Patterns of somatic mutation in human cancer genomes

Greenman, Christopher; Stephens, Philip J.; Smith, Raffaella; Dalgliesh, Gillian L.; Hunter, Chris; Bignell, Graham R.; Davies, Helen; Teague, Jon W.; Butler, Adam; Stevens, C; Edkins, Sarah; O’Meara, Sarah; Västrik, Imre; Schmidt, Esther; Avis, Tim; Barthorpe, Syd; Bhamra, Gurpreet; Buck, Gemma; Choudhury, Bhudipa; Clements, Jody; Cole, Jennifer; Dicks, Ed; Forbes, Simon; Gray, Kristian; Halliday, Kelly; Harrison, Rachel; Hills, Katy; Hinton, Jon; Jenkinson, Andy; Jones, David R.; Menzies, Andy; Mironenko, Tatiana; Perry, Janet; Raine, Keiran; Richardson, David; Shepherd, Rebecca; Small, Alex; Tofts, Calli; Varian, Jennifer; Webb, Tony; West, Sofie; Widaa, Sara; Yates, Andy; Cahill, Daniel P.; Louis, David N.; Goldstraw, Peter; Nicholson, Andrew G.; Brasseur, Francis; Looijenga, Leendert H. J.; Weber, Barbara; Chiew, Yoke Eng; deFazio, Anna; Greaves, Mel; Green, Anthony; Campbell, Peter J.; Birney, Ewan; Easton, Douglas F.; Chenevix-Trench, Georgia; Tan, Min; Khoo, Sok Kean; Teh, Bin Tean; Yuen, Siu Tsan; Leung, Suet Yi; Wooster, Richard; Futreal, P. Andrew; Stratton, Michael R.

doi:10.1038/nature05610

Cited by 2,805 publications

(2,449 citation statements)

References 35 publications

Supporting

104

Mentioning

2,316

Contrasting

Unclassified

Order By: Relevance

“…Each protein has a ~60 amino-acid Gla domain at its amino terminus, a region rich in glutamic 19 , genuine insights into the biological roles of these receptors were only obtained when mice lacking TYRO3, AXL, MER or GAS6 were generated and analysed [20][21][22][23][24][25] .…”

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

“…In contrast to most other receptor PTKs, expression of the TAMs is substantially upregulated postnatally, and is maintained at relatively high levels in adult tissues. Although cDNAs encoding the TAM receptors have been cloned repeatedly from tumour cells, and TAM receptors, particularly AXL, have been implicated in cancer progression 19 , genuine insights into the biological roles of these receptors were only obtained when mice lacking TYRO3, AXL, MER or GAS6 were generated and analysed [20][21][22][23][24][25] .…”

Section: Biological Roles Of Tam Signallingmentioning

confidence: 99%

“…In addition to the roles discussed in this Review, TAM receptor signalling has been shown have important regulatory roles in vascular smooth-muscle homeostasis [92][93][94] , in platelet function and thrombus stabilization 23,95,96 , in erythropoiesis 97 and in cancer development and progression 19,98,99 . TAM receptors are also implicated in the regulation of osteoclast function 100,101 , in the control of oligodendrocyte cell survival 102,103 , and in the infection of dendritic cells and other cells by Ebola and Marburg viruses 104,105 .…”

Section: Box 1 | Tam Receptor Signalling In Other Tissues and Organsmentioning

confidence: 99%

See 2 more Smart Citations

Immunobiology of the TAM receptors

2008

View full text Add to dashboard Cite

Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

show abstract

Section: Tam Receptors and Ligandsmentioning

confidence: 99%

Section: Biological Roles Of Tam Signallingmentioning

confidence: 99%

Section: Box 1 | Tam Receptor Signalling In Other Tissues and Organsmentioning

confidence: 99%

See 1 more Smart Citation

Immunobiology of the TAM receptors

2008

View full text Add to dashboard Cite

show abstract

“…Since 2002, the number of recognized cancer genes has grown from 115 to 457[94]. Multiple international efforts, including the Cancer Genomes Project[95], the Cancer Genome Atlas[96] and the International Cancer Genome Consortium[97], have set out to uncover new driver mutations and survey the association between mutated genes and drug efficacy.…”

Section: Mps Applications In Mutation Analysismentioning

confidence: 99%

“…In an attempt to identify both somatic and germline mutations in protein coding genes, and thereby discover new oncogenes and tumor suppressor genes, genome resequencing projects have targeted the exome[100], the transcriptome[101] and even the complete genomes of tumor and matched normal tissues[102]. Although some of the early data was generated using capillary sequencing[95], the majority of cancer sequencing projects have relied on MPS[102]. …”

Section: Mps Applications In Mutation Analysismentioning

confidence: 99%

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

Gundry

Vijg

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

View full text Add to dashboard Cite

DNA mutations are the source of genetic variation within populations. The majority of mutations with observable effects are deleterious. In humans mutations in the germ line can cause genetic disease. In somatic cells multiple rounds of mutations and selection lead to cancer. The study of genetic variation has progressed rapidly since the completion of the draft sequence of the human genome. Recent advances in sequencing technology, most importantly the introduction of massively parallel sequencing (MPS), have resulted in more than a hundred-fold reduction in the time and cost required for sequencing nucleic acids. These improvements have greatly expanded the use of sequencing as a practical tool for mutation analysis. While in the past the high cost of sequencing limited mutation analysis to selectable markers or small forward mutation targets assumed to be representative for the genome overall, current platforms allow whole genome sequencing for less than $5,000. This has already given rise to direct estimates of germline mutation rates in multiple organisms including humans by comparing whole genome sequences between parents and offspring. Here we present a brief history of the field of mutation research, with a focus on classical tools for the measurement of mutation rates. We then review MPS, how it is currently applied and the new insight into human and animal mutation frequencies and spectra that has been obtained from whole genome sequencing. While great progress has been made, we note that the single most important limitation of current MPS approaches for mutation analysis is the inability to address low-abundance mutations that turn somatic tissues into mosaics of cells. Such mutations are at the basis of intra-tumor heterogeneity, with important implications for clinical diagnosis, and could also contribute to somatic diseases other than cancer, including aging. Some possible approaches to gain access to low-abundance mutations are discussed, with a brief overview of new sequencing platforms that are currently waiting in the wings to advance this exploding field even further.

show abstract

Cutaneous Toxic Effects Associated With Vemurafenib and Inhibition of the BRAF Pathway

Huang¹,

Hepper²,

Anadkat³

et al. 2012

Arch Dermatol

View full text Add to dashboard Cite

Background: The development of a novel BRAF inhibitor, vemurafenib, has been associated with impressive tumor regression in patients with BRAF-positive stage IV melanoma. In the phase 3 clinical trials, dermatologic toxic effects associated with vemurafenib were described, namely, the development of eruptive squamous cell carcinomas. Herein, 3 cases are presented that highlight the development of squamous cell carcinomas and other cutaneous sequelae that have not been previously reported and are reminiscent of those observed with administration of the multikinase inhibitor sorafenib tosylate. In addition, the current understanding of the molecular mechanisms underlying these toxic effects is reviewed. Observations: The development of keratosis pilarislike eruptions; seborrheic dermatitis-like rashes; and hy-perkeratotic, tender plantar papules reminiscent of those seen in sorafenib-associated hand-foot skin reaction, as well as squamous cell carcinomas, is presented in association with vemurafenib-based treatment of metastatic melanoma. Conclusions: The development of sorafenib-like cutaneous sequelae (squamous cell carcinomas, keratosis pilaris-like eruptions, seborrheic dermatitis-like rashes, and hand-foot skin reaction) associated with vemurafenib administration suggests that BRAF inhibition alone may be sufficient to induce these changes.

show abstract

Patterns of somatic mutation in human cancer genomes

Cited by 2,805 publications

References 35 publications

Immunobiology of the TAM receptors

Immunobiology of the TAM receptors

Direct mutation analysis by high-throughput sequencing: From germline to low-abundant, somatic variants

Cutaneous Toxic Effects Associated With Vemurafenib and Inhibition of the BRAF Pathway

Contact Info

Product

Resources

About