ORCID Profile
0000-0002-2972-5481
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: Elsevier BV
Date: 08-2016
Publisher: Springer Science and Business Media LLC
Date: 15-02-2023
DOI: 10.1038/S41467-023-36606-W
Abstract: Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1–2% is frequently quoted due to the possibility of parental germline mosaicism but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing in idualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)—that could be quantified in semen for paternal cases (recurrence risks of 5.6–12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-11-2013
Abstract: Harvey rat sarcoma viral oncogene homolog ( HRAS ) occupies an important place in medical history, because it was the first gene in which acquired mutations that led to activation of a normal protein were associated with cancer, making it the prototype of the now canonical oncogene mechanism. Here, we explore what happens when similar HRAS mutations occur in male germ cells, an issue of practical importance because the mutations cause a serious congenital disorder, Costello syndrome, if transmitted to offspring. We provide evidence that the mutant germ cells are positively selected, leading to an increased burden of the mutations as men age. Although there are many parallels between this germline process and classical oncogenesis, there are interesting differences of detail, which are explored in this paper.
Publisher: Elsevier BV
Date: 10-2015
Publisher: Proceedings of the National Academy of Sciences
Date: 08-02-2016
Abstract: A major goal in genetics is to understand the processes that shape the frequency of new mutations, particularly those causing human disease. Here, we focus on specific mutations in the male germline that, although initially rare, confer a growth or survival advantage to the stem cell, leading to clonal expansion over time: a process similar to early tumor growth and currently described only in humans. Previous studies supporting this “selfish” selection quantified mutations in sperm or testis pieces using methods that destroyed their cellular origins. Here, we pinpoint and identify pathogenic mutations directly within in idual seminiferous tubules, the structures that generate spermatozoa. This methodology provides unprecedented precision in documenting the spectrum and prevalence of selfish mutations in men’s testes.
Publisher: Hindawi Limited
Date: 08-02-2011
DOI: 10.1002/HUMU.21457
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 11-07-2014
Publisher: Elsevier BV
Date: 07-2011
Publisher: BMJ
Date: 14-08-2014
Publisher: Oxford University Press (OUP)
Date: 17-01-2013
DOI: 10.1093/HMG/DDT015
Publisher: Public Library of Science (PLoS)
Date: 22-05-2017
Publisher: Elsevier BV
Date: 02-1999
DOI: 10.1086/302245
Publisher: Oxford University Press (OUP)
Date: 11-02-2013
DOI: 10.1093/BRAIN/AWT010
Publisher: Springer Science and Business Media LLC
Date: 27-01-2013
DOI: 10.1038/NG.2531
Publisher: Springer Science and Business Media LLC
Date: 18-05-2201
DOI: 10.1038/NG.3304
Publisher: American Psychiatric Association Publishing
Date: 06-2013
Publisher: Elsevier BV
Date: 09-2015
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2503
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Andrew Wilkie.