Andrew P Futreal

Publications (5)20.51 Total impact

• Article: CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes.

  Anna Hackett, Patrick S Tarpey, Andrea Licata, James Cox, Annabel Whibley, Jackie Boyle, Carolyn Rogers, John Grigg, Michael Partington, Roger E Stevenson, [......], Gillian Turner, Meredith Wilson, Andrew P Futreal, Mark Corbett, Marie Shaw, Jozef Gecz, F Lucy Raymond, Michael R Stratton, Charles E Schwartz, Fatima E Abidi
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  ABSTRACT: Mutations of the calcium/calmodulin-dependent serine protein kinase (CASK) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.
  European journal of human genetics: EJHG 12/2009; 18(5):544-52. · 3.56 Impact Factor
• Article: In vitro differential sensitivity of melanomas to phenothiazines is based on the presence of codon 600 BRAF mutation.

  Ogechi N Ikediobi, Mark Reimers, Steffen Durinck, Paul E Blower, Andrew P Futreal, Michael R Stratton, John N Weinstein
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  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. We previously sequenced 24 cancer genes in those cell lines. Eleven of the genes were found to be mutated in three or more of the lines. Using a pharmacogenomic approach, we analyzed the relationship between drug activity and mutations in those 11 genes (APC, RB1, KRAS, NRAS, BRAF, PIK3CA, PTEN, STK11, MADH4, TP53, and CDKN2A). That analysis identified an association between mutation in BRAF and the antiproliferative potential of phenothiazine compounds. Phenothiazines have been used as antipsychotics and as adjunct antiemetics during cancer chemotherapy and more recently have been reported to have anticancer properties. However, to date, the anticancer mechanism of action of phenothiazines has not been elucidated. To follow up on the initial pharmacologic observations in the NCI-60 screen, we did pharmacologic experiments on 11 of the NCI-60 cell lines and, prospectively, on an additional 24 lines. The studies provide evidence that BRAF mutation (codon 600) in melanoma as opposed to RAS mutation is predictive of an increase in sensitivity to phenothiazines as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay (Wilcoxon P = 0.007). That pattern of increased sensitivity to phenothiazines based on the presence of codon 600 BRAF mutation may be unique to melanomas, as we do not observe it in a panel of colorectal cancers. The findings reported here have potential implications for the use of phenothiazines in the treatment of V600E BRAF mutant melanoma.
  Molecular Cancer Therapeutics 06/2008; 7(6):1337-46. · 5.23 Impact Factor
• Article: Sequencing analysis of BRAF mutations in human cancers.

  Richard Wooster, Andrew P Futreal, Michael R Stratton
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  ABSTRACT: Cancers arise because of the accumulation of mutations in critical genes that alter normal programs of cell proliferation, differentiation, and death. The RAS-RAF-MEK-ERK-MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in approximately 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. ARAF and c-RAF are infrequently mutated in human cancer. However, BRAF is mutated in a wide range of human cancers. Most mutations are within the kinase domain, with a single amino acid substitution (V600E) accounting for most mutations.
  Methods in Enzymology 02/2006; 407:218-24. · 2.04 Impact Factor
• Source

  Available from: Dafydd Gareth Evans

  Article: Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium.

  Deborah Thompson, Csilla I Szabo, Jon Mangion, Rogier A Oldenburg, Fabrice Odefrey, Sheila Seal, Rita Barfoot, Karin Kroeze-Jansema, Dawn Teare, Nazneen Rahman, [......], Fergus J Couch, Diana M Eccles, D Gareth Evans, Jenny Chang-Claude, Gilbert Lenoir, Barbara L Weber, Peter Devilee, Douglas F Easton, David E Goldgar, Michael R Stratton
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  ABSTRACT: The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate "BRCA3" locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (alpha) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603-9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (alpha = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at alpha = 0.65 was -11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.
  Proceedings of the National Academy of Sciences 02/2002; 99(2):827-31. · 9.68 Impact Factor
• Article: Corrigendum to: CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes

  Anna Hackett, Patrick S Tarpey, Andrea Licata, James Cox, Annabel Whibley, Jackie Boyle, Carolyn Rogers, John Grigg, Michael Partington, Roger E Stevenson, [......], Gillian Turner, Meredith Wilson, Andrew P Futreal, Mark Corbett, Marie Shaw, Jozef Gecz, F Lucy Raymond, Michael R Stratton, Charles E Schwartz, Fatima E Abidi