Mutation analysis of 24 known cancer genes in the NCI-60 cell line set.
Ogechi Ikediobi,Helen Davies,Graham R. Bignell,Sarah Edkins,Claire Stevens,Sarah O’Meara,Thomas Santarius,Tim Avis,Syd Barthorpe,Lisa Brackenbury,Gemma Buck,Adam Butler,Jody Clements,Jennifer Cole,Ed Dicks,Simon A. Forbes,Kristian Gray,Kelly Halliday,Rachel Harrison,Katy Hills,Jonathan Hinton,Christopher I. Hunter,Andy Jenkinson,David T. Jones,Vivienne Kosmidou,Richard Lugg,Andrew Menzies,Tatiana Mironenko,Adrian Parker,Janet Perry,Keiran Raine,David S. Richardson,Rebecca Shepherd,Alex Small,Raffaella Smith,Helen Solomon,Philip J. Stephens,Jon W. Teague,Calli Tofts,Jennifer Varian,Tony Webb,Sofie West,Sara Widaa,Andrew D. Yates,William C. Reinhold,John N. Weinstein,Michael R. Stratton,P. Andrew Futreal,Richard Wooster +48 more
TLDR
Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCi-60 cell lines for molecularly targeted screens.Abstract:
The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.read more
Citations
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High-throughput oncogene mutation profiling in human cancer
Roman K. Thomas,Alissa C. Baker,Ralph M. Debiasi,Ralph M. Debiasi,Wendy Winckler,Wendy Winckler,Thomas LaFramboise,Thomas LaFramboise,William M. Lin,William M. Lin,Meng Wang,Meng Wang,Whei Feng,Whei Feng,Thomas Zander,Laura E. MacConnaill,Laura E. MacConnaill,Jeffrey C. Lee,Jeffrey C. Lee,Rick Nicoletti,Rick Nicoletti,Charlie Hatton,Charlie Hatton,Mary Goyette,Luc Girard,Kuntal Majmudar,Liuda Ziaugra,Kwok-Kin Wong,Stacey Gabriel,Rameen Beroukhim,Rameen Beroukhim,Michael Peyton,Jordi Barretina,Jordi Barretina,Amit Dutt,Amit Dutt,Caroline Emery,Heidi Greulich,Heidi Greulich,Kinjal Shah,Kinjal Shah,Hidefumi Sasaki,Adi F. Gazdar,John D. Minna,Scott A. Armstrong,Ingo K. Mellinghoff,F. Stephen Hodi,Glenn Dranoff,Paul S. Mischel,Timothy F. Cloughesy,Stan F. Nelson,Linda M. Liau,Kirsten D. Mertz,Kirsten D. Mertz,Mark A. Rubin,Holger Moch,Massimo Loda,William J. Catalona,Jonathan A. Fletcher,Sabina Signoretti,Frederic J. Kaye,Kenneth C. Anderson,George D. Demetri,Reinhard Dummer,Stephan N. Wagner,Meenhard Herlyn,William R. Sellers,William R. Sellers,Matthew Meyerson,Matthew Meyerson,Levi A. Garraway,Levi A. Garraway +71 more
TL;DR: High-throughput genotyping is adapted to query 238 known oncogene mutations across 1,000 human tumor samples and established robust mutation distributions spanning 17 cancer types, offering a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time'.
Journal ArticleDOI
Epigenetic and genetic features of 24 colon cancer cell lines.
Deeqa Ahmed,Peter W. Eide,Ina A. Eilertsen,Stine A. Danielsen,Mette Eknæs,Merete Hektoen,Guro Elisabeth Lind,Guro Elisabeth Lind,Ragnhild A. Lothe,Ragnhild A. Lothe +9 more
TL;DR: Molecular features of a large number of colon cancer cell lines are presented to aid the selection of suitable in vitro models for descriptive and functional research.
Journal ArticleDOI
Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity
Austin M. Dulak,Petar Stojanov,Petar Stojanov,Petar Stojanov,Shouyong Peng,Shouyong Peng,Michael S. Lawrence,Cameron Fox,Chip Stewart,Santhoshi Bandla,Yu Imamura,Steven E. Schumacher,Steven E. Schumacher,Erica Shefler,Aaron McKenna,Scott L. Carter,Kristian Cibulskis,Andrey Sivachenko,Gordon Saksena,Douglas Voet,Alex H. Ramos,Daniel Auclair,Kristin Thompson,Carrie Sougnez,Robert C. Onofrio,Candace Guiducci,Rameen Beroukhim,Zhongren Zhou,Lin Lin,Jules Lin,Rishindra M. Reddy,Andrew C. Chang,Rodney Landrenau,Arjun Pennathur,Shuji Ogino,James D. Luketich,Todd R. Golub,Stacey Gabriel,Eric S. Lander,Eric S. Lander,Eric S. Lander,David G. Beer,Tony E. Godfrey,Gad Getz,Gad Getz,Adam J. Bass +45 more
Abstract: The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ~15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.
Journal ArticleDOI
The genetics of the p53 pathway, apoptosis and cancer therapy
TL;DR: The p53 pathway has been shown to mediate cellular stress responses; p53 can initiate DNA repair, cell-cycle arrest, senescence and, importantly, apoptosis and this work focuses on how best to use knowledge of this pathway to tailor current therapies and develop novel ones.
Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity
Austin M. Dulak,Petar Stojanov,Petar Stojanov,Petar Stojanov,Shouyong Peng,Shouyong Peng,Michael S. Lawrence,Cameron Fox,Chip Stewart,Santhoshi Bandla,Yu Imamura,Steven E. Schumacher,Steven E. Schumacher,Erica Shefler,Aaron McKenna,Scott L. Carter,Kristian Cibulskis,Andrey Sivachenko,Gordon Saksena,Douglas Voet,Alex H. Ramos,Daniel Auclair,Kristin Thompson,Carrie Sougnez,Robert C. Onofrio,Candace Guiducci,Rameen Beroukhim,Zhongren Zhou,Lin Lin,Jules Lin,Rishindra M. Reddy,Andrew C. Chang,Rodney Landrenau,Arjun Pennathur,Shuji Ogino,James D. Luketich,Todd R. Golub,Stacey Gabriel,Eric S. Lander,Eric S. Lander,Eric S. Lander,David G. Beer,Tony E. Godfrey,Gad Getz,Gad Getz,Adam J. Bass +45 more
TL;DR: A mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides is identified and the potential activation of the RAC1 pathway is suggested as a contributor to EAC tumorigenesis.
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TL;DR: Gene-drug relationships for the clinical agents 5-fluorouracil and L-asparaginase exemplify how variations in the transcript levels of particular genes relate to mechanisms of drug sensitivity and resistance.
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