Publications (5)0 Total impact
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JG Stone,
G Coleman,
B Gusterson,
A Marossy,
SR Lakhani,
A Ward,
A Nash,
A McKinna,
R A'Hern, MR Stratton,
RS Houlston
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ABSTRACT: Lobular carcinoma in situ (LCIS) is an unusual histological pattern of non-invasive neoplastic disease of the breast occurring predominantly in women aged between 40 and 50 years. LCIS is frequently multicentric and bilateral suggesting a genetic basis to the disease. The high frequency of microsatellite instability in lobular breast cancers, coupled with increased risk of breast cancer associated with germline mismatch repair gene mutations raises the possibility that mutations MSH2 or MLH1 might confer susceptibility to LCIS. To explore this possibility we have examined a series of 71 LCIS patients fur germline MSH2 and MLH1 mutations. No mutations were detected in MSH2, Two sequence variants were identified in MLH1. The first was a CTT --> CAT substitution, codon 607 (exon 16) changing leucine to histidine. The other mutation detected in MLH1 was a TAC --> TAA substitution codon 750 (exon 19) creating a stop codon, predicted to generate a truncated protein, These findings suggest that mutations in MLH1 may underlie a subset of LCIS cases (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
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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.
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