R Smith

Publications (4)0 Total impact

• Article: A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer

  P. Stephens, S Edkins, H. Davies, C Greenman, C Cox, C Hunter, G Bignell, J. Teague, R Smith, C Stevens, [......], M A Pierotti, B. Teh, S T Yuen, A G Nicholson, S Lakhani, D F Easton, B L Weber, M R Stratton, P A Futreal, R Wooster
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  ABSTRACT: We examined the coding sequence of 518 protein kinases, similar to 1.3 Mb of DNA per sample, in 25 breast cancers. In many tumors, we detected no somatic mutations. But a few had numerous somatic mutations with distinctive patterns indicative of either a mutator phenotype or a past exposure.
• Article: Somatic mutations of the protein kinase gene family in human lung cancer

  H. Davies, C Hunter, R Smith, P. Stephens, C Greenman, G Bignell, B Teague, A Butler, S Edkins, C Stevens, [......], BT Teh, ST Yuen, SR Lakhani, DF Easton, BL Weber, P Goldstraw, AG Nicholson, R Wooster, MR Stratton, PA Futreal
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  ABSTRACT: Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (similar to 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of similar to 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.
• Article: Lung cancer: Intragenic ERBB2 kinase mutations in tumours

  P. Stephens, C Hunter, G Bignell, S Edkins, H. Davies, J. Teague, C Stevens, S. O'Meara, R Smith, A Parker, [......], B. Teh, G. Chenevix-Trench, B L Weber, S T Yuen, G Harris, P Goldstraw, A G Nicholson, P A Futreal, R Wooster, M R Stratton
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  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.
  Stephens, P. and Hunter, C. and Bignell, G. and Edkins, S. and Davies, H. and Teague, J. and Stevens, C. and O'Meara, S. and Smith, R. and Parker, A. and Barthorpe, A. and Blow, M. and Brackenbury, L. and Butler, A. and Clarke, O. and Cole, J. and Dicks, E. and Dike, A. and Drozd, A. and Edwards, K. and Forbes, S. and Foster, R. and Gray, K. and Greenman, C. and Halliday, K. and Hills, K. and Kosmidou, V. and Lugg, R. and Menzies, A. and Perry, J. and Petty, R. and Raine, K. and Ratford, L. and Shepherd, R. and Small, A. and Stephens, Y. and Tofts, C. and Varian, J. and West, S. and Widaa, S. and Yates, A. and Brasseur, F. and Cooper, C.S. and Flanagan, A.M. and Knowles, M. and Leung, S.Y. and Louis, D.N. and Looijenga, L.H.J. and Malkowicz, B. and Pierotti, M.A. and Teh, B. and Chenevix-Trench, G. and Weber, B.L. and Yuen, S.T. and Harris, G. and Goldstraw, P. and Nicholson, A.G. and Futreal, P.A. and Wooster, R. and Stratton, M.R. (2004) Lung cancer: Intragenic ERBB2 kinase mutations in tumours. Nature, 431 (7008). pp. 525-526. ISSN 00280836.
• Article: A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation

  P. S. Tarpey, R. Smith, E. Pleasance, A. Whibley, S. Edkins, C. Hardy, S. O'Meara, C. Latimer, E. Dicks, A. Menzies, [......], M. Field, C. Skinner, R. E. Stevenson, M. Bobrow, G. Turner, C. E. Schwartz, J. Gecz, F. L. Raymond, P. A. Futreal, M. R. Stratton
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  ABSTRACT: Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.
  Nat Genet. 41(5):535-43.