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Andy Menzies

Bio: Andy Menzies is an academic researcher from Wellcome Trust Sanger Institute. The author has contributed to research in topics: Cancer & Genomics. The author has an hindex of 9, co-authored 10 publications receiving 3908 citations.

Papers
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Journal ArticleDOI
08 Mar 2007-Nature
TL;DR: More than 1,000 somatic mutations found in 274 megabases of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers reveal the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
Abstract: Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.

2,732 citations

Journal ArticleDOI
30 Sep 2004-Nature
TL;DR: The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies as mentioned in this paper.
Abstract: The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations.

761 citations

01 Jan 2009
TL;DR: Seven protocadherin 19 (PCDH19) gene mutations in seven families with EFMR resulted in the introduction of a premature termination codon and two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding.

337 citations

Journal ArticleDOI
Sam Behjati1, Gunes Gundem1, David C. Wedge1, David C. Wedge2, Nicola D. Roberts1, Patrick S. Tarpey1, Susanna L. Cooke1, Peter Van Loo3, Peter Van Loo4, Ludmil B. Alexandrov1, Manasa Ramakrishna1, Helen Davies1, Serena Nik-Zainal1, Claire Hardy1, Calli Latimer1, Keiran Raine1, Lucy Stebbings1, Andy Menzies1, David T. Jones1, Rebecca Shepherd1, Adam Butler1, Jon W. Teague1, Mette Jorgensen5, Bhavisha Khatri6, Nischalan Pillay5, Nischalan Pillay6, Adam Shlien1, P. Andrew Futreal1, P. Andrew Futreal7, Christophe Badie8, Colin Cooper9, Rosalind A. Eeles1, Douglas F. Easton10, Christopher S. Foster11, David E. Neal1, Daniel Brewer9, Freddie C. Hamdy1, Freddie C. Hamdy12, Yong-Jie Lu, Andy G. Lynch, Charlie E. Massi, Anthony C. H. Ng, Hayley C. Whitaker, Yongwei Yu, Hongwei Zhang, Elizabeth Bancroft, Daniel M. Berney, Niedzica Camacho, Cathy Corbishley, Tokhir Dadaev, Nening Dennis, Tim Dudderidge, Sandra L. Edwards, Cyril Fisher, Jilur Ghori, Vincent J. Gnanapragasam, Christopher Greenman, Steve Hawkins, Steven Hazell, William J. Howat, Katalin Karaszi, Jonathan Kay, Zsofia Kote-Jarai, Barbara Kremeyer, Pardeep Kumar, Adam Lambert, Daniel Leongamornlert, Naomi Livni, Hayley J. Luxton, Lucy Matthews, Erik Mayer, Susan Merson, David Nicol, Chris Ogden, Sarah O’Meara, Gill Pelvender, Nimish Shah, Simon Tavaré, Sarah Thomas, Alan J. Thompson, Claire Verrill, Anne Y. Warren, Jorge Zamora, Ultan McDermott1, G. Steven Bova10, Andrea L. Richardson11, Adrienne M. Flanagan5, Adrienne M. Flanagan6, Michael R. Stratton1, Peter J. Campbell12, Peter J. Campbell1 
TL;DR: Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type, and a significant increase in balanced inversions in radiation-associated tumours is observed.
Abstract: Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.

209 citations


Cited by
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Journal ArticleDOI
23 Oct 2008-Nature
TL;DR: The interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated gliobeasts, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
Abstract: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

6,761 citations

Journal ArticleDOI
Michael S. Lawrence1, Petar Stojanov2, Petar Stojanov1, Paz Polak2, Paz Polak3, Paz Polak1, Gregory V. Kryukov1, Gregory V. Kryukov2, Gregory V. Kryukov3, Kristian Cibulskis1, Andrey Sivachenko1, Scott L. Carter1, Chip Stewart1, Craig H. Mermel2, Craig H. Mermel1, Steven A. Roberts4, Adam Kiezun1, Peter S. Hammerman2, Peter S. Hammerman1, Aaron McKenna1, Aaron McKenna5, Yotam Drier, Lihua Zou1, Alex H. Ramos1, Trevor J. Pugh2, Trevor J. Pugh1, Nicolas Stransky1, Elena Helman1, Elena Helman6, Jaegil Kim1, Carrie Sougnez1, Lauren Ambrogio1, Elizabeth Nickerson1, Erica Shefler1, Maria L. Cortes1, Daniel Auclair1, Gordon Saksena1, Douglas Voet1, Michael S. Noble1, Daniel DiCara1, Pei Lin1, Lee Lichtenstein1, David I. Heiman1, Timothy Fennell1, Marcin Imielinski1, Marcin Imielinski2, Bryan Hernandez1, Eran Hodis1, Eran Hodis2, Sylvan C. Baca1, Sylvan C. Baca2, Austin M. Dulak1, Austin M. Dulak2, Jens G. Lohr2, Jens G. Lohr1, Dan A. Landau2, Dan A. Landau1, Dan A. Landau7, Catherine J. Wu2, Jorge Melendez-Zajgla, Alfredo Hidalgo-Miranda, Amnon Koren2, Amnon Koren1, Steven A. McCarroll1, Steven A. McCarroll2, Jaume Mora8, Ryan S. Lee9, Ryan S. Lee2, Brian D. Crompton9, Brian D. Crompton2, Robert C. Onofrio1, Melissa Parkin1, Wendy Winckler1, Kristin G. Ardlie1, Stacey Gabriel1, Charles W. M. Roberts2, Charles W. M. Roberts9, Jaclyn A. Biegel10, Kimberly Stegmaier9, Kimberly Stegmaier1, Kimberly Stegmaier2, Adam J. Bass2, Adam J. Bass1, Levi A. Garraway1, Levi A. Garraway2, Matthew Meyerson2, Matthew Meyerson1, Todd R. Golub, Dmitry A. Gordenin4, Shamil R. Sunyaev2, Shamil R. Sunyaev3, Shamil R. Sunyaev1, Eric S. Lander2, Eric S. Lander6, Eric S. Lander1, Gad Getz2, Gad Getz1 
11 Jul 2013-Nature
TL;DR: A fundamental problem with cancer genome studies is described: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds and the list includes many implausible genes, suggesting extensive false-positive findings that overshadow true driver events.
Abstract: Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.

4,411 citations

Journal ArticleDOI
01 Jan 2014-Nature
TL;DR: In this paper, the authors report molecular profiling of 230 resected lung adnocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

4,104 citations

Journal ArticleDOI
TL;DR: Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients.
Abstract: Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)

3,399 citations

Journal ArticleDOI
TL;DR: Analysis of genomic and clinical outcome data from 218 prostate cancer tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score.

3,310 citations