear consensus framework that is binding on those in the field. To guide and inform the implementation of authorship frameworks it would be useful to understand the extent of the practice in the scientific literature, but studies that have systematically quantified the prevalence of this phenomenon in the biomedical literature have not been performed to date. To address this issue, we quantified the prevalence of publications by deceased authors in the biomedical literature from the period 1990–2020. We screened 2,601,457 peer-reviewed papers from the full text Europe PubMed Central database. We applied natural language processing, stringent filtering and manual curation to identify a final set of 1,439 deceased authors. We then determined these authors published a total of 38,907 papers over their careers with 5,477 published after death. The number of deceased publications has been growing rapidly, a 146-fold increase since the year 2000. This rate of increase was still significant when accounting for the growing total number of publications and pool of authors. We found that more than 50% of deceased author papers were first submitted after the death of the author and that over 60% of these papers failed to acknowledge the deceased authors status. Most deceased authors published less than 10 papers after death but a small pool of 30 authors published significantly more. A pool of 266 authors published more than 90% of their total publications after death. Our analysis indicates that the attribution of deceased authorship in the literature is not an occasional occurrence but a burgeoning trend. A consensus framework to address authorship by deceased scientists is warranted.
Publisher: Cold Spring Harbor Laboratory
Date: 03-2023
DOI: 10.1101/2023.02.27.23285541
Abstract: Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n=135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n=137 80xCRCs, 33xECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
Publisher: Zenodo
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2020
DOI: 10.1101/2020.07.08.194480
Abstract: Homoplasic single nucleotide polymorphisms (SNPs) are considered important signatures of strong (positive) selective pressure, and hence of adaptive evolution for clinically relevant traits such as antibiotic resistance and virulence. Here we present a new tool, SNPPar, for efficient detection and analysis of homoplasic SNPs from large WGS datasets ( ,000 isolates and/or ,000 SNPs). SNPPar takes as input a SNP alignment, tree and annotated reference genome, and uses a combination of simple monophyly tests and ancestral state reconstruction (ASR, via TreeTime) to assign mutation events to branches and identify homoplasies. Mutations are annotated at the level of codon and gene, to facilitate analysis of convergent evolution. Testing on simulated data (120 Mycobacterium tuberculosis alignments representing local and global s les) showed SNPPar can detect homoplasic SNPs with very high sensitivity (zero false-positives in all tests) and high specificity (zero false-negatives in 89% of tests). SNPPar analysis of three empirically s led datasets ( E. anophelis, B. dolosa and M. tuberculosis ) produced results that were in concordance with previous studies, in terms of both in idual homoplasies and evidence of convergence at the codon and gene levels. SNPPar analysis of a simulated alignment of ∼64,000 genome-wide SNPs from 2000 M. tuberculosis genomes took ∼23 minutes and ∼2.6 GB of RAM to generate complete annotated results on a laptop. This analysis required ASR be conducted for only 1.25% of SNPs, and the ASR step took ∼23 seconds and 0.4 GB RAM. SNPPar automates the detection and annotation of homoplasic SNPs efficiently and accurately from large SNP alignments. As demonstrated by the ex les included here, this information can be readily used to explore the role of homoplasy in parallel and/or convergent evolution at the level of nucleotide, codon and/or gene. DNA sequences of bacterial pathogens are mutating all the time most changes are deleterious or neutral, but sometimes a mutation leads to functional change that allows the pathogen to evade a potential threat. These random mutational changes (single nucleotide polymorphisms, or SNPs) are so very rarely beneficial, that when they do arise in parallel in distantly related isolates (known as homoplasic SNPs) this indicates that the change may be positively selected because it confers an adaptive advantage to the bacteria. Finding homoplasic SNPs in large sets of bacterial genomes is challenging as current tools require substantial time and computational resources to run. Here we present SNPPar, a software program to efficiently and accurately automate the detection and annotation of homoplasic SNPs from large whole-genome sequence data sets. We use simulated data to demonstrate accuracy of the program, and re-analyse published datasets using SNPPar to illustrate how the results can be used to gain insights into the evolution of antibiotic resistance and other traits. We envisage SNPPar will help facilitate the undertaking of long-term, real-time surveillance of bacterial pathogens, and their adaptive evolutionary response to interventions and control measures such as new drugs or vaccines. The authors confirm all supporting data, code and protocols have been provided within the article, through supplementary data files or other online sources as indicated in the article. New content generated for this paper is: SNPPar code is available from -j-e/SNPPar . The version described here is v1.0. A GitHub repository containing the full protocol, ‘in-house’ code and data used to carry out the validation and performance testing is available at -j-e/SNPPar_test . This repository includes all the simulated and real data sets used here. The authors confirm all supporting data, code and protocols have been provided within the article, through supplementary data files or other online sources as indicated in the article.
Publisher: ACM
Date: 30-09-2007
Publisher: Code Ocean
Date: 2018
Publisher: MDPI AG
Date: 27-03-2020
DOI: 10.3390/APP10072298
Abstract: Given an object of interest that evolves in time, one often wants to detect possible changes in its properties. The first changes may be small and occur in different scales and it may be crucial to detect them as early as possible. Ex les include identification of potentially malignant changes in skin moles or the gradual onset of food quality deterioration. Statistical scale-space methodologies can be very useful in such situations since exploring the measurements in multiple resolutions can help identify even subtle changes. We extend a recently proposed scale-space methodology to a technique that successfully detects such small changes and at the same time keeps false alarms at a very low level. The potential of the novel methodology is first demonstrated with hyperspectral skin mole data artificially distorted to include a very small change. Our real data application considers hyperspectral images used for food quality detection. In these experiments the performance of the proposed method is either superior or on par with a standard approach such as principal component analysis.
Publisher: Oxford University Press (OUP)
Date: 05-01-2023
DOI: 10.1093/JNCI/DJAD001
Abstract: Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic “two-hit” model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically erse populations.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1038/GIM.2017.265
Abstract: The abstract to this article contained errors in the Results and Conclusions section. The corrected sections are shown below.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1038/GIM.2017.185
Publisher: Springer Science and Business Media LLC
Date: 19-01-2018
Publisher: Cold Spring Harbor Laboratory
Date: 27-09-2023
Publisher: Springer Science and Business Media LLC
Date: 14-06-2017
Publisher: Springer Science and Business Media LLC
Date: 14-02-2020
Publisher: Springer Science and Business Media LLC
Date: 20-11-2014
Publisher: Zenodo
Date: 2022
Publisher: American Chemical Society (ACS)
Date: 08-04-2015
DOI: 10.1021/AC504767D
Abstract: The metabolic fate of a compound can often determine the success of a new drug lead. Thus, significant effort is directed toward identifying the metabolites formed from a given molecule. Here, an automated and nontargeted procedure is introduced for detecting drug metabolites without authentic metabolite standards via the use of stable isotope labeling, liquid chromatography mass spectrometry (LC/MS), and high-performance computing. LC/MS of blood plasma extracts from rats that were administered a 1:1 mixture of acetaminophen (APAP) and (13)C6-APAP resulted in mass spectra that contained "twin" ions for drug metabolites that were not detected in control spectra (i.e., no APAP administered). Because of the development of a program (high-resolution twin-ion metabolite extraction HiTIME) that can identify twin-ions in high-resolution mass spectra without centroiding (i.e., reduction of mass spectral peaks to single data points), 9 doublets corresponding to APAP metabolites were identified. This is nearly twice that obtained by use of existing programs that make use of centroiding to reduce computational cost under these conditions with a quadrupole time-of-flight mass spectrometer. By a manual search for all reported APAP metabolite ions, no additional twin-ion signals were assigned. These data indicate that all the major metabolites of APAP and multiple low-abundance metabolites (e.g., acetaminophen hydroxy- and methoxysulfate) that are rarely reported were detected. This methodology can be used to detect drug metabolites without prior knowledge of their identity. HiTIME is freely available from jpop/HiTIME .
Publisher: MDPI AG
Date: 10-10-2023
Publisher: Oxford University Press (OUP)
Date: 12-04-2012
DOI: 10.1093/BIOINFORMATICS/BTS167
Abstract: Summary: Bpipe is a simple, dedicated programming language for defining and executing bioinformatics pipelines. It specializes in enabling users to turn existing pipelines based on shell scripts or command line tools into highly flexible, adaptable and maintainable workflows with a minimum of effort. Bpipe ensures that pipelines execute in a controlled and repeatable fashion and keeps audit trails and logs to ensure that experimental results are reproducible. Requiring only Java as a dependency, Bpipe is fully self-contained and cross-platform, making it very easy to adopt and deploy into existing environments. Availability and implementation: Bpipe is freely available from bpipe.org under a BSD License. Contact: simon.sadedin@mcri.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2021
DOI: 10.1038/S41523-021-00360-3
Abstract: Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1–16.2] for BRCA1 , 4.0 [1.9–9.1] for BRCA2 , 3.4 [1.4–8.4] for ATM and 4.3 [1.0–17.0] for PALB2 . Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.
Publisher: BMJ
Date: 07-01-2021
DOI: 10.1136/GUTJNL-2019-320462
Abstract: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers. Whole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers. The combination of mutational signatures SBS18 and SBS36 contributing % of a CRC’s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10 -5 ), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99) however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls. Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.
Publisher: Cold Spring Harbor Laboratory
Date: 17-11-2022
DOI: 10.1101/2022.11.16.516773
Abstract: A person’s germline genome strongly influences their risk of developing cancer. Yet the molecular mechanisms linking the host genome to the specific somatic molecular phenotypes of in idual cancers are largely unknown. We quantified the relationships between germline polymorphisms and somatic mutational features in prostate cancer. Across 1,991 prostate tumors, we identified 23 co-occurring germline and somatic events in close 2D or 3D spatial genomic proximity, affecting 10 cancer driver genes. These driver quantitative trait loci (dQTLs) overlap active regulatory regions, and shape the tumor epigenome, transcriptome and proteome. Some dQTLs are active in multiple cancer types, and information content analyses imply hundreds of undiscovered dQTLs. Specific dQTLs explain at least 16.7% ancestry-biases in rates of TMPRSS2-ERG gene fusions and 67.3% of ancestry-biases in rates of FOXA1 point mutations. These data reveal extensive influences of common germline variation on somatic mutational landscapes.
Publisher: Microbiology Society
Date: 07-12-2021
Abstract: Homoplasic SNPs are considered important signatures of strong (positive) selective pressure, and hence of adaptive evolution for clinically relevant traits such as antibiotic resistance and virulence. Here we present a new tool, SNPPar, for efficient detection and analysis of homoplasic SNPs from large whole genome sequencing datasets ( isolates and/or 000 SNPs). SNPPar takes as input an SNP alignment, tree and annotated reference genome, and uses a combination of simple monophyly tests and ancestral state reconstruction (ASR, via TreeTime) to assign mutation events to branches and identify homoplasies. Mutations are annotated at the level of codon and gene, to facilitate analysis of convergent evolution. Testing on simulated data (120 Mycobacterium tuberculosis alignments representing local and global s les) showed SNPPar can detect homoplasic SNPs with very high specificity (zero false-positives in all tests) and high sensitivity (zero false-negatives in 89 % of tests). SNPPar analysis of three empirically s led datasets ( Elizabethkingia anophelis , Burkholderia dolosa and M. tuberculosis ) produced results that were in concordance with previous studies, in terms of both in idual homoplasies and evidence of convergence at the codon and gene levels. SNPPar analysis of a simulated alignment of ~64 000 genome-wide SNPs from 2000 M. tuberculosis genomes took ~23 min and ~2.6 GB of RAM to generate complete annotated results on a laptop. This analysis required ASR be conducted for only 1.25 % of SNPs, and the ASR step took ~23 s and 0.4 GB of RAM. SNPPar automates the detection and annotation of homoplasic SNPs efficiently and accurately from large SNP alignments. As demonstrated by the ex les included here, this information can be readily used to explore the role of homoplasy in parallel and/or convergent evolution at the level of nucleotide, codon and/or gene.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Springer Science and Business Media LLC
Date: 09-06-2021
DOI: 10.1038/S41391-021-00379-4
Abstract: Recent publications have shown patients with defects in the DNA mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer. Moreover, this increased incidence of prostate cancer is accompanied by rapid disease progression and poor clinical outcomes. We show that androgen-receptor activation, a key driver of prostate carcinogenesis, can disrupt the MSH2 gene in prostate cancer. We screened tumours from two cohorts (recurrent/non-recurrent) of prostate cancer patients to confirm the loss of MSH2 protein expression and identified decreased MSH2 expression in recurrent cases. Stratifying the independent TCGA prostate cancer cohort for MSH2/6 expression revealed that patients with lower levels of MSH2/6 had significant worse outcomes, in contrast, endometrial and colorectal cancer patients with lower MSH2/6 levels. MMRd endometrial and colorectal tumours showed the expected increase in mutational burden, microsatellite instability and enhanced immune cell mobilisation but this was not evident in prostate tumours. We have shown that loss or reduced levels of MSH2/MSH6 protein in prostate cancer is associated with poor outcome. However, our data indicate that this is not associated with a statistically significant increase in mutational burden, microsatellite instability or immune cell mobilisation in a cohort of primary prostate cancers.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2021
DOI: 10.1007/S10689-021-00283-9
Abstract: Germline loss-of-function variants in AXIN2 are associated with oligodontia and ectodermal dysplasia. The association between colorectal cancer (CRC) and colonic polyposis is less clear despite this gene now being included in multi-gene panels for CRC. Study participants were people with genetically unexplained colonic polyposis recruited to the Genetics of Colonic Polyposis Study who had a rare germline AXIN2 gene variant identified from either clinical multi-gene panel testing (n=2) or from whole genome/exome sequencing (n=2). Variant segregation in relatives and characterisation of tumour tissue were performed where possible. Four different germline pathogenic variants in AXIN2 were identified in four families. Five of the seven carriers of the c.1049delC, p.Pro350Leufs*13 variant, two of the six carriers of the c.1994dupG, p.Asn666Glnfs*41 variant, all three carriers of c.1972delA, p.Ser658Alafs*31 variant and the single proband carrier of the c.2405G>C, p.Arg802Thr variant, which creates an alternate splice form resulting in a frameshift mutation (p.Glu763Ilefs*42), were affected by CRC and/or polyposis. Carriers had a mean age at diagnosis of CRC olyposis of 52.5 ± 9.2 years. Colonic polyps were typically pan colonic with counts ranging from 5 to >100 (median 12.5) comprising predominantly adenomatous polyps but also serrated polyps. Two CRCs from carriers displayed evidence of a second hit via loss of heterozygosity. Oligodontia was observed in carriers from two families. Germline AXIN2 pathogenic variants from four families were associated with CRC and/or polyposis in multiple family members. These findings support the inclusion of AXIN2 in CRC and polyposis multigene panels for clinical testing.
Publisher: Cold Spring Harbor Laboratory
Date: 19-11-2021
DOI: 10.1101/2021.11.16.468904
Abstract: Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA variants. Ultimately, the goal of many of these studies is to associate genetic variants to phenotypes or fitness. We introduce VIVID, an interactive, user-friendly web application that integrates a wide range of approaches for encoding genotypic to phenotypic information in any organism or disease, from an in idual or population, in three-dimensional (3D) space. It allows mutation mapping and annotation, calculation of interactions and conservation scores, prediction of harmful effects, analysis of ersity and selection, and 3-dimensional (3D) visualisation of genotypic information encoded in Variant Call Format (VCF) on AlphaFold2 protein models. VIVID enables the rapid assessment of genes of interest in the study of adaptive evolution and the genetic load, and it helps prioritising targets for experimental validation. We demonstrate the utility of VIVID by exploring the evolutionary genetics of the parasitic protist Plasmodium falciparum , revealing geographic variation in the signature of balancing selection in potential targets of functional antibodies.
Publisher: Public Library of Science (PLoS)
Date: 13-08-2013
Publisher: Elsevier BV
Date: 12-2020
Publisher: F1000 Research Ltd
Date: 04-06-2018
DOI: 10.12688/F1000RESEARCH.12344.2
Abstract: Throughout history, the life sciences have been revolutionised by technological advances in our era this is manifested by advances in instrumentation for data generation, and consequently researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a ‘life cycle’ view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain. Here we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on ‘omics’ datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices.
Publisher: F1000 Research Ltd
Date: 31-08-2017
DOI: 10.12688/F1000RESEARCH.12344.1
Abstract: Throughout history, the life sciences have been revolutionised by technological advances in our era this is manifested by advances in instrumentation for data generation, and consequently researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a ‘life cycle’ view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain. Here we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on ‘omics’ datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices.
Publisher: Cold Spring Harbor Laboratory
Date: 17-03-2020
DOI: 10.1101/2020.03.12.20034991
Abstract: People who develop mismatch repair (MMR) deficient cancer in the absence of a germline MMR gene pathogenic variant or hypermethylation of the MLH1 gene promoter in their tumor are classified as having suspected Lynch syndrome (SLS). We applied germline whole genome sequencing (WGS) and targeted and genome-wide tumor sequencing approaches to identify the underlying cause of tumor MMR-deficiency in SLS. Germline WGS was performed on 14 cancer-affected people with SLS, including two sets of first-degree relatives. Tumor tissue was sequenced for somatic MMR gene mutations by targeted, whole exome sequencing or WGS. Germline pathogenic variants, including complex structural rearrangements and non-coding variants, were assessed for the MMR genes. Tumor mutation burden and mutational signatures. Germline WGS identified pathogenic MMR variants in 3 of the 14 (21.4%) SLS cases including a 9.5Mb inversion disrupting exons 1-7 of MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8/11 (72.7%) tumors tested, supporting a non-inherited cause of tumor MMR-deficiency. In the second mother-daughter pair, the combined analysis of germline and tumor by WGS supported a somatic rather than inherited cause of their tumor MMR-deficiency, through presence of double somatic MSH2 mutations in their respective tumors. Germline WGS of people with SLS improved the identification of Lynch syndrome. When coupled with tumor sequencing, % of the people with SLS were resolved as having double somatic MMR mutations and a non-inherited cause for their tumor MMR-deficiency.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-2018
DOI: 10.1200/JGO.18.50600
Abstract: Background: Germline BRCA1 or BRCA2 pathogenic variants in ovarian cancer patients may be informative in risk management and treatment, with the advent of poly(ADP-ribose) polymerase inhibitors. In the era of precision medicine, companion diagnostics for BRCA1 and BRCA2 genes have been featured as a strategy in the Malaysia National Strategic Plan for Cancer Control Program (2016-2020). To facilitate this strategy, frequency data from Malaysia's understudied multiethnic population will be required. Aim: To determine the prevalence of BRCA1 and BRCA2 germline variants in a population-based cohort of ovarian cancer patients in Malaysia. Methods: From August 2016, women with nonmucinous epithelial ovarian, peritoneal or fallopian tube carcinoma are prospectively recruited to the Malaysia-wide population-based MaGiC Observational Study. DNA were tested using a Hi-Plex next generation sequencing method and multiplex ligation-dependent probe lification to detect 10 bp alterations and exon deletions or duplications in the BRCA1 and BRCA2 genes. Results: Interim results from 325 patients tested until March 2018 have identified BRCA1 and BRCA2 pathogenic variants in 9.8% (32/325) and 3.1% (10/325) patients, respectively. Variants of uncertain significance were detected in 13.2% (43/325) patients and no pathogenic variants were detected in 73.8% (240/325) patients. Taken together, the frequency of BRCA1/2 pathogenic variants in ovarian cancer patients is approximately 12.9% (42/325). Conclusion: The identification of BRCA1 or BRCA2 carriers across the country have enabled the concentration of efforts from limited genetic counseling resources to high risk families. Results arising from the completion of this study will supplement cancer control programs and genetic services in Malaysia.
Publisher: Cold Spring Harbor Laboratory
Date: 15-12-2019
DOI: 10.1101/2019.12.11.19014597
Abstract: Germline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers. Whole exome sequencing of formalin-fixed paraffin embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers. The combination of mutational signatures SBS18 and SBS36 contributing % of a CRC’s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10 −5 ), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99), however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls. Assessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool. Identifying carriers of pathogenic variants (PVs) in moderate/high-risk colorectal cancer (CRC) and polyposis susceptibility genes has clinical relevance for diagnosis, targeted screening and prevention strategies, prognosis, and treatment options. However, challenges still remain in the identification of carriers and the classification of rare variants in these genes. Previous studies have identified tumour mutational signatures that result from defective DNA repair including DNA mismatch repair (MMR) deficiency and base excision repair defects, DNA repair mechanisms that underlie the common hereditary CRC and polyposis syndromes but their diagnostic utility in CRC is unknown. Single base substitution (SBS)-related mutational signatures derived from whole exome sequencing of formalin-fixed paraffin embedded (FFPE)-derived CRC tissue DNA can effectively discriminate CRCs that developed in biallelic MUTYH PV carriers from CRC-affected non-carriers. CRCs that develop in MMR PV carriers (Lynch syndrome) can be effectively differentiated from sporadic MMR-proficient CRC by a combination of indel (ID) signatures, but the SBS and ID tumour mutational signatures are less effective at discriminating Lynch syndrome-related CRC from sporadic MMR-deficient CRC resulting from MLH1 gene promoter hypermethylation. The SBS and ID mutational signatures associated with biallelic MUTYH PV carriers and MMR PV carriers are robust to changes in experimental settings. We demonstrate the optimal experimental settings for calculating mutational signatures and define thresholds that optimise sensitivity and specificity for classifying CRC aetiology as hereditary or non-hereditary. Deriving SBS- and ID-related mutational signatures from CRCs can identify carriers of PVs in hereditary CRC and polyposis susceptibility genes. The application of mutational signatures has the potential to improve the diagnosis of hereditary CRC and aid in variant classification, leading to improved clinical management and CRC prevention.
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.SCITOTENV.2018.08.032
Abstract: With a growing number of available datasets especially from satellite remote sensing, there is a great opportunity to improve our knowledge of the state of the hydrological processes via data assimilation. Observations can be assimilated into numerical models using dynamics and data-driven approaches. The present study aims to assess these assimilation frameworks for integrating different sets of satellite measurements in a hydrological context. To this end, we implement a traditional data assimilation system based on the Square Root Analysis (SQRA) filtering scheme and the newly developed data-driven Kalman-Takens technique to update the water components of a hydrological model with the Gravity Recovery And Climate Experiment (GRACE) terrestrial water storage (TWS), and soil moisture products from the Advanced Microwave Scanning Radiometer - Earth Observing System (AMSR-E) and Soil Moisture and Ocean Salinity (SMOS) in a 5-day temporal scale. While SQRA relies on a physical model for forecasting, the Kalman-Takens only requires a trajectory of the system based on past data. We are particularly interested in testing both methods for assimilating different combination of the satellite data. In most of the cases, simultaneous assimilation of the satellite data by either standard SQRA or Kalman-Takens achieves the largest improvements in the hydrological state, in terms of the agreement with independent in-situ measurements. Furthermore, the Kalman-Takens approach performs comparably well to dynamical method at a fraction of the computational cost.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2022
DOI: 10.1038/S41467-022-30916-1
Abstract: Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87–100%)). All monoallelic MUTYH carriers are classified with the non- MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers ( p = 2 × 10 −23 and p = 6 × 10 −11 , respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers.
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: ACM
Date: 27-08-2003
Publisher: Future Science Ltd
Date: 09-2019
Abstract: We have previously reported Hi-Plex, a multiplex PCR methodology for building targeted DNA sequencing libraries that offers a low-cost protocol compatible with high-throughput processing. Here, we detail an improved protocol, Hi-Plex2, that more effectively enables the robust construction of small-to-medium panel-size libraries while maintaining low cost, simplicity and accuracy benefits of the Hi-Plex platform. Hi-Plex2 was applied to three panels, comprising 291, 740 and 1193 licons, targeting genes associated with risk for breast and/or colon cancer. We show substantial reduction of off-target lification to enable library construction for small-to-medium-sized design panels not possible using the previous Hi-Plex chemistry.
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.JMOLDX.2022.10.003
Abstract: Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. Tumor features, in idually and in combination, derived from whole-exome sequenced (WES) colorectal cancers (CRCs) and panel-sequenced CRCs, endometrial cancers (ECs), and sebaceous skin tumors (SSTs) were assessed for their accuracy in detecting dMMR. CRCs (n = 300) with WES, where mismatch repair status was determined by immunohistochemistry, were assessed for microsatellite instability (MSMuTect, MANTIS, MSIseq, and MSISensor), Catalogue of Somatic Mutations in Cancer tumor mutational signatures, and somatic mutation counts. A 10-fold cross-validation approach (100 repeats) evaluated the dMMR prediction accuracy for i) in idual features, ii) Lasso statistical model, and iii) an additive feature combination approach. Panel-sequenced tumors (29 CRCs, 22 ECs, and 20 SSTs) were assessed for the top performing dMMR predicting features/models using these three approaches. For WES CRCs, 10 features provided >80% dMMR prediction accuracy, with MSMuTect, MSIseq, and MANTIS achieving ≥99% accuracy. The Lasso model achieved 98.3% accuracy. The additive feature approach, with three or more of six of MSMuTect, MANTIS, MSIseq, MSISensor, insertion-deletion count, or tumor mutational signature small insertion/deletion 2 + small insertion/deletion 7 achieved 99.7% accuracy. For the panel-sequenced tumors, the additive feature combination approach of three or more of six achieved accuracies of 100%, 95.5%, and 100% for CRCs, ECs, and SSTs, respectively. The microsatellite instability calling tools performed well in WES CRCs however, an approach combining tumor features may improve dMMR prediction in both WES and panel-sequenced data across tissue types.
Publisher: Elsevier BV
Date: 07-2020
Publisher: Oxford University Press (OUP)
Date: 06-12-2018
Publisher: MDPI AG
Date: 15-10-2018
DOI: 10.3390/IJMS19103172
Abstract: DNA methylation influences predisposition, development and prognosis for many diseases, including cancer. However, it is not uncommon to encounter s les with incorrect sex labelling or atypical sex chromosome arrangement. Sex is one of the strongest influencers of the genomic distribution of DNA methylation and, therefore, correct assignment of sex and filtering of abnormal s les are essential for the quality control of study data. Differences in sex chromosome copy numbers between sexes and X-chromosome inactivation in females result in distinctive sex-specific patterns in the distribution of DNA methylation levels. In this study, we present a software tool, sEst, which incorporates clustering analysis to infer sex and to detect sex-chromosome abnormalities from DNA methylation microarray data. Testing with two publicly available datasets demonstrated that sEst not only correctly inferred the sex of the test s les, but also identified mislabelled s les and s les with potential sex-chromosome abnormalities, such as Klinefelter syndrome and Turner syndrome, the latter being a feature not offered by existing methods. Considering that sex and the sex-chromosome abnormalities can have large effects on many phenotypes, including diseases, our method can make a significant contribution to DNA methylation studies that are based on microarray platforms.
Publisher: Cold Spring Harbor Laboratory
Date: 12-03-2023
DOI: 10.1101/2023.03.10.23287127
Abstract: The microbiome has long been suspected of a role in colorectal cancer (CRC) tumorigenesis. The mutational signature SBS88 mechanistically links CRC development with the strain of Escherichia coli harboring the pks island that produces the genotoxin colibactin, but the genomic, pathological and survival characteristics associated with SBS88-positive tumors are unknown. SBS88-positive CRCs were identified from targeted sequencing data from 5,292 CRCs from 17 studies and tested for their association with clinico-pathological features, oncogenic pathways, genomic characteristics and survival. In total, 7.5% (398/5,292) of the CRCs were SBS88-positive, of which 98.7% (392/398) were microsatellite stable/microsatellite instability low (MSS/MSI-L), compared with 80% (3916/4894) of SBS88 negative tumors (p=1.5×10 -28 ). Analysis of MSS/MSI-L CRCs demonstrated that SBS88 positive CRCs were associated with the distal colon (OR=1.84, 95% CI=1.40-2.42, p=1×10 -5 ) and rectum (OR=1.90, 95% CI=1.44-2.51, p=6×10 -6 ) tumor sites compared with the proximal colon. The top seven recurrent somatic mutations associated with SBS88-positive CRCs demonstrated mutational contexts associated with colibactin-induced DNA damage, the strongest of which was the APC :c.835-8A G mutation (OR=65.5, 95%CI=39.0-110.0, p=3×10 -80 ). Large copy number alterations (CNAs) including CNA loss on 14q and gains on 13q, 16q and 20p were significantly enriched in SBS88- positive CRCs. SBS88-positive CRCs were associated with better CRC-specific survival (p=0.007 hazard ratio of 0.69, 95% CI=0.52-0.90) when stratified by age, sex, study, and by stage. SBS88-positivity, a biomarker of colibactin-induced DNA damage, can identify a novel subtype of CRC characterized by recurrent somatic mutations, copy number alterations and better survival. These findings provide new insights for treatment and prevention strategies for this subtype of CRC.
Publisher: Wiley
Date: 08-05-2020
DOI: 10.1002/IJC.33024
Publisher: Cold Spring Harbor Laboratory
Date: 11-11-2021
Abstract: Cryptosporidiosis is a leading cause of waterborne diarrheal disease globally and an important contributor to mortality in infants and the immunosuppressed. Despite its importance, the Cryptosporidium community has only had access to a good, but incomplete, Cryptosporidium parvum IOWA reference genome sequence. Incomplete reference sequences h er annotation, experimental design, and interpretation. We have generated a new C. parvum IOWA genome assembly supported by Pacific Biosciences (PacBio) and Oxford Nanopore long-read technologies and a new comparative and consistent genome annotation for three closely related species: C. parvum , Cryptosporidium hominis , and Cryptosporidium tyzzeri . We made 1926 C. parvum annotation updates based on experimental evidence. They include new transporters, ncRNAs, introns, and altered gene structures. The new assembly and annotation revealed a complete Dnmt2 methylase ortholog. Comparative annotation between C. parvum , C. hominis , and C. tyzzeri revealed that most “missing” orthologs are found, suggesting that the biological differences between the species must result from gene copy number variation, differences in gene regulation, and single-nucleotide variants (SNVs). Using the new assembly and annotation as reference, 190 genes are identified as evolving under positive selection, including many not detected previously. The new C. parvum IOWA reference genome assembly is larger, gap free, and lacks ambiguous bases. This chromosomal assembly recovers all 16 chromosome ends, 13 of which are contiguously assembled. The three remaining chromosome ends are provisionally placed. These ends represent duplication of entire chromosome ends including subtelomeric regions revealing a new level of genome plasticity that will both inform and impact future research.
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2017
DOI: 10.1101/167619
Abstract: Throughout history, the life sciences have been revolutionised by technological advances in our era this is manifested by advances in instrumentation for data generation, and consequently researchers now routinely handle large amounts of heterogeneous data in digital formats. The simultaneous transitions towards biology as a data science and towards a ‘life cycle’ view of research data pose new challenges. Researchers face a bewildering landscape of data management requirements, recommendations and regulations, without necessarily being able to access data management training or possessing a clear understanding of practical approaches that can assist in data management in their particular research domain. Here we provide an overview of best practice data life cycle approaches for researchers in the life sciences/bioinformatics space with a particular focus on ‘omics’ datasets and computer-based data processing and analysis. We discuss the different stages of the data life cycle and provide practical suggestions for useful tools and resources to improve data management practices.
Publisher: Unpublished
Date: 2017
Publisher: IEEE
Date: 08-2011
Publisher: Hindawi Limited
Date: 2020
DOI: 10.1017/S0016672320000075
Abstract: To characterize the spectrum of BRCA1 and BRCA2 pathogenic germline variants in women from south-west Poland and west Ukraine affected with breast or ovarian cancer. Testing in women at high risk of breast and ovarian cancer in these regions is currently mainly limited to founder mutations. Unrelated women affected with breast and/or ovarian cancer from Poland (n = 337) and Ukraine (n = 123) were screened by targeted sequencing. Excluded from targeted sequencing were 34 Polish women who had previously been identified as carrying a founder mutation in BRCA1 . No prior testing had been conducted among the Ukrainian women. Thus, this study screened BRCA1 and BRCA2 in the germline DNA of 426 women in total. We identified 31 and 18 women as carriers of pathogenic/likely pathogenic (P/LP) genetic variants in BRCA1 and BRCA2 , respectively. We observed five BRCA1 and eight BRCA2 P/LP variants (13/337, 3.9%) in the Polish women. Combined with the 34/337 (10.1%) founder variants identified prior to this study, the overall P/LP variant frequency in the Polish women was thus 14% (47/337). Among the Ukrainian women, 16/123 (13%) women were identified as carrying a founder mutation and 20/123 (16.3%) were found to carry non-founder P/LP variants (10 in BRCA1 and 10 in BRCA2 ). These results indicate that genetic testing in women at high risk of breast and ovarian cancer in Poland and Ukraine should not be limited to founder mutations. Extended testing will enhance risk stratification and management for these women and their families.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2017
DOI: 10.1158/1538-7445.AM2017-4266
Abstract: Background: Tumour mismatch repair (MMR) deficiency, determined by immunohistochemical (IHC) loss of MMR protein expression, is used diagnostically to identify in iduals with Lynch syndrome. A high proportion of colorectal cancers (CRCs) and endometrial cancers (ECs) that demonstrate tumor MMR-deficiency are categorised as having “Lynch-like syndrome” due to the absence of tumor MLH1 methylation or germline MMR gene mutations after standard screening approaches. The aim of this study was to investigate somatic causes of tumor MMR-deficiency in patients with Lynch-like syndrome. Methods: Population-based participants with incident MMR-deficient colorectal (n=193 ACCFR and MCCS) or endometrial cancer (n=197 ANECS and MCCS) were categorised as either Lynch syndrome, MLH1 methylated or Lynch-like after screening for germline MMR gene mutations and for tumor MLH1 gene promoter hypermethylation. Lynch-like tumors were tested for somatic MMR gene mutations (point mutations and loss of heterozygosity) using AmpliSeq-Ion Proton custom capture sequencing and for MSH2 or MSH6 gene promoter methylation. Overall survival for molecularly defined subgroups of Lynch-like CRCs were compared to Lynch syndrome related CRCs using cox regression models to estimate hazard ratios (HR) and 95% confidence intervals adjusting for age at CRC diagnosis, sex, AJCC stage and grade. Results: Lynch-like tumors comprised 32% (63/193) and 23% (45/197) of the MMR-deficient CRCs and ECs, respectively compared with 27% and 15% for Lynch syndrome and 41% and 62% for MLH1 methylated CRCs and ECs, respectively. Two somatic mutations were identified in the MMR gene indicated by the pattern of MMR IHC loss of expression were identified in 36.7% (18/49) and 47.8% (11/23) of the Lynch-like CRCs and ECs tested. The proportion of tumors with double somatic alterations was highest for both CRC and EC tumors showing MSH2-deficiency (40% and 64.3%). The mean age at diagnosis for the Lynch-like CRCs with double somatic mutations was 49.7 ± 15.8years which was not significantly different from the Lynch syndrome CRCs (n=52 45.4 ± 11.3years p=0.2) but was significantly different compared with the MLH1 methylated CRCs (n=83 70 ± 8.9years p=0.0001). The adjusted HR for double somatic Lynch-like CRCs was 2.58 (95% CI, 0.77-8.67) compared with Lynch syndrome CRCs (p=0.1). No evidence of tumor MSH2 or MSH6 gene promoter methylation was identified in either MSH2-deficient or MSH6-deficient Lynch-like CRCs or ECs tested (n=34 and n=12, respectively). Conclusions: Double somatic mutations in the MMR genes represent a significant proportion of the unexplained Lynch-like MMR-deficient subtype for both population-based CRC and EC. Triaging strategies used to identify Lynch syndrome for both CRC and EC should include tumor testing for somatic mutations in the MMR genes. Note: This abstract was not presented at the meeting. Citation Format: Daniel D. Buchanan, Mark Clendenning, Harindra Jayasekara, Jihoon E. Joo, Ee M. Wong, Melissa C. Southey, Rhiannon J. Walters, Bernard J. Pope, Aung K. Win, John L. Hopper, Mark A. Jenkins, Roger L. Milne, Graham G. Giles, Dallas R. English, Finlay A. Macrae, Amanda B. Spurdle, Ingrid M. Winship, Christophe Rosty. Double somatic mutations as a cause of tumor mismatch repair-deficiency in population-based colorectal and endometrial cancer with Lynch-like syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017 2017 Apr 1-5 Washington, DC. Philadelphia (PA): AACR Cancer Res 2017 (13 Suppl):Abstract nr 4266. doi:10.1158/1538-7445.AM2017-4266
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.CLGC.2022.05.007
Abstract: Disease recurrence is common following prostatectomy in patients with localised prostate cancer with high-risk features. Although androgen deprivation therapy increases the rates of organ-confined disease and negative surgical margins, there is no significant benefit on disease recurrence. Multiple lines of evidence suggest that (Fibroblast Growth Factor/Fibroblast Growth Factor Receptor) FGF/FGFR-signalling is important in supporting prostate epithelial cell survival in hostile conditions, including acute androgen deprivation. Given the recent availability of oral FGFR inhibitors, we investigated whether combination therapy could improve tumour response in the neo-adjuvant setting. We conducted an open label phase II study of the combination of erdafitinib (3 months) and androgen deprivation therapy (4 months) in men with localised prostate cancer with high-risk features prior to prostatectomy using a Simon's 2 stage design. The co-primary endpoints were safety and tolerability and pathological response in the prostatectomy specimen. The effect of treatment on residual tumours was explored by global transcriptional profiling with RNA-sequencing. Nine patients were enrolled in the first stage of the trial. The treatment combination was poorly tolerated. Erdafitinib treatment was discontinued early in six patients, three of whom also required dose interruptions/reductions. Androgen deprivation therapy for 4 months was completed in all patients. The most common adverse events were hyperphosphataemia, taste disturbance, dry mouth and nail changes. No patients achieved a complete pathological response, although patients who tolerated erdafitinib for longer had smaller residual tumours, associated with reduced transcriptional signatures of epithelial cell proliferation. Although there was a possible enhanced anti-tumour effect of androgen deprivation therapy in combination with erdafitnib in treatment naïve prostate cancer, the poor tolerability in this patient population prohibits the use of this combination in this setting.
Publisher: Cold Spring Harbor Laboratory
Date: 21-06-2022
DOI: 10.1101/2022.06.20.22276419
Abstract: Identifying tumor DNA mismatch repair deficiency (dMMR) is important for precision medicine. We assessed tumor features, in idually and in combination, in whole-exome sequenced (WES) colorectal cancers (CRCs) and in panel sequenced CRCs, endometrial cancers (ECs) and sebaceous skin tumors (SSTs) for their accuracy in detecting dMMR. CRCs (n=300) with WES, where MMR status was determined by immunohistochemistry, were assessed for microsatellite instability (MSMuTect, MANTIS, MSIseq, MSISensor), COSMIC tumor mutational signatures (TMS) and somatic mutation counts. A 10-fold cross-validation approach (100 repeats) evaluated the dMMR prediction accuracy for 1) in idual features, 2) Lasso statistical model and 3) an additive feature combination approach. Panel sequenced tumors (29 CRCs, 22 ECs, 20 SSTs) were assessed for the top performing dMMR predicting features/models using these three approaches. For WES CRCs, 10 features provided % dMMR prediction accuracy, with MSMuTect, MSIseq, and MANTIS achieving ≥99% accuracy. The Lasso model achieved 98.3%. The additive feature approach with ≥3/6 of MSMuTect, MANTIS, MSIseq, MSISensor, INDEL count or TMS ID2+ID7 achieved 99.7% accuracy. For the panel sequenced tumors, the additive feature combination approach of ≥3/6 achieved accuracies of 100%, 95.5% and 100%, for CRCs, ECs, and SSTs, respectively. The microsatellite instability calling tools performed well in WES CRCs, however, an approach combining tumor features may improve dMMR prediction in both WES and panel sequenced data across tissue types.
Publisher: Wiley
Date: 22-04-2019
DOI: 10.1002/WICS.1465
Abstract: Skin cancer is one of the most common types of cancer. Skin cancers are classified as nonmelanoma and melanoma, with the first type being the most frequent and the second type being the most deadly. The key to effective treatment of skin cancer is early detection. With the recent increase of computational power, the number of algorithms to detect and classify skin lesions has increased. The overall verdict on systems based on clinical and dermoscopic images captured with conventional RGB (red, green, and blue) cameras is that they do not outperform dermatologists. Computer‐based systems based on conventional RGB images seem to have reached an upper limit in their performance, while emerging technologies such as hyperspectral and multispectral imaging might possibly improve the results. These types of images can explore spectral regions beyond the human eye capabilities. Feature selection and dimensionality reduction are crucial parts of extracting salient information from this type of data. It is necessary to extend current classification methodologies to use all of the spatiospectral information, and deep learning models should be explored since they are capable of learning robust feature detectors from data. There is a lack of large, high‐quality datasets of hyperspectral skin lesion images, and there is a need for tools that can aid with monitoring the evolution of skin lesions over time. To understand the rich information contained in hyperspectral images, further research using data science and statistical methodologies, such as functional data analysis, scale‐space theory, machine learning, and so on, are essential. This article is categorized under: Applications of Computational Statistics Health and Medical Data/Informatics
Publisher: Springer Science and Business Media LLC
Date: 07-03-2023
DOI: 10.1186/S12885-023-10624-9
Abstract: A subset of meningiomas progress in histopathological grade but drivers of progression are poorly understood. We aimed to identify somatic mutations and copy number alterations (CNAs) associated with grade progression in a unique matched tumour dataset. Utilising a prospective database, we identified 10 patients with meningiomas that had undergone grade progression and for whom matched pre- and post-progression tissue (n = 50 s les) was available for targeted next-generation sequencing. Mutations in NF2 were identified in 4/10 patients, of these 94% were non-skull base tumours. In one patient, three different NF2 mutations were identified in four tumours. NF2 mutated tumours showed large-scale CNAs, with highly recurrent losses in 1p, 10, 22q, and frequent CNAs on chromosomes 2, 3 and 4. There was a correlation between grade and CNAs in two patients. Two patients with tumours without detected NF2 mutations showed a combination of loss and high gain on chromosome 17q. Mutations in SETD2 , TP53 , TERT promoter and NF2 were not uniform across recurrent tumours, however did not correspond with the onset of grade progression. Meningiomas that progress in grade generally have a mutational profile already detectable in the pre-progressed tumour, suggesting an aggressive phenotype. CNA profiling shows frequent alterations in NF2 mutated tumours compared to non NF2 mutated tumours. The pattern of CNAs may be associated with grade progression in a subset of cases.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2012
Publisher: F1000 Research Ltd
Date: 13-06-2017
DOI: 10.12688/F1000RESEARCH.11407.1
Abstract: Scientific research relies on computer software, yet software is not always developed following practices that ensure its quality and sustainability. This manuscript does not aim to propose new software development best practices, but rather to provide simple recommendations that encourage the adoption of existing best practices. Software development best practices promote better quality software, and better quality software improves the reproducibility and reusability of research. These recommendations are designed around Open Source values, and provide practical suggestions that contribute to making research software and its source code more discoverable, reusable and transparent. This manuscript is aimed at developers, but also at organisations, projects, journals and funders that can increase the quality and sustainability of research software by encouraging the adoption of these recommendations.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 10-2011
Publisher: Elsevier BV
Date: 09-2002
Publisher: Springer Science and Business Media LLC
Date: 17-08-2020
DOI: 10.1186/S13073-020-00770-1
Abstract: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic redictive value in metastatic prostate cancer, its utility in localised disease is unknown. We performed whole-genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and lification panel against the highest prevalence, highest confidence aberrations for each in idual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 h and 6 weeks) surgery. In a separate cohort ( n = 189), we identified the presence of ctDNA TP53 mutations in preoperative plasma in a retrospective cohort and determined its association with biochemical- and metastasis-free survival. Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4 95% CIs 1.2–4.8, p = 0.014). CtDNA is uncommonly detected in localised prostate cancer, but its presence portends more rapidly progressive disease.
Publisher: Wiley
Date: 04-06-2019
DOI: 10.1002/MGG3.781
Location: No location found
Start Date: 2017
End Date: 2019
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: Cancer Australia
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: Cancer Australia
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2019
End Date: 2022
Funder: Movember Foundation
View Funded ActivityStart Date: 2012
End Date: 2013
Funder: National Health and Medical Research Council
View Funded Activity