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2. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, RV, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, CG, Fiedler, K, McCarthy, DJ, Sullivan, PB, Rodrigues, A, Travis, SPL, Moore, C, Sambrook, J, Ouwehand, WH, Roberts, DJ, Danesh, J, Russell, RK, Wilson, DC, Kelsen, JR, Cornall, R, Denson, LA, Kugathasan, S, Knaus, UG, Serra, EG, Anderson, CA, Duerr, RH, McGovern, DPB, Cho, J, Powrie, F, Li, VSW, Muise, AM, and Uhlig, HH

Published
2018
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3. Mortality Among Adults With Cancer Undergoing Chemotherapy or Immunotherapy and Infected With COVID-19

Author

Várnai, C, Palles, C, Arnold, R, Curley, HM, Purshouse, K, Cheng, VWT, Booth, S, Campton, NA, Collins, GP, Hughes, DJ, Kulasekararaj, AG, Lee, AJX, Olsson-Brown, AC, Sharma-Oates, A, Van Hemelrijck, M, Lee, LYW, Kerr, R, Middleton, G, Cazier, J-B, and UKCCMP Team

Abstract

Importance Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. Objective To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. Design, Setting, and Participants The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. Exposures SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. Main Outcomes and Measures The primary end point was all-cause mortality within the primary hospitalization. Results Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19–related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). Conclusions and Relevance The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed.

Published
2022

4. A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer

Author

Fernandez-Rozadilla, C., Cazier, J. B., Tomlinson, I., Brea-Fernández, A., Lamas, M. J., Baiget, M., López-Fernández, L. A., Clofent, J., Bujanda, L., Gonzalez, D., de Castro, L., Hemminki, K., Bessa, X., Andreu, M., Jover, R., Xicola, R., Llor, X., Moreno, V., Castells, A., Castellví-Bel, S., Carracedo, A., Ruiz-Ponte, C., and The EPICOLON Consortium

Published
2014
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5. Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration

Author

Fernandez-Rozadilla, C, Cazier, J B, Moreno, V, Crous-Bou, M, Guinó, E, Durán, G, Lamas, M J, López, R, Candamio, S, Gallardo, E, Paré, L, Baiget, M, Páez, D, López-Fernández, L A, Cortejoso, L, García, M I, Bujanda, L, González, D, Gonzalo, V, Rodrigo, L, Reñé, J M, Jover, R, Brea-Fernández, A, Andreu, M, Bessa, X, Llor, X, Xicola, R, Palles, C, Tomlinson, I, Castellví-Bel, S, Castells, A, Ruiz-Ponte, C, and Carracedo, A

Published
2013
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6. COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study

Author

Lee, LY, Cazier, J-B, Angelis, V, Arnold, R, Bisht, V, Campton, NA, Chackathayil, J, Cheng, VW, Curley, HM, Fittall, MW, Freeman-Mills, L, Gennatas, S, Goel, A, Hartley, S, Hughes, DJ, Kerr, D, Lee, AJ, Lee, RJ, McGrath, SE, Middleton, CP, Murugaesu, N, Newsom-Davis, T, Okines, AF, Olsson-Brown, AC, Palles, C, Pan, Y, Pettengell, R, Powles, T, Protheroe, EA, Purshouse, K, Sharma-Oates, A, Sivakumar, S, Smith, AJ, Starkey, T, Turnbull, CD, Várnai, C, Yousaf, N, Team, UK Coronavirus Monitoring Project, Kerr, R, and Middleton, G

Subjects
Male, medicine.medical_specialty, Coronavirus Infections/complications, Comorbidity, Disease, 030204 cardiovascular system & hematology, Betacoronavirus, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Risk Factors, Cause of Death, Internal medicine, Clinical endpoint, Humans, Medicine, Neoplasms/complications, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Pandemics, Aged, Cause of death, Manchester Cancer Research Centre, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Age Factors, Antineoplastic Agents/therapeutic use, Cancer, Odds ratio, General Medicine, Middle Aged, medicine.disease, Female, Observational study, Pneumonia, Viral/complications, business
Abstract

Background Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer. Methods In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission. Findings From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56–10·02]; p Interpretation Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment. Funding University of Birmingham, University of Oxford.

Published
2020
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9. 1703P UK Coronavirus Cancer Monitoring Project (UKCCMP): A national reporting network for real time data of the COVID-19 pandemic

Author

Olsson-Brown, A.C., primary, Hughes, D.J., additional, Purshouse, K., additional, Lee, L., additional, Cheng, V.W., additional, Lee, A.J.X., additional, Protheroe, E., additional, Smith, A., additional, Curley, H., additional, Arnold, R., additional, Cazier, J-B., additional, D'Costa, J., additional, Palles, C., additional, Campton, N., additional, Varnai, C., additional, Sivakumar, S., additional, Kerr, R., additional, and Middleton, G., additional

Published
2020
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11. Association between loss of Y chromosome and poor prognosis in male head and neck squamous cell carcinoma

Author

Hollows, R., Wei, W., Cazier, J.-B., Mehanna, H., Parry, G., Halford, G., and Murray, P.

Subjects
therapeutic resistance, Male, Databases, Factual, Disease-Free Survival, Cohort Studies, Sex Factors, Humans, aneuploidy, In Situ Hybridization, Fluorescence, Aged, Retrospective Studies, Chromosomes, Human, Y, Y chromosome, Squamous Cell Carcinoma of Head and Neck, Original Articles, Middle Aged, Prognosis, Survival Analysis, United States, Up-Regulation, Gene Expression Regulation, Neoplastic, immune system, stomatognathic diseases, Head and Neck Neoplasms, Mutation, Original Article, head and neck cancer, Female
Abstract

Background Head and neck squamous cell carcinoma (HNSCC) is more prevalent in men than women and this disparity cannot be fully explained by known risk factors. Recent studies have shown that loss of Y chromosome (LoY) confers an increased risk of solid cancer and reduces life expectancy in men. Methods Using publicly available data from The Cancer Genome Atlas, we investigated the prevalence of LoY and its association with clinicopathological features in male HNSCC. Results LoY was detectable in around 25% of male HNSCC. Men with human papillomavirus‐negative tumors exhibiting LoY experienced significantly worse overall survival than those with no LoY. Moreover, LoY tumors exhibited overexpression of genes involved in redox processes, including genes previously implicated in resistance to both radiotherapy and cisplatin‐based chemotherapeutics. Conclusion LoY may be an indicator of poor prognosis in male HNSCC that is linked to the overexpression of genes associated with resistance to standard care therapies.

Published
2019

12. The Genetic Population Structure of Robinson Crusoe Island, Chile.

Author

Mountford, HS, Villanueva, P, Fernández, MA, Jara, L, De Barbieri, Z, Carvajal-Carmona, LG, Cazier, J-B, Newbury, DF, Mountford, HS, Villanueva, P, Fernández, MA, Jara, L, De Barbieri, Z, Carvajal-Carmona, LG, Cazier, J-B, and Newbury, DF

Abstract

Studies examining genetic conditions common in Latin America are highly underrepresented in the scientific literature. Understanding of the population structure is limited, particularly Chile, in part due to the lack of available population specific data. An important first-step in elucidating disease mechanisms in Latin America countries is to understand the genetic structure of isolated populations. Robinson Crusoe Island (RCI) is a small land mass off the coast of Chile. The current population of over 900 inhabitants are primarily descended from a small number of founders who colonized the island in the late 1800s. Extensive genealogical records can trace the ancestry of almost the entire population. We perform a comprehensive genetic analysis to investigate the ancestry of the island population, examining ancestral mitochondrial and Y chromosome haplogroups, as well as autosomal admixture. Mitochondrial and Y chromosome haplogroups indicated a substantial European genetic contribution to the current RCI population. Analysis of the mitochondrial haplogroups found in the present-day population revealed that 79.1% of islanders carried European haplogroups, compared to 60.0% of the mainland Chilean controls from Santiago. Both groups showed a substantially lower contribution of indigenous haplogroups than expected. Analysis of the Y chromosome haplogroups also showed predominantly European haplogroups detected in 92.3% of male islanders and 86.7% of mainland Chilean controls. Using the near-complete genealogical data collected from the RCI population, we successfully inferred the ancestral haplogroups of 16/23 founder individuals, revealing genetic ancestry from Northern and Southern Europe. As mitochondrial and Y investigations only provide information for direct maternal and paternal lineages, we expanded this to investigate genetic admixture using the autosomes. Admixture analysis identified substantial indigenous genetic admixture in the RCI population (46.9%)

Published
2020

13. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., McCarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., McGovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., McVean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., McCarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, James, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthias, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Miles, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics Consortium, COLORS in IBD, Oxford IBD cohort study investigators, WGS500 Consortium, INTERVAL Study, Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., Mccarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., Mcgovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., Mcvean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., Mccarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, Jame, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthia, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Mile, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics, Consortium, COLORS in, Ibd, Oxford IBD cohort study, Investigator, Wgs500, Consortium, and Interval, Study

Subjects
Male, Genotype, Colon, Immunology, Mutation, Missense, Genetic Association Studie, Polymorphism, Single Nucleotide, Article, Mice, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Child, Genetic Association Studies, Genes, Modifier, Genome, Animal, Inflammatory Bowel Disease, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases, digestive system diseases, Host-Pathogen Interaction, Mice, Inbred C57BL, Child, Preschool, Host-Pathogen Interactions, NADPH Oxidase 1, Reactive Oxygen Species, Reactive Oxygen Specie, Human
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018

14. Systems genetics of Hepatic Metabolome Reveals Octopamine as a Target for Non-Alcoholic Fatty Liver Disease Treatment

Author

Brial, F., Le Lay, A., Hedjazi, L., Tsang, T., Fearnside, J.F., Otto, G.W., Alzaid, F., Wilder, S.P., Venteclef, N., Cazier, J-B, Nicholson, J.K., Day, C., Burt, A.D., Gut, I.G., Lathrop, M., Dumas, M-E, Gauguier, D., Brial, F., Le Lay, A., Hedjazi, L., Tsang, T., Fearnside, J.F., Otto, G.W., Alzaid, F., Wilder, S.P., Venteclef, N., Cazier, J-B, Nicholson, J.K., Day, C., Burt, A.D., Gut, I.G., Lathrop, M., Dumas, M-E, and Gauguier, D.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. To disentangle etiological relationships between these conditions and identify genetically-determined metabolites involved in NAFLD processes, we mapped 1H nuclear magnetic resonance (NMR) metabolomic and disease-related phenotypes in a mouse F2 cross derived from strains showing resistance (BALB/c) and increased susceptibility (129S6) to these diseases. Quantitative trait locus (QTL) analysis based on single nucleotide polymorphism (SNP) genotypes identified diet responsive QTLs in F2 mice fed control or high fat diet (HFD). In HFD fed F2 mice we mapped on chromosome 18 a QTL regulating liver micro- and macrovesicular steatosis and inflammation, independently from glucose intolerance and adiposity, which was linked to chromosome 4. Linkage analysis of liver metabolomic profiling data identified a QTL for octopamine, which co-localised with the QTL for liver histopathology in the cross. Functional relationship between these two QTLs was validated in vivo in mice chronically treated with octopamine, which exhibited reduction in liver histopathology and metabolic benefits, underlining its role as a mechanistic biomarker of fatty liver with potential therapeutic applications.

Published
2019

15. The evolutionary landscape of colorectal tumorigenesis

Author

Cross, W., Kovac, M., Mustonen, V., Temko, D., Davis, H., Baker, A.-M., Biswas, S., Arnold, R., Chegwidden, L., Gatenbee, C., Anderson, A.R., Koelzer, V.H., Martinez, P., Jiang, X., Domingo, E., Woodcock, D.J., Feng, Y., Kovacova, M., Maughan, T., Adams, R., Bach, S., Beggs, A., Brown, L., Buffa, F., Cazier, J.-B., Blake, A., Wu, C.-H., Chatzpili, E., Richman, S., Dunne, P., Harkin, P., Higgins, G., Hill, J., Holmes, C., Horgan, D., Kaplan, R., Kennedy, R., Lawler, M., Leedham, S., McDermott, U., McKenna, G., Middleton, G., Morton, D., Murray, G., Quirke, P., Salto-Tellez, M., Samuel, L., Schuh, A., Sebag-Montefiore, D., Seymour, M., Sharma, R., Sullivan, R., Tomlinson, I., West, N., Wilson, R., Jansen, M., Rodriguez-Justo, M., Ashraf, S., Guy, R., Cunningham, C., East, J.E., Wedge, D.C., Wang, L.M., Palles, C., Heinimann, K., Sottoriva, A., Graham, T.A., and Tomlinson, I.P.M.

Subjects
0301 basic medicine, Adenoma, Fitness landscape, Carcinogenesis, Evolutionary landscape, Biology, medicine.disease_cause, Models, Biological, Article, Evolution, Molecular, 03 medical and health sciences, medicine, Humans, Stabilizing selection, Ecology, Evolution, Behavior and Systematics, Exome sequencing, Ecology, Manchester Cancer Research Centre, Genetic heterogeneity, ResearchInstitutes_Networks_Beacons/mcrc, Carcinoma, Cancer, medicine.disease, 030104 developmental biology, Evolutionary biology, Mutation, Colorectal Neoplasms
Abstract

The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome/exome sequencing of 24 benign and malignant colorectal tumours, we probe the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations, which are considered to be functionally important in the carcinogenic process, that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a “punctuated” fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilising selection.

Published
2018
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16. Translational study identifies XPF and MUS81 as predictive biomarkers for oxaliplatin-based peri-operative chemotherapy in patients with esophageal adenocarcinoma

Author

MacGregor, T. P., primary, Carter, R., additional, Gillies, R. S., additional, Findlay, J. M., additional, Kartsonaki, C., additional, Castro-Giner, F., additional, Sahgal, N., additional, Wang, L. M., additional, Chetty, R., additional, Maynard, N. D., additional, Cazier, J. B., additional, Buffa, F., additional, McHugh, P. J., additional, Tomlinson, I., additional, Middleton, M. R., additional, and Sharma, R. A., additional

Published
2018
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18. Technical and implementation issues in using next-generation sequencing of cancers in clinical practice

Author

Ulahannan, D, Kovac, M B, Mulholland, P J, Cazier, J-B, and Tomlinson, I

Subjects
Genome, Molecular Diagnostic Techniques, Neoplasms, Mutation, Humans, next-generation sequencing, Minireview, Sequence Analysis, DNA, Precision Medicine, cancer genome analysis
Abstract

Next-generation sequencing (NGS) of cancer genomes promises to revolutionise oncology, with the ability to design and use targeted drugs, to predict outcome and response, and to classify tumours. It is continually becoming cheaper, faster and more reliable, with the capability to identify rare yet clinically important somatic mutations. Technical challenges include sequencing samples of low quality and/or quantity, reliable identification of structural and copy number variation, and assessment of intratumour heterogeneity. Once these problems are overcome, the use of the data to guide clinical decision making is not straightforward, and there is a risk of premature use of molecular changes to guide patient management in the absence of supporting evidence. Paradoxically, NGS may simply move the bottleneck of personalised medicine from data acquisition to the identification of reliable biomarkers. Standardised cancer NGS data collection on an international scale would be a significant step towards optimising patient care.

Published
2016
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20. Correction: Corrigendum: Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

Author

Cazier, J. -B., Rao, S. R., McLean, C. M., Walker, A. K., Wright, B. J., Jaeger, E. E. M., Kartsonaki, C., Marsden, L., Yau, C., Camps, C., Kaisaki, P., Taylor, J., Catto, J. W., Tomlinson, I. P. M., Kiltie, A. E., and Hamdy, F. C.

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, Corrigenda, General Biochemistry, Genetics and Molecular Biology
Published
2014
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21. Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

Author

Cazier, J.-B., Rao, S.R., McLean, C.M., Walker, A.L., Wright, B.J., Jaeger, E.E.M., Kartsonaki, C., Marsden, L., Yau, C., Camps, C., Kaisaki, P., Taylor, J., Catto, J.W., Tomlinson, I.P.M., Kiltie, A.E., and Hamdy, F.C.

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Genome, Base Sequence, Urinary Bladder Neoplasms, Molecular Sequence Data, Mutation, Genetic Variation, Humans, Sequence Analysis, DNA, Neoplasm Grading, Cadherins, Article
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 amplification, 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 diversity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater diversity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression., Bladder cancer is a complex genetic disease and a common cause of death due to malignancy. Here, the authors carry out whole-genome sequencing of 14 bladder cancers to characterize the genomic landscape of the disease and show that mutational burden is associated with tumour progression in these samples.

Published
2014

22. Erratum: Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas (Nature Genetics (2013) 45 (136-144))

Author

Palles, C, Cazier, J-B, Howarth, KM, Domingo, E, Jones, AM, Broderick, P, Kemp, Z, Spain, SL, Almeida, EG, Salguero, I, Sherborne, A, Chubb, D, Carvajal-Carmona, LG, Ma, Y, Kaur, K, Dobbins, S, Barclay, E, Gorman, M, Martin, L, Kovac, MB, Humphray, S, Lucassen, A, Holmes, CC, Bentley, D, Donnelly, P, Taylor, J, Petridis, C, Roylance, R, Sawyer, EJ, Kerr, DJ, Clark, S, Grimes, J, Kearsey, SE, Thomas, HJW, McVean, G, Houlston, RS, and Tomlinson, I

Published
2013

23. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Author

Su, Z., Gay, L.J., Strange, A., Palles, C., Band, G., Whiteman, D.C., Lescai, F., Langford, C., Nanji, M., Edkins, S., van der Winkel, A., Levine, D., Sasieni, P., Bellenguez, C., Howarth, K., Freeman, C., Trudgill, N., Tucker, A.T., Pirinen, M., Peppelenbosch, M.P., van der Laan, L.J.W., Kuipers, E.J., Drenth, J.P.H., Peters, W.H., Reynolds, J.V., Kelleher, D.P., McManus, R., Grabsch, H., Prenen, H., Bisschops, R., Krishnadath, K., Siersema, P.D., van Baal, J.W.P.M., Middleton, M., Petty, R., Gillies, R., Burch, N., Bhandari, P., Paterson, S., Edwards, C., Penman, I., Vaidya, K., Ang, Y., Murray, I., Patel, P., Ye, W., Mullins, P., Wu, A.H., Bird, N.C., Dallal, H., Shaheen, N.J., Murray, L.J., Koss, K., Bernstein, L., Romero, Y., Hardie, L.J., Zhang, R., Winter, H., Corley, D.A., Panter, S., Risch, H.A., Reid, B.J., Sargeant, I., Gammon, M.D., Smart, H., Dhar, A., McMurtry, H., Ali, H., Liu, G., Casson, A.G., Chow, W.-H., Rutter, M., Tawil, A., Morris, D., Nwokolo, C., Isaacs, P., Rodgers, C., Ragunath, K., MacDonald, C., Haigh, C., Monk, D., Davies, G., Wajed, S., Johnston, D., Gibbons, M., Cullen, S., Church, N., Langley, R., Griffin, M., Alderson, D., Deloukas, P., Hunt, S.E., Gray, E., Dronov, S., Potter, S.C., Tashakkori-Ghanbaria, A., Anderson, M., Brooks, C., Blackwell, J.M., Bramon, E., Brown, M.A., Casas, J.P., Corvin, A., Duncanson, A., Markus, H.S., Mathew, C.G., Palmer, C.N.A., Plomin, R., Rautanen, A., Sawcer, S.J., Trembath, R.C., Viswanathan, A.C., Wood, N., Trynka, G., Wijmenga, C., Cazier, J.-B., Atherfold, P., Nicholson, A.M., Gellatly, N.L., Glancy, D., Cooper, S.C., Cunningham, D., Lind, T., Hapeshi, J., Ferry, D., Rathbone, B., Brown, J., Love, S., Attwood, S., MacGregor, S., Watson, P., Sanders, S., Ek, W., Harrison, R.F., Moayyedi, P., de Caestecker, J., Barr, H., Stupka, E., Vaughan, T.L., Peltonen, L., Spencer, C.C.A., Tomlinson, I., Donnelly, P., Jankowski, J.A.Z., Genetics, E.A., and Consor, W.T.C.C.

Subjects
digestive system diseases
Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined = 4.09 × 10−9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13–1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined = 2.74 × 10−10; OR = 1.14, 95% CI = 1.10–1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Published
2012

24. Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders

Author

van Schouwenburg, PA, Davenport, EE, Kienzler, A-K, Marwah, I, Wright, B, Lucas, M, Malinauskas, T, Martin, HC, Lockstone, HE, Cazier, J-B, Chapel, HM, Knight, JC, Patel, SY, van Schouwenburg, PA, Davenport, EE, Kienzler, A-K, Marwah, I, Wright, B, Lucas, M, Malinauskas, T, Martin, HC, Lockstone, HE, Cazier, J-B, Chapel, HM, Knight, JC, and Patel, SY

Abstract

Common Variable Immunodeficiency Disorders (CVIDs) are the most prevalent cause of primary antibody failure. CVIDs are highly variable and a genetic causes have been identified in <5% of patients. Here, we performed whole genome sequencing (WGS) of 34 CVID patients (94% sporadic) and combined them with transcriptomic profiling (RNA-sequencing of B cells) from three patients and three healthy controls. We identified variants in CVID disease genes TNFRSF13B, TNFRSF13C, LRBA and NLRP12 and enrichment of variants in known and novel disease pathways. The pathways identified include B-cell receptor signalling, non-homologous end-joining, regulation of apoptosis, T cell regulation and ICOS signalling. Our data confirm the polygenic nature of CVID and suggest individual-specific aetiologies in many cases. Together our data show that WGS in combination with RNA-sequencing allows for a better understanding of CVIDs and the identification of novel disease associated pathways.

Published
2015

25. Genetic studies of body mass index yield new insights for obesity biology

Author

Locke, A, Kahali, B, Berndt, S, Justice, A, Pers, T, Day, F, Powell, C, Vedantam, S, Buchkovich, M, Yang, J, Croteau-Chonka, D, Esko, T, Fall, T, Ferreira, T, Gustafsson, S, Kutalik, Z, Luan, J, Magi, R, Randall, J, Winkler, T, Wood, A, Workalemahu, T, Faul, J, Smith, J, Zhao, J, Zhao, W, Chen, J, Fehrmann, R, Hedman, A, Karjalainen, J, Schmidt, E, Absher, D, Amin, N, Anderson, D, Beekman, M, Bolton, J, Bragg-Gresham, J, Buyske, S, Demirkan, A, Deng, G, Ehret, G, Feenstra, B, Feitosa, M, Fischer, K, Goel, A, Gong, J, Jackson, A, Kanoni, S, Kleber, M, Kristiansson, K, Lim, U, Lotay, V, Mangino, M, Leach, I, Medina-Gomez, C, Medland, S, Nalls, M, Palmer, C, Pasko, D, Pechlivanis, S, Peters, M, Prokopenko, I, Shungin, D, Stancakova, A, Strawbridge, R, Sung, Y, Tanaka, T, Teumer, A, Trompet, S, van der Laan, S, van Setten, J, Van Vliet-Ostaptchouk, J, Wang, Z, Yengo, L, Zhang, W, Isaacs, A, Albrecht, E, Arnlov, J, Arscott, G, Attwood, A, Bandinelli, S, Barrett, A, Bas, I, Bellis, C, Bennett, A, Berne, C, Blagieva, R, Bluher, M, Bohringer, S, Bonnycastle, L, Bottcher, Y, Boyd, H, Bruinenberg, M, Caspersen, I, Chen, Y, Clarke, R, Daw, E, de Craen, A, Delgado, G, Dimitriou, M, Doney, A, Eklund, N, Estrada, K, Eury, E, Folkersen, L, Fraser, R, Garcia, M, Geller, F, Giedraitis, V, Gigante, B, Go, A, Golay, A, Goodall, A, Gordon, S, Gorski, M, Grabe, H, Grallert, H, Grammer, T, Grassler, J, Gronberg, H, Groves, C, Gusto, G, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hartman, C, Hassinen, M, Hayward, C, Heard-Costa, N, Helmer, Q, Hengstenberg, C, Holmen, O, Hottenga, J, James, A, Jeff, J, Johansson, A, Jolley, J, Juliusdottir, T, Kinnunen, L, Koenig, W, Koskenvuo, M, Kratzer, W, Laitinen, J, Lamina, C, Leander, K, Lee, N, Lichtner, P, Lind, L, Lindstrom, J, Lo, K, Lobbens, S, Lorbeer, R, Lu, Y, Mach, F, Magnusson, P, Mahajan, A, Mcardle, W, Mclachlan, S, Menni, C, Merger, S, Mihailov, E, Milani, L, Moayyeri, A, Monda, K, Morken, M, Mulas, A, Muller, G, Muller-Nurasyid, M, Musk, A, Nagaraja, R, Nothen, M, Nolte, I, Pilz, S, Rayner, N, Renstrom, F, Rettig, R, Ried, J, Ripke, S, Robertson, N, Rose, L, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, F, Scott, W, Seufferlein, T, Shi, J, Smith, A, Smolonska, J, Stanton, A, Steinthorsdottir, V, Stirrups, K, Stringham, H, Sundstrom, J, Swertz, M, Swift, A, Syvanen, A, Tan, S, Tayo, B, Thorand, B, Thorleifsson, G, Tyrer, J, Uh, H, Vandenput, L, Verhulst, F, Vermeulen, S, Verweij, N, Vonk, J, Waite, L, Warren, H, Waterworth, D, Weedon, M, Wilkens, L, Willenborg, C, Wilsgaard, T, Wojczynski, M, Wong, A, Wright, A, Zhang, Q, Brennan, E, Choi, M, Dastani, Z, Drong, A, Eriksson, P, Franco-Cereceda, A, Gadin, J, Gharavi, A, Goddard, M, Handsaker, R, Huang, J, Karpe, F, Kathiresan, S, Keildson, S, Kiryluk, K, Kubo, M, Lee, J, Liang, L, Lifton, R, Ma, B, Mccarroll, S, Mcknight, A, Min, J, Moffatt, M, Montgomery, G, Murabito, J, Nicholson, G, Nyholt, D, Okada, Y, Perry, J, Dorajoo, R, Reinmaa, E, Salem, R, Sandholm, N, Scott, R, Stolk, L, Takahashi, A, Van't Hooft, F, Vinkhuyzen, A, Westra, H, Zheng, W, Zondervan, K, Heath, A, Arveiler, D, Bakker, S, Beilby, J, Bergman, R, Blangero, J, Bovet, P, Campbell, H, Caulfield, M, Cesana, G, Chakravarti, A, Chasman, D, Chines, P, Collins, F, Crawford, D, Cupples, L, Cusi, D, Danesh, J, de Faire, U, Den Ruijter, H, Dominiczak, A, Erbel, R, Erdmann, J, Eriksson, J, Farrall, M, Felix, S, Ferrannini, E, Ferrieres, J, Ford, I, Forouhi, N, Forrester, T, Franco, O, Gansevoort, R, Gejman, P, Gieger, C, Gottesman, O, Gudnason, V, Gyllensten, U, Hall, A, Harris, T, Hattersley, A, Hicks, A, Hindorff, L, Hingorani, A, Hofman, A, Homuth, G, Hovingh, G, Humphries, S, Hunt, S, Hypponen, E, Illig, T, Jacobs, K, Jarvelin, M, Jockel, K, Johansen, B, Jousilahti, P, Jukema, J, Jula, A, Kaprio, J, Kastelein, J, Keinanen-Kiukaanniemi, S, Kiemeney, L, Knekt, P, Kooner, J, Kooperberg, C, Kovacs, P, Kraja, A, Kumari, M, Kuusisto, J, Lakka, T, Langenberg, C, Marchand, L, Lehtimaki, T, Lyssenko, V, Mannisto, S, Marette, A, Matise, T, Mckenzie, C, Mcknight, B, Moll, F, Morris, A, Murray, J, Nelis, M, Ohlsson, C, Oldehinkel, A, Ong, K, Madden, P, Pasterkamp, G, Peden, J, Peters, A, Postma, D, Pramstaller, P, Price, J, Qi, L, Raitakari, O, Rankinen, T, Rao, D, Rice, T, Ridker, P, Rioux, J, Ritchie, M, Rudan, I, Salomaa, V, Samani, N, Saramies, J, Sarzynski, M, Schunkert, H, Schwarz, P, Sever, P, Shuldiner, A, Sinisalo, J, Stolk, R, Strauch, K, Tonjes, A, Tregouet, D, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, M, Volker, U, Waeber, G, Willemsen, G, Witteman, J, Zillikens, M, Adair, L, Amouyel, P, Asselbergs, F, Assimes, T, Bochud, M, Boehm, B, Boerwinkle, E, Bornstein, S, Bottinger, E, Bouchard, C, Cauchi, S, Chambers, J, Chanock, S, Cooper, R, de Bakker, P, Dedoussis, G, Ferrucci, L, Franks, P, Froguel, P, Groop, L, Haiman, C, Hamsten, A, Hui, J, Hunter, D, Hveem, K, Kaplan, R, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, Martin, N, Marz, W, Melbye, M, Metspalu, A, Moebus, S, Munroe, P, Njolstad, I, Oostra, B, Pedersen, N, Perola, M, Perusse, L, Peters, U, Power, C, Quertermous, T, Rauramaa, R, Rivadeneira, F, Saaristo, T, Saleheen, D, Sattar, N, Schadt, E, Schlessinger, D, Slagboom, P, Snieder, H, Spector, T, Thorsteinsdottir, U, Stumvoll, M, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, van der Harst, P, Walker, M, Wallaschofski, H, Wareham, N, Watkins, H, Weir, D, Wichmann, H, Wilson, J, Zanen, P, Borecki, I, Deloukas, P, Fox, C, Heid, I, O'Connell, J, Strachan, D, Stefansson, K, van Duijn, C, Abecasis, G, Franke, L, Frayling, T, Mccarthy, M, Visscher, P, Scherag, A, Willer, C, Boehnke, M, Mohlke, K, Lindgren, C, Beckmann, J, Barroso, I, North, K, Ingelsson, E, Hirschhorn, J, Loos, R, Speliotes, E, Thompson, J, Goldstein, B, Konig, I, Cazier, J, Grundberg, E, Havulinna, A, Ho, W, Hopewell, J, Eriksson, N, Lundmark, P, Lyytikainen, L, Rafelt, S, Tikkanen, E, Van Zuydam, N, Voight, B, Ziegler, A, Altshuler, D, Balmforth, A, Braund, P, Burgdorf, C, Claudi-Boehm, S, Cox, D, Do, R, El Mokhtari, N, Fontanillas, P, Hager, J, Han, B, Kang, H, Kessler, T, Knowles, J, Kolovou, G, Langford, C, Lokki, M, Lundmark, A, Meisinger, C, Melander, O, Maouche, S, Nikus, K, Rasheed, A, Rosinger, S, Rubin, D, Rumpf, M, Schafer, A, Sivananthan, M, Song, C, Stewart, A, Thorgeirsson, G, van der Schoot, C, Wagner, P, Wells, G, Wild, P, Tsun-Po, Y, Basart, H, Brambilla, P, Cambien, F, Cupples, A, Dehghan, A, Diemert, P, Epstein, S, Evans, A, Ferrario, M, Gauguier, D, Hazen, S, Holm, H, Iribarren, C, Jang, Y, Kahonen, M, Kee, F, Kim, H, Klopp, N, Kuulasmaa, K, Laaksonen, R, Ouwehand, W, Parish, S, Park, J, Rader, D, Shah, S, Stark, K, Wallentin, L, Zimmermann, M, Nieminen, M, Sandhu, M, Pastinen, T, Zalloua, P, Siegbahn, A, Schreiber, S, Ripatti, S, Blankenberg, S, O'Donnell, C, Reilly, M, Collins, R, Roberts, R, Pattaro, C, Kottgen, A, Garnaas, M, Boger, C, Fuchsberger, C, Olden, M, Chen, M, Tin, A, Taliun, D, Li, M, Gao, X, Yang, Q, Hundertmark, C, Foster, M, O'Seaghdha, C, Glazer, N, Liu, C, Struchalin, M, Li, G, Johnson, A, Gierman, H, Hwang, S, Atkinson, E, Lohman, K, Cornelis, M, Chouraki, V, Holliday, E, Sorice, R, Deshmukh, H, Ulivi, S, Chu, A, Murgia, F, Imboden, M, Kollerits, B, Pistis, G, Launer, L, Aspelund, T, Eiriksdottir, G, Mitchell, B, Schmidt, H, Cavalieri, M, Rao, M, Hu, F, de Andrade, M, Turner, S, Ding, J, Andrews, J, Freedman, B, Doring, A, Kolcic, I, Zemunik, T, Boban, M, Minelli, C, Wheeler, H, Igl, W, Zaboli, G, Wild, S, Ellinghaus, D, Nothlings, U, Jacobs, G, Biffar, R, Endlich, K, Ernst, F, Kroemer, H, Nauck, M, Stracke, S, Volzke, H, Aulchenko, Y, Polasek, O, Hastie, N, Vitart, V, Helmer, C, Wang, J, Ruggiero, D, Bergmann, S, Viikari, J, Nikopensius, T, Province, M, Ketkar, S, Colhoun, H, Robino, A, Giulianini, F, Kramer, B, Portas, L, Buckley, B, Adam, M, Thun, G, Paulweber, B, Haun, M, Sala, C, Metzger, M, Mitchell, P, Ciullo, M, Kim, S, Vollenweider, P, Gasparini, P, Pirastu, M, Probst-Hensch, N, Kronenberg, F, Toniolo, D, Coresh, J, Schmidt, R, Siscovick, D, Kardia, S, Curhan, G, Franke, A, Parsa, A, Goessling, W, Kao, W, de Boer, I, Peralta, C, Akylbekova, E, Kramer, H, Arking, D, Franceschini, N, Egan, J, Hernandez, D, Townsend, R, Lumley, T, Psaty, B, Kestenbaum, B, Haritunians, T, Mooser, V, Florez, J, Meigs, J, Lu, X, Leak, T, Aasarod, K, Skorpen, F, Baumert, J, Devuyst, O, Mychaleckyj, J, Kedenko, L, Coassin, S, Hallan, S, Navis, G, Shlipak, M, Bull, S, Paterson, A, Rotter, J, Dreisbach, A, Anderson, C, Guo, Q, Henders, A, Lambert, A, Lee, S, Kraft, P, Kennedy, S, Macgregor, S, Missmer, S, Painter, J, Roseman, F, Treloar, S, Wallace, L, Forsblom, C, Isakova, T, Mckay, G, Williams, W, Sadlier, D, Makinen, V, Swan, E, Boright, A, Ahlqvist, E, Keller, B, Huang, H, Ahola, A, Fagerholm, E, Gordin, D, Harjutsalo, V, He, B, Heikkila, O, Hietala, K, Kyto, J, Lahermo, P, Lehto, M, Osterholm, A, Parkkonen, M, Pitkaniemi, J, Rosengard-Barlund, M, Saraheimo, M, Sarti, C, Soderlund, J, Soro-Paavonen, A, Syreeni, A, Thorn, L, Tikkanen, H, Tolonen, N, Tryggvason, K, Waden, J, Gill, G, Prior, S, Guiducci, C, Mirel, D, Taylor, A, Hosseini, M, Parving, H, Rossing, P, Tarnow, L, Ladenvall, C, Alhenc-Gelas, F, Lefebvre, P, Rigalleau, V, Roussel, R, Maestroni, A, Maestroni, S, Falhammar, H, Gu, T, Mollsten, A, Cimponeriu, D, Mihai, I, Mota, M, Mota, E, Serafinceanu, C, Stavarachi, M, Hanson, R, Nelson, R, Kretzler, M, Panduru, N, Gu, H, Brismar, K, Zerbini, G, Hadjadj, S, Marre, M, Lajer, M, Waggott, D, Savage, D, Bain, S, Martin, F, Godson, C, Groop, P, Maxwell, A, Sengupta, S, Peloso, G, Ganna, A, Mora, S, Chang, H, Den Hertog, H, Donnelly, L, Freitag, D, Gurdasani, D, Heikkila, K, Johnson, T, Kaakinen, M, Kettunen, J, Li, X, Montasser, M, Petersen, A, Saxena, R, Service, S, Sidore, C, Surakka, I, Teslovich, T, Van den Herik, E, Volcik, K, Wu, Y, Asiki, G, Been, L, Burnett, M, Elliott, P, Eyjolfsson, G, Goodarzi, M, Gravito, M, Hartikainen, A, Hung, Y, Jones, M, Kaleebu, P, Khaw, K, Kim, E, Komulainen, P, Lin, S, Narisu, N, Nieminen, T, Nsubuga, R, Olafsson, I, Palotie, A, Papamarkou, T, Pomilla, C, Pouta, A, Ruokonen, A, Seeley, J, Silander, K, Tiret, L, van Pelt, L, Wainwright, N, Wijmenga, C, Young, E, Bennett, F, Boomsma, D, Burnier, M, Feranil, A, Freimer, N, Hsiung, C, Kesaniemi, A, Koudstaal, P, Krauss, R, Kyvik, K, Meneton, P, Moilanen, L, Sanghera, D, Sheu, W, Whitfield, J, Wolffenbuttel, B, Ordovas, J, Rich, S, Johnson, L, Larson, M, Levy, D, Newton-Cheh, C, O'Reilly, P, Palmas, W, Rice, K, Snider, H, Tobin, M, Verwoert, G, Pihur, V, Heath, S, Sober, S, Arora, P, Zhang, F, Lucas, G, Milaneschi, Y, Parker, A, Fava, C, Fox, E, Go, M, Sjogren, M, Vinay, D, Alexander, M, Tabara, Y, Shaw-Hawkins, S, Whincup, P, Shi, G, Seielstad, M, Sim, X, Nguyen, K, Matullo, G, Gaunt, T, Onland-Moret, N, Cooper, M, Platou, C, Org, E, Hardy, R, Dahgam, S, Palmen, J, Kuznetsova, T, Uiterwaal, C, Adeyemo, A, Ludwig, B, Tomaszewski, M, Tzoulaki, I, Palmer, N, Chang, Y, Steinle, N, Grobbee, D, Morrison, A, Najjar, S, Hadley, D, Brown, M, Connell, J, Day, I, Lawlor, D, Lawrence, R, Ongen, H, Li, Y, Young, J, Bis, J, Chaturvedi, N, Islam, M, Jafar, T, Kulkarni, S, Howard, P, Guarrera, S, Ricceri, F, Emilsson, V, Plump, A, Weder, A, Sun, Y, Scott, L, Peltonen, L, Vartiainen, E, Brand, S, Staessen, J, Wang, T, Burton, P, Artigas, M, Dong, Y, Wang, X, Zhu, H, Rudock, M, Heckbert, S, Smith, N, Wiggins, K, Doumatey, A, Shriner, D, Veldre, G, Viigimaa, M, Kinra, S, Prabhakaran, D, Tripathy, V, Langefeld, C, Rosengren, A, Thelle, D, Corsi, A, Singleton, A, Hilton, G, Salako, T, Iwai, N, Kita, Y, Ogihara, T, Ohkubo, T, Okamura, T, Ueshima, H, Umemura, S, Eyheramendy, S, Meitinger, T, Cho, Y, Scott, J, Sehmi, J, Hedblad, B, Nilsson, P, Smith, G, Raffel, L, Yao, J, Schwartz, S, Ikram, M, W, L, Mosley, T, Seshadri, S, Shrine, N, Wain, L, Zitting, P, Cooper, J, van Gilst, W, Janipalli, C, Mani, K, Yajnik, C, Mattace-Raso, F, 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A., Freitag D. F., Gurdasani D., Heikkila K., Johnson T., Kaakinen M., Kettunen J., Li X., Montasser M. E., Petersen A. K., Saxena R., Service S. K., Sidore C., Surakka I., Teslovich T. M., Van den Herik E. G., Volcik K. A., Wu Y., Asiki G., Been L. F., Burnett M. S., Elliott P., Eyjolfsson G. I., Goodarzi M. O., Gravito M. L., Hartikainen A. L., Hung Y. J., Jones M. R., Kaleebu P., Khaw K. T., Kim E., Komulainen P., Lin S. Y., Narisu N., Nieminen T. V., Nsubuga R. N., Olafsson I., Palotie A., Papamarkou T., Pomilla C., Pouta A., Ruokonen A., Seeley J., Silander K., Tiret L., van Pelt L., Wainwright N., Wijmenga C., Young E. H., Bennett F., Boomsma D. I., Burnier M., Chen Y. D., Feranil A. B., Freimer N. B., Hsiung C. A., Kesaniemi A., Koudstaal P. J., Krauss R. M., Kyvik K. O., Meneton P., Moilanen L., Sanghera D. K., Sheu W. H., Whitfield J. B., Wolffenbuttel B. H., Ordovas J. M., Rich S. S., Johnson A., Johnson L., Larson M., Levy D., Newton-Cheh C., O'reilly P., Palmas W., Rice K., Smith A., Snider H., Tobin M., Verwoert G., Rice K. M., Verwoert G. C., Pihur V., Heath S., Sober S., Arora P., Zhang F., Lucas G., Milaneschi Y., Parker A. N., Fava C., Fox E. R., Go M. J., Sjogren M., Vinay D., Alexander M., Tabara Y., Shaw-Hawkins S., Whincup P. H., Shi G., Seielstad M., Sim X., Nguyen K. D., Matullo G., Gaunt T. R., Onland-Moret N. C., Cooper M. N., Platou C. G., Org E., Hardy R., Dahgam S., Palmen J., Kuznetsova T., Uiterwaal C. S., Adeyemo A., Ludwig B., Tomaszewski M., Tzoulaki I., Palmer N. D., Chang Y. P., Steinle N. I., Grobbee D. E., Morrison A. C., Najjar S., Hadley D., Brown M. J., Connell J. M., Day I. N., Lawlor D. A., Lawrence R. W., Ongen H., Li Y., Young J. H., Bis J. C., Bolton J. A., Chaturvedi N., Islam M., Jafar T. H., Kulkarni S. R., Howard P., Guarrera S., Ricceri F., Emilsson V., Plump A., Weder A. B., Sun Y. V., Scott L. J., Peltonen L., Vartiainen E., Brand S. M., Staessen J. A., Wang T. J., Burton P. R., Artigas M. S., Dong Y., Wang X., Zhu H., Rudock M. E., Heckbert S. R., Smith N. L., Wiggins K. L., Doumatey A., Shriner D., Veldre G., Viigimaa M., Kinra S., Prabhakaran D., Tripathy V., Langefeld C. D., Rosengren A., Thelle D. S., Corsi A. M., Singleton A., Hilton G., Salako T., Iwai N., Kita Y., Ogihara T., Ohkubo T., Okamura T., Ueshima H., Umemura S., Eyheramendy S., Meitinger T., Cho Y. S., Kim H. L., Scott J., Sehmi J. S., Hedblad B., Nilsson P., Smith G. D., Raffel L. J., Yao J., Schwartz S. M., Ikram M., W L., Mosley T. H., Seshadri S., Shrine N. R., Wain L. V., Zitting P., Cooper J. A., van Gilst W. H., Janipalli C. S., Mani K., Yajnik C. S., Mattace-Raso F. U., Lakatta E. G., Orru M., Scuteri A., Ala-Korpela M., Kangas A. J., Soininen P., Tukiainen T., Wurtz P., Ong R. T., Dorr M., Galan P., Hercberg S., Lathrop M., Zelenika D., Zhai G., Meschia J. F., Sharma P., Terzic J., Kumar M., Denniff M., Zukowska-Szczechowska E., Wagenknecht L. E., Fowkes F., Charchar F. J., Guo X., Rotimi C., Bots M. L., Brand E., Talmud P. J., Nyberg F., Laan M., Palmer L. J., van der Schouw Y. T., Casas J. P., Vineis P., Ganesh S. K., Wong T. Y., Tai E. S., Morris R. W., Marmot M. G., Miki T., Chandak G. R., Zhu X., Elosua R., Soranzo N., Sijbrands E. J., Uda M., Vasan R. S., Alizadeh B. Z., de Boer R. A., Boezen H. M., Hillege H. L., van der Klauw M. M., Ormel J., Rosmalen J. G., Slaets J. P., Lagou V., Welch R. P., Wheeler E., Rehnberg E., Rasmussen-Torvik L. J., Lecoeur C., Johnson P. C., Sennblad B., Salo P., Timpson N. J., Evans D. M., St Pourcain B., Bielak L. F., Horikoshi M., Navarro P., Raychaudhuri S., Chen H., Rybin D., Willems S. M., Song K., An P., Marullo L., Jansen H., Pankow J. S., Edkins S., Varga T. V., Oksa H., Antonella M., Kong A., Herder C., Antti J., Small K., Miljkovic I., Atalay M., Kiess W., Smit J. H., Campbell S., Fowkes G. R., Rathmann W., Maerz W., Watanabe R. M., de Geus E. J., Penninx B. W., Toenjes A., Peyser P. A., Korner A., Dupuis J., Cucca F., Balkau B., Bouatia-Naji N., Purcell S., Musunuru K., Ardissino D., Mannucci P. M., Anand S., Engert J. C., Morgan T., Spertus J. A., Stoll M., Girelli D., McKeown P. P., Patterson C. C., Merlini P. A., Berzuini C., Bernardinelli L., Peyvandi F., Tubaro M., Celli P., Fetiveau R., Marziliano N., Casari G., Galli M., Ribichini F., Rossi M., Bernardi F., Zonzin P., Piazza A., Yee J., Friedlander Y., Marrugat J., Subirana I., Sala J., Ramos R., Williams G., Nathan D. M., Macrae C. A., Berglund G., Asselta R., Duga S., Spreafico M., Daly M. J., Nemesh J., Korn J. M., Surti A., Gianniny L., Parkin M., Burtt N., Gabriel S. B., Wright B. J., Ball S. G., Schunkert I., Linsel-Nitschke P., Lieb W., Fischer M., Grosshennig A., Preuss M., Scholz M., Chen Z., Wilensky R., Matthai W., Qasim A., Hakonarson H. H., Devaney J., Pichard A. D., Kent K. M., Satler L., Lindsay J. M., Waksman R., Knouff C. W., Scheffold T., Berger K., Huge A., Martinelli N., Olivieri O., Corrocher R., Xie C., Ahmadi K. R., Ainali C., Bataille V., Bell J. T., Buil A., Dermitzakis E. T., Dimas A. S., Durbin R., Glass D., Hassanali N., Ingle C., Knowles D., Krestyaninova M., Lowe C. E., Meduri E., Di Meglio P., Montgomery S. B., Nestle F. O., Nica A. C., Nisbet J., O'rahilly S., Parts L., Potter S., Sekowska M., Shin S. Y., Surdulescu G., Travers M. E., Tsaprouni L., Tsoka S., Wilk A., Yang T. P., Higashio J., Williams R., Nato A., Ambite J. L., Deelman E., Manolio T., Heiss G., Taylor K., Avery C., Graff M., Lin D., Quibrera M., Cochran B., Kao L., Umans J., Cole S., Maccluer J., Person S., Gross M., Fornage M., Durda P., Jenny N., Patsy B., Arnold A., Buzkova P., Haines J., Murdock D., Glenn K., Brown-Gentry K., Thornton-Wells T., Dumitrescu L., Bush W. S., Mitchell S. L., Goodloe R., Wilson S., Boston J., Malinowski J., Restrepo N., Oetjens M., Fowke J., Spencer K., Pendergrass S., Le Marchand L., Park L., Tiirikainen M., Kolonel L., Cheng I., Wang H., Shohet R., Stram D., Henderson B., Monroe K., Anderson G., Carlson C., Prentice R., Lacroix A., Wu C., Carty C., Rosse S., Young A., Kocarnik J., Lin Y., Jackson R., Duggan D., Kuller L., He C., Sulem P., Barbalic M., Broer L., Byrne E. M., Gudbjartsson D. F., McArdle P. F., Porcu E., van Wingerden S. W., Zhuang W. V., Lauc L. B., Broekmans F. J., Burri A., Chen C., Corre T., Coviello A. D., D'adamo P., Davies G., Deary I. J., Ebrahim S., Fauser B. C., Ferreli L., Folsom A. R., Hankinson S. E., Hass M., Janssens A. C., Karasik D., Keyzer J., Kiel D. P., Lahti J., Lai S., Laisk T., Laven J. S., Liu J., Lopez L. M., Louwers Y. V., Marongiu M., Klaric I. M., Masciullo C., Melzer D., Newman A. B., Pare G., Peeters P. H., Pop V. J., Raikkonen K., Salumets A., Stacey S. N., Starr J. M., Stathopoulou M. G., Styrkarsdottir U., Tenesa A., Tryggvadottir L., Tsui K., van Dam R. M., van Gils C. H., van Nierop P., Vink J. M., Voorhuis M., Widen E., Wijnands-Van Gent C. J., Yerges-Armstrong L. M., Zgaga L., Zygmunt M., Buring J. E., Crisponi L., Demerath E. W., Streeten E. A., Murray A., Visser J. A., Lunetta K. L., Elks C. E., Cousminer D. L., Koller D. L., Lin P., Smith E. N., Warrington N. M., Alavere H., Berenson G. S., Blackburn H., Busonero F., Chen W., Couper D., Easton D. F., Eriksson J., Foroud T., Kilpelainen T. O., Li S., Murray S. S., Ness A. R., Northstone K., Peacock M., Pennell C. E., Pharoah P., Rafnar T., Rice J. P., Ring S. M., Schork N. J., Segre A. V., Sovio U., Srinivasan S. R., Tammesoo M. L., van Meurs J. B., Young L., Bierut L. J., and Econs M. J.

Abstract

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10-8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20 % of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Published
2015

26. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer

Author

Houlston, RS, Webb, E, Broderick, P, Pittman, AM, Di Bernardo, MC, Lubbe, S, Chandler, I, Vijayakrishnan, J, Sullivan, K, Penegar, S, Carvajal-Carmona, L, Howarth, K, Jaeger, E, Spain, SL, Walther, A, Barclay, E, Martin, L, Gorman, M, Domingo, E, Teixeira, AS, Kerr, D, Cazier, J-B, Niittymaki, I, Tuupanen, S, Karhu, A, Aaltonen, LA, Tomlinson, IPM, Farrington, SM, Tenesa, A, Prendergast, JGD, Barnetson, RA, Cetnarskyj, R, Porteous, ME, Pharoah, PDP, Koessler, T, Hampe, J, Buch, S, Schafmayer, C, Tepel, J, Schreiber, S, Voelzke, H, Chang-Claude, J, Hoffmeister, M, Brenner, H, Zanke, BW, Montpetit, A, Hudson, TJ, Gallinger, S, Campbell, H, Dunlop, MG, Study, COGENT, Consor, CCAS, Consortium, C, and Assoc, ICCG

Subjects
Male, Colorectal cancer, Single-nucleotide polymorphism, Genome-wide association study, Biology, Genome, Article, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, medicine, Genetics, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Aged, 0303 health sciences, Genome, Human, Case-control study, Middle Aged, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Meta-analysis, Case-Control Studies, Human genome, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.

Published
2008
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27. Choice of transcripts and software has a large effect on variant annotation

Author

McCarthy, DJ, Humburg, P, Kanapin, A, Rivas, MA, Gaulton, K, Cazier, J-B, Donnelly, P, McCarthy, DJ, Humburg, P, Kanapin, A, Rivas, MA, Gaulton, K, Cazier, J-B, and Donnelly, P

Abstract

BACKGROUND: Variant annotation is a crucial step in the analysis of genome sequencing data. Functional annotation results can have a strong influence on the ultimate conclusions of disease studies. Incorrect or incomplete annotations can cause researchers both to overlook potentially disease-relevant DNA variants and to dilute interesting variants in a pool of false positives. Researchers are aware of these issues in general, but the extent of the dependency of final results on the choice of transcripts and software used for annotation has not been quantified in detail. METHODS: This paper quantifies the extent of differences in annotation of 80 million variants from a whole-genome sequencing study. We compare results using the RefSeq and Ensembl transcript sets as the basis for variant annotation with the software Annovar, and also compare the results from two annotation software packages, Annovar and VEP (Ensembl's Variant Effect Predictor), when using Ensembl transcripts. RESULTS: We found only 44% agreement in annotations for putative loss-of-function variants when using the RefSeq and Ensembl transcript sets as the basis for annotation with Annovar. The rate of matching annotations for loss-of-function and nonsynonymous variants combined was 79% and for all exonic variants it was 83%. When comparing results from Annovar and VEP using Ensembl transcripts, matching annotations were seen for only 65% of loss-of-function variants and 87% of all exonic variants, with splicing variants revealed as the category with the greatest discrepancy. Using these comparisons, we characterised the types of apparent errors made by Annovar and VEP and discuss their impact on the analysis of DNA variants in genome sequencing studies. CONCLUSIONS: Variant annotation is not yet a solved problem. Choice of transcript set can have a large effect on the ultimate variant annotations obtained in a whole-genome sequencing study. Choice of annotation software can also have a substantial eff

Published
2014

28. Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden

Author

Cazier, J-B, Rao, SR, McLean, CM, Walker, AL, Wright, BJ, Jaeger, EEM, Kartsonaki, C, Marsden, L, Yau, C, Camps, C, Kaisaki, P, Taylor, J, Catto, JW, Tomlinson, IPM, Kiltie, AE, Hamdy, FC, Cazier, J-B, Rao, SR, McLean, CM, Walker, AL, Wright, BJ, Jaeger, EEM, Kartsonaki, C, Marsden, L, Yau, C, Camps, C, Kaisaki, P, Taylor, J, Catto, JW, Tomlinson, IPM, Kiltie, AE, and Hamdy, FC

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 amplification, 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 diversity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater diversity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression.

Published
2014

29. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis

Author

Martin, HC, Kim, GE, Pagnamenta, AT, Murakami, Y, Carvill, GL, Meyer, E, Copley, RR, Rimmer, A, Barcia, G, Fleming, MR, Kronengold, J, Brown, MR, Hudspith, KA, Broxholme, J, Kanapin, A, Cazier, J-B, Kinoshita, T, Nabbout, R, Bentley, D, McVean, G, Heavin, S, Zaiwalla, Z, McShane, T, Mefford, HC, Shears, D, Stewart, H, Kurian, MA, Scheffer, IE, Blair, E, Donnelly, P, Kaczmarek, LK, Taylor, JC, Martin, HC, Kim, GE, Pagnamenta, AT, Murakami, Y, Carvill, GL, Meyer, E, Copley, RR, Rimmer, A, Barcia, G, Fleming, MR, Kronengold, J, Brown, MR, Hudspith, KA, Broxholme, J, Kanapin, A, Cazier, J-B, Kinoshita, T, Nabbout, R, Bentley, D, McVean, G, Heavin, S, Zaiwalla, Z, McShane, T, Mefford, HC, Shears, D, Stewart, H, Kurian, MA, Scheffer, IE, Blair, E, Donnelly, P, Kaczmarek, LK, and Taylor, JC

Abstract

In severe early-onset epilepsy, precise clinical and molecular genetic diagnosis is complex, as many metabolic and electro-physiological processes have been implicated in disease causation. The clinical phenotypes share many features such as complex seizure types and developmental delay. Molecular diagnosis has historically been confined to sequential testing of candidate genes known to be associated with specific sub-phenotypes, but the diagnostic yield of this approach can be low. We conducted whole-genome sequencing (WGS) on six patients with severe early-onset epilepsy who had previously been refractory to molecular diagnosis, and their parents. Four of these patients had a clinical diagnosis of Ohtahara Syndrome (OS) and two patients had severe non-syndromic early-onset epilepsy (NSEOE). In two OS cases, we found de novo non-synonymous mutations in the genes KCNQ2 and SCN2A. In a third OS case, WGS revealed paternal isodisomy for chromosome 9, leading to identification of the causal homozygous missense variant in KCNT1, which produced a substantial increase in potassium channel current. The fourth OS patient had a recessive mutation in PIGQ that led to exon skipping and defective glycophosphatidyl inositol biosynthesis. The two patients with NSEOE had likely pathogenic de novo mutations in CBL and CSNK1G1, respectively. Mutations in these genes were not found among 500 additional individuals with epilepsy. This work reveals two novel genes for OS, KCNT1 and PIGQ. It also uncovers unexpected genetic mechanisms and emphasizes the power of WGS as a clinical tool for making molecular diagnoses, particularly for highly heterogeneous disorders.

Published
2014

30. NOX1loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, RV, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, CG, Fiedler, K, McCarthy, DJ, Sullivan, PB, Rodrigues, A, Travis, SPL, Moore, C, Sambrook, J, Ouwehand, WH, Roberts, DJ, Danesh, J, Russell, RK, Wilson, DC, Kelsen, JR, Cornall, R, Denson, LA, Kugathasan, S, Knaus, UG, Serra, EG, Anderson, CA, Duerr, RH, McGovern, DPB, Cho, J, Powrie, F, Li, VSW, Muise, AM, and Uhlig, HH

Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivocolonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018
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31. Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

Author

Sengupta, N, Yau, C, Sakthianandeswaren, A, Mouradov, D, Gibbs, P, Suraweera, N, Cazier, J-B, Polanco-Echeverry, G, Ghosh, A, Thaha, M, Ahmed, S, Feakins, R, Propper, D, Dorudi, S, Sieber, O, Silver, A, Lai, C, Sengupta, N, Yau, C, Sakthianandeswaren, A, Mouradov, D, Gibbs, P, Suraweera, N, Cazier, J-B, Polanco-Echeverry, G, Ghosh, A, Thaha, M, Ahmed, S, Feakins, R, Propper, D, Dorudi, S, Sieber, O, Silver, A, and Lai, C

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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 samples. 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. CONCLUSIONS: 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.

Published
2013

32. Multiple segmental uniparental disomy associated with abnormal DNA methylation of imprinted loci in Silver-Russell syndrome

Author

Dias, R.P. (Renuka), Bogdarina, I. (Irina), Cazier, J.-B. (Jean-Baptiste), Buchanan, C. (Charles), Donaldson, M.C. (Magruder), Johnston, L. (Linda), Hokken-Koelega, A.C.S. (Anita), Clark, A.J. (Adrian), Dias, R.P. (Renuka), Bogdarina, I. (Irina), Cazier, J.-B. (Jean-Baptiste), Buchanan, C. (Charles), Donaldson, M.C. (Magruder), Johnston, L. (Linda), Hokken-Koelega, A.C.S. (Anita), and Clark, A.J. (Adrian)

Abstract

Background: Silver-Russell syndrome (SRS; online inheritance in man 180860) is a low-birth-weight syndrome characterized by postnatal growth restriction and variable dysmorphic features. Although maternal uniparental disomy (UPD) of chromosome 7 and hypomethylation of H19 have been reported in up to 50% of all cases, no unifying mechanism is apparent. Subjects and Methods: Ten patients and their parents were studied using the Illumina GoldenGate methylation array and the Illumina 370K HumHap single-nucleotide polymorphism array to identify aberrations in DNA methylation as well as genomic changes including copy number changes and uniparental disomy events. Results: We found evidence of UPD events outside chromosome 7 in all patients. In up to 30% of patients with SRS, DNA methylation changes occur in imprinted gene loci outside 11p15.5 (PEG3, PLAGL1, and GRB10), not previously consistently linked with SRS. Furthermore, hypermethylation of GRB10 was associated with increased mRNA expression. In addition, 20% of patients appear to have DNA methylation abnormalities within multiple loci. Not all the imprinted loci with methylation defects were affected directly by UPD. Conclusions: The association of widespread UPD associated with abnormal methylation and mRNA expression in imprinted genes in SRS is consistent with the concept of UPD as an initial genomic abnormality leading to unstable DNA methylation within the regulatory network of imprinted genes. Furthermore, disruption of any one of these genes may contribute to the heterogeneous clinical spectrum of SRS. Copyright

Published
2012
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33. Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13

Author

Spain, SL, Carvajal-Carmona, LG, Howarth, KM, Jones, AM, Su, Z, Cazier, J-B, Williams, J, Aaltonen, LA, Pharoah, P, Kerr, DJ, Cheadle, J, Li, L, Casey, G, Vodicka, P, Sieber, O, Lipton, L, Gibbs, P, Martin, NG, Montgomery, GW, Young, J, Baird, PN, Morreau, H, van Wezel, T, Ruiz-Ponte, C, Fernandez-Rozadilla, C, Carracedo, A, Castells, A, Castellvi-Bel, S, Dunlop, M, Houlston, RS, Tomlinson, IPM, Spain, SL, Carvajal-Carmona, LG, Howarth, KM, Jones, AM, Su, Z, Cazier, J-B, Williams, J, Aaltonen, LA, Pharoah, P, Kerr, DJ, Cheadle, J, Li, L, Casey, G, Vodicka, P, Sieber, O, Lipton, L, Gibbs, P, Martin, NG, Montgomery, GW, Young, J, Baird, PN, Morreau, H, van Wezel, T, Ruiz-Ponte, C, Fernandez-Rozadilla, C, Carracedo, A, Castells, A, Castellvi-Bel, S, Dunlop, M, Houlston, RS, and Tomlinson, IPM

Abstract

In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases.

Published
2012

34. Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

Author

Dunlop, MG, Dobbins, SE, Farrington, SM, Jones, AM, Palles, C, Whiffin, N, Tenesa, A, Spain, S, Broderick, P, Ooi, L-Y, Domingo, E, Smillie, C, Henrion, M, Frampton, M, Martin, L, Grimes, G, Gorman, M, Semple, C, Ma, YP, Barclay, E, Prendergast, J, Cazier, J-B, Olver, B, Penegar, S, Lubbe, S, Chander, I, Carvajal-Carmona, LG, Ballereau, S, Lloyd, A, Vijayakrishnan, J, Zgaga, L, Rudan, I, Theodoratou, E, Starr, JM, Deary, I, Kirac, I, Kovacevic, D, Aaltonen, LA, Renkonen-Sinisalo, L, Mecklin, J-P, Matsuda, K, Nakamura, Y, Okada, Y, Gallinger, S, Duggan, DJ, Conti, D, Newcomb, P, Hopper, J, Jenkins, MA, Schumacher, F, Casey, G, Easton, D, Shah, M, Pharoah, P, Lindblom, A, Liu, T, Smith, CG, West, H, Cheadle, JP, Midgley, R, Kerr, DJ, Campbell, H, Tomlinson, IP, Houlston, RS, Dunlop, MG, Dobbins, SE, Farrington, SM, Jones, AM, Palles, C, Whiffin, N, Tenesa, A, Spain, S, Broderick, P, Ooi, L-Y, Domingo, E, Smillie, C, Henrion, M, Frampton, M, Martin, L, Grimes, G, Gorman, M, Semple, C, Ma, YP, Barclay, E, Prendergast, J, Cazier, J-B, Olver, B, Penegar, S, Lubbe, S, Chander, I, Carvajal-Carmona, LG, Ballereau, S, Lloyd, A, Vijayakrishnan, J, Zgaga, L, Rudan, I, Theodoratou, E, Starr, JM, Deary, I, Kirac, I, Kovacevic, D, Aaltonen, LA, Renkonen-Sinisalo, L, Mecklin, J-P, Matsuda, K, Nakamura, Y, Okada, Y, Gallinger, S, Duggan, DJ, Conti, D, Newcomb, P, Hopper, J, Jenkins, MA, Schumacher, F, Casey, G, Easton, D, Shah, M, Pharoah, P, Lindblom, A, Liu, T, Smith, CG, West, H, Cheadle, JP, Midgley, R, Kerr, DJ, Campbell, H, Tomlinson, IP, and Houlston, RS

Abstract

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.

Published
2012

35. Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer

Author

Gibson, G, Tomlinson, IPM, Carvajal-Carmona, LG, Dobbins, SE, Tenesa, A, Jones, AM, Howarth, K, Palles, C, Broderick, P, Jaeger, EEM, Farrington, S, Lewis, A, Prendergast, JGD, Pittman, AM, Theodoratou, E, Olver, B, Walker, M, Penegar, S, Barclay, E, Whiffin, N, Martin, L, Ballereau, S, Lloyd, A, Gorman, M, Lubbe, S, Howie, B, Marchini, J, Ruiz-Ponte, C, Fernandez-Rozadilla, C, Castells, A, Carracedo, A, Castellvi-Bel, S, Duggan, D, Conti, D, Cazier, J-B, Campbell, H, Sieber, O, Lipton, L, Gibbs, P, Martin, NG, Montgomery, GW, Young, J, Baird, PN, Gallinger, S, Newcomb, P, Hopper, J, Jenkins, MA, Aaltonen, LA, Kerr, DJ, Cheadle, J, Pharoah, P, Casey, G, Houlston, RS, Dunlop, MG, Gibson, G, Tomlinson, IPM, Carvajal-Carmona, LG, Dobbins, SE, Tenesa, A, Jones, AM, Howarth, K, Palles, C, Broderick, P, Jaeger, EEM, Farrington, S, Lewis, A, Prendergast, JGD, Pittman, AM, Theodoratou, E, Olver, B, Walker, M, Penegar, S, Barclay, E, Whiffin, N, Martin, L, Ballereau, S, Lloyd, A, Gorman, M, Lubbe, S, Howie, B, Marchini, J, Ruiz-Ponte, C, Fernandez-Rozadilla, C, Castells, A, Carracedo, A, Castellvi-Bel, S, Duggan, D, Conti, D, Cazier, J-B, Campbell, H, Sieber, O, Lipton, L, Gibbs, P, Martin, NG, Montgomery, GW, Young, J, Baird, PN, Gallinger, S, Newcomb, P, Hopper, J, Jenkins, MA, Aaltonen, LA, Kerr, DJ, Cheadle, J, Pharoah, P, Casey, G, Houlston, RS, and Dunlop, MG

Abstract

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.

Published
2011

40. Synopses of Research Articles.

Author

Savage, D. F., Egea, P. F., Robles, Colmenares Y., O'Connell III, J. D., Stroud, R. M., Giannetti, A. M., Snow, P. M., Zak, O., Björkman, P. J., Styrkársdóttir, U., Cazier, J-B., Kong, A., Rolfsson, O., Larsen, H., Boutin, P., Dina, C., Vasseur, F., Dubois, S., Corset, L., and Kunwar, P. S.

Subjects
RESEARCH, SCIENTIFIC literature, AQUAPORINS, TRANSFERRIN, OBESITY
Abstract

Presents summaries of several research papers as of December 2003. Details of a study on the atomic structure of aquaporin and a water channel from Escherichia coli, conducted by Robert Stroud and colleagues; Results of research on the structural mechanism of transferrin receptor, conducted by Pamela Bjorkman and colleagues; Research on the genetic factors of obesity. INSETS: Structural Mechanism Shows How Transferrin Receptor Binds ...;GAD2 Identi . ed as Candidate Gene for Obesity;Dose of PTEN Gene Drives Progression of Prostate Cancer.

Published
2003

41. Association of coronary artery disease and chronic kidney disease in Lebanese population

Author

Aline Milane, Khazen, G., Zeineddine, N., Amro, M., Masri, L., Ghassibe-Sabbagh, M., Youhanna, S., Salloum, A. K., Haber, M., Platt, D. E., Cazier, J. -B, Othman, R., Kabbani, S., Sbeite, H., Chami, Y., Chammas, E., El Bayeh, H., Gauguier, D., Abchee, A. B., Zalloua, P., and Barbari, A.

Subjects
Original Article
Abstract

Background: More evidence is emerging on the strong association between chronic kidney disease (CKD) and cardiovascular disease. We assessed the relationship between coronary artery disease (CAD) and renal dysfunction level (RDL) in a group of Lebanese patients. Methods: A total of 1268 patients undergoing cardiac catheterization were sequentially enrolled in a multicenter cross sectional study. Angiograms were reviewed and CAD severity scores (CADSS) were determined. Estimated glomerular filtration rate (eGFR) was calculated and clinical and laboratory data were obtained. CKD was defined as eGFR < 60 ml/min. Logistic regression model was performed using multivariate analysis including all traditional risk factors associated with both diseases. ANOVA and the Tukeytestswere used to compare subgroups of patients and to assess the impact of each disease on the severity of the other. Results: Among the 82% patients who exhibited variable degrees of CAD, 20.6% had an eGFR < 60 ml/min. Logistic regression analysis revealed a bidirectional independent association between CAD and CKD with an OR = 2.01 (P < 0.01) and an OR = 1.99 (P < 0.01) for CAD and CKD frequencies, respectively. We observed a steady increase in the CADSS mean as eGFR declined and a progressive reduction in renal function with the worsening of CAD (P < 0.05). This correlation remained highly significant despite considerable inter-patient variability and was at its highest at the most advanced stages of both diseases. Conclusions: Our results show a strong, independent and graded bidirectional relationship between CAD severity and RDL. We propose to add CAD to the list of risk factors for the development and progression of CKD.

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