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Genome instability

About: Genome instability is a research topic. Over the lifetime, 6897 publications have been published within this topic receiving 394659 citations. The topic is also known as: genetic instability & genomic instability.


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Journal ArticleDOI
14 Apr 2005-Nature
TL;DR: It is shown that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions commonly express markers of an activated DNA damage response.
Abstract: During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.

2,641 citations

Journal ArticleDOI
23 Jan 2014-Nature
TL;DR: It is found that large-scale genomic analysis can identify nearly all known cancer genes in these cancer types and 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis.
Abstract: Although a few cancer genes are mutated in a high proportion of tumours of a given type (.20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600– 5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics. Comprehensive knowledge of the genes underlying human cancers is a critical foundation for cancer diagnostics, therapeutics, clinical-trial design and selection of rational combination therapies. It is now possible to use genomic analysis to identify cancer genes in an unbiased fashion, based on the presence of somatic mutations at a rate significantly higher than the expected background level. Systematic studies have revealed many new cancer genes, as well as new classes of cancer genes 1,2 . They have also made clear that, although some cancer genes are mutated at high frequencies, most cancer genes in most patients occur at intermediate frequencies (2–20%) or lower. Accordingly, a complete catalogue of mutations in this frequency class will be essential for recognizing dysregulated pathways and optimal targets for therapeutic intervention. However, recent work suggests major gaps in our knowledge of cancer genes of intermediate frequency. For example, a study of 183 lung adenocarcinomas 3 found that 15% of patients lacked even a single mutation affecting any of the 10 known hallmarks of cancer, and 38% had 3 or fewer such mutations. In this paper, we analysed somatic point mutations (substitutions and small insertion and deletions) in nearly 5,000 human cancers and their matched normal-tissue samples (‘tumour–normal pairs’) across 21 tumour types. The questions that we examine here are: first, whether large-scale genomic analysis across tumour types can reliably identify all known cancer genes; second, whether it will reveal many new candidate cancer genes; and third, how far we are from having a complete catalogue of cancer genes (at least those of intermediate frequency). We used rigorous statistical methods to enumerate candidate cancer genes and then carefully inspected each gene to identify those with strong biological connections to cancer and mutational patterns consistent with the expected function. The analysis reveals nearly all known cancer genes and revealed 33 novel candidates, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Importantly, the data show that the

2,565 citations

Journal ArticleDOI
TL;DR: Targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas reveals the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease.

2,082 citations

Journal ArticleDOI
Nicola Waddell1, Marina Pajic2, Ann-Marie Patch3, David K. Chang2, Karin S. Kassahn3, Peter Bailey3, Amber L. Johns2, David Miller3, Katia Nones3, Kelly Quek3, Michael C.J. Quinn3, Alan J. Robertson3, Muhammad Zaki Hidayatullah Fadlullah3, Timothy J. C. Bruxner3, Angelika N. Christ3, Ivon Harliwong3, Senel Idrisoglu3, Suzanne Manning3, Craig Nourse3, Ehsan Nourbakhsh3, Shivangi Wani3, Peter J. Wilson3, Emma Markham3, Nicole Cloonan1, Matthew J. Anderson3, J. Lynn Fink3, Oliver Holmes3, Stephen H. Kazakoff3, Conrad Leonard3, Felicity Newell3, Barsha Poudel3, Sarah Song3, Darrin Taylor3, Nick Waddell3, Scott Wood3, Qinying Xu3, Jianmin Wu2, Mark Pinese2, Mark J. Cowley2, Hong C. Lee2, Marc D. Jones2, Adnan Nagrial2, Jeremy L. Humphris2, Lorraine A. Chantrill2, Venessa T. Chin2, Angela Steinmann2, Amanda Mawson2, Emily S. Humphrey2, Emily K. Colvin2, Angela Chou2, Christopher J. Scarlett2, Andreia V. Pinho2, Marc Giry-Laterriere2, Ilse Rooman2, Jaswinder S. Samra4, James G. Kench2, Jessica A. Pettitt2, Neil D. Merrett5, Christopher W. Toon2, Krishna Epari6, Nam Q. Nguyen7, Andrew Barbour8, Nikolajs Zeps9, Nigel B. Jamieson10, Janet Graham11, Simone P. Niclou, Rolf Bjerkvig12, Robert Grützmann13, Daniela Aust13, Ralph H. Hruban14, Anirban Maitra15, Christine A. Iacobuzio-Donahue16, Christopher L. Wolfgang14, Richard A. Morgan14, Rita T. Lawlor17, Vincenzo Corbo, Claudio Bassi, Massimo Falconi, Giuseppe Zamboni17, Giampaolo Tortora, Margaret A. Tempero18, Anthony J. Gill2, James R. Eshleman14, Christian Pilarsky13, Aldo Scarpa17, Elizabeth A. Musgrove19, John V. Pearson1, Andrew V. Biankin2, Sean M. Grimmond3 
26 Feb 2015-Nature
TL;DR: Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency, and 4 of 5 individuals with these measures of defective DNA maintenance responded to platinum therapy.
Abstract: Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

2,035 citations

Journal ArticleDOI
TL;DR: The mutation patterns of the tumour suppressor TP53, ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogen- induced DNA damage.
Abstract: Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.

1,935 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
2023978
2022735
2021503
2020465
2019420
2018375