ORCID Profile
0000-0001-7615-8523
Current Organisation
University of Oxford
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Publisher: Springer Science and Business Media LLC
Date: 29-04-2014
DOI: 10.1038/NCOMMS4756
Abstract: Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former are not mutually exclusive with TP53 mutations or MDM2 lification, showing that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade and greater clonal ersity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater ersity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression.
Publisher: Oxford University Press (OUP)
Date: 19-12-2017
DOI: 10.1093/IBD/IZX024
Abstract: DUOX2 and DUOXA2 form the predominant H2O2-producing system in human colorectal mucosa. Inflammation, hypoxia, and 5-aminosalicylic acid increase H2O2 production, supporting innate defense and mucosal healing. Thiocyanate reacts with H2O2 in the presence of lactoperoxidase (LPO) to form hypothiocyanate (OSCN-), which acts as a biocide and H2O2 scavenging system to reduce damage during inflammation. We aimed to discover the organization of Duox2, Duoxa2, and Lpo expression in colonic crypts of Lieberkühn (intestinal glands) of mice and how distributions respond to dextran sodium sulfate (DSS)-induced colitis and subsequent mucosal regeneration. We studied tissue from DSS-exposed mice and human biopsies using in situ hybridization, reverse transcription quantitative polymerase chain reaction, and cDNA microarray analysis. Duox2 mRNA expression was mostly in the upper crypt quintile while Duoxa2 was more apically focused. Most Lpo mRNA was in the basal quintile, where stem cells reside. Duox2 and Duoxa2 mRNA were increased during the induction and resolution of DSS colitis, while Lpo expression did not increase during the acute phase. Patterns of Lpo expression differed from Duox2 in normal, inflamed, and regenerative mouse crypts (P & 0.001). We found no evidence of LPO expression in the human gut. The spatial and temporal separation of H2O2-consuming and -producing enzymes enables a thiocyanate- H2O2 “scavenging” system in murine intestinal crypts to protect the stem roliferative zones from DNA damage, while still supporting higher H2O2 concentrations apically to aid mucosal healing. The absence of LPO expression in the human gut suggests an alternative mechanism or less protection from DNA damage during H2O2-driven mucosal healing.
Publisher: Cold Spring Harbor Laboratory
Date: 17-04-2022
DOI: 10.1101/2022.04.17.488593
Abstract: Genetically predicted levels of multi-omic traits can uncover the molecular underpinnings of common phenotypes in a highly efficient manner. Here, we utilised a large cohort (INTERVAL N=50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, N=3,175 Olink, N=4,822), plasma metabolomics (Metabolon HD4, N=8,153), serum metabolomics (Nightingale, N=37,359), and whole blood Illumina RNA sequencing (N=4,136). We used machine learning to train genetic scores for 17,227 molecular traits, including 10,521 which reached Bonferroni-adjusted significance. We evaluated genetic score performances in external validation across European, Asian and African American ancestries, and assessed their longitudinal stability within erse in iduals. We demonstrated the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of UK Biobank to identify disease associations using a phenome-wide scan. Finally, we developed a portal ( OmicsPred.org ) to facilitate public access to all genetic scores and validation results as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2014
DOI: 10.1038/NCOMMS5264
Publisher: Springer Science and Business Media LLC
Date: 03-01-2013
Abstract: Prevalence of colorectal cancer (CRC) in the British Bangladeshi population (BAN) is low compared to British Caucasians (CAU). Genetic background may influence mutations and disease features. We characterized the clinicopathological features of BAN CRCs and interrogated their genomes using mutation profiling and high-density single nucleotide polymorphism (SNP) arrays and compared findings to CAU CRCs. Age of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10 -5 ) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25% p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN s les. No BRAF mutations was seen in our BAN MSS CRCs (CAU CRCs, 12% p=0.08). Array data revealed similar patterns of gains (chromosome 7 and 8q), losses (8p, 17p and 18q) and LOH (4q, 17p and 18q) in BAN and CAU CRCs. A small deletion on chromosome 16p13.2 involving the alternative splicing factor RBFOX1 only was found in significantly more BAN (50%) than CAU CRCs (15%) cases (p=0.04). Focal deletions targeting the 5’ end of the gene were also identified. Novel RBFOX1 mutations were found in CRC cell lines and tumours mRNA and protein expression was reduced in tumours. KRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.
Publisher: Springer Science and Business Media LLC
Date: 09-2010
Publisher: Cold Spring Harbor Laboratory
Date: 31-03-2022
DOI: 10.1101/2022.03.25.22272958
Abstract: Understanding how genetic variants influence disease risk and complex traits (variant-to-function) is one of the major challenges in human genetics. Here we present a model-driven framework to leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues, including skeletal muscle, adipose, liver, brain and heart. As proof of concept, we build personalised organ-specific metabolic flux models for 524,615 in iduals of the INTERVAL and UK Biobank cohorts and perform a fluxome-wide association study (FWAS) to identify 4,411 associations between personalised flux values and the concentration of metabolites in blood. Furthermore, we apply FWAS to identify 97 metabolic fluxes associated with the risk of developing coronary artery disease, many of which are linked to processes previously described to play in role in the disease. Our work demonstrates that genetically personalised metabolic models can elucidate the downstream effects of genetic variants on biochemical reactions involved in common human diseases.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
DOI: 10.1038/AJG.2013.292
Abstract: Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC). Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of "double-negative" (MSI-/CIN-) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specific molecular changes, such as mutations in KRAS and BRAF, that have been associated with prognosis. It is not known which of MSI, CIN, and the specific gene mutations are primary predictors of survival. We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS, NRAS, BRAF, PIK3CA, FBXW7, and TP53, and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II/III CRC. We followed up promising associations in an Australian community-based cohort (N=375). In the VICTOR patients, no specific mutation was associated with DFS, but in idually MSI and CIN showed significant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR)=0.58, 95% confidence interval (CI) 0.36-0.93, and P=0.021 for CIN, HR=1.54, 95% CI 1.14-2.08, and P=0.005), and joint CIN/MSI testing significantly improved the prognostic prediction of MSI alone (P=0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN+/- variable. All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. MSI and CIN are independent predictors of DFS for stage II/III CRC. Prognostic molecular tests for CRC relapse should currently use MSI and a quantitative measure of CIN rather than specific gene mutations.
Publisher: Springer Science and Business Media LLC
Date: 04-2010
DOI: 10.1038/NATURE08979
Publisher: Springer Science and Business Media LLC
Date: 10-10-2014
DOI: 10.1038/NCOMMS5809
Publisher: Springer Science and Business Media LLC
Date: 29-03-2023
Publisher: Springer Science and Business Media LLC
Date: 18-05-2201
DOI: 10.1038/NG.3304
Publisher: Oxford University Press (OUP)
Date: 24-07-2008
DOI: 10.1093/BIOINFORMATICS/BTN386
Abstract: Summary: Current genotyping algorithms typically call genotypes by clustering allele-specific intensity data on a single nucleotide polymorphism (SNP) by SNP basis. This approach assumes the availability of a large number of control s les that have been s led on the same array and platform. We have developed a SNP genotyping algorithm for the Illumina Infinium SNP genotyping assay that is entirely within-s le and does not require the need for a population of control s les nor parameters derived from such a population. Our algorithm exhibits high concordance with current methods and & % call accuracy on HapMap s les. The ability to call genotypes using only within-s le information makes the method computationally light and practical for studies involving small s le sizes and provides a valuable independent quality control metric for other population-based approaches. Availability: www.stats.ox.ac.uk/~giannoul/GenoSNP/ Contact: cholmes@stats.ox.ac.uk
Publisher: Elsevier BV
Date: 10-2017
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Christopher Yau.