Crook, T.Brooks, L. A.Crossland, S.Osin, P.Barker, K. T.Waller, J.Philp, E.Smith, P. D.Yulug, I.Peto, J.Parker, G.Allday, M. J.Crompton, M. R.Gusterson, B. A.2016-02-082016-02-0819980950-9232http://hdl.handle.net/11693/25402The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P < 0.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16(INK4), Ki-ras and β-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not reflect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF β type II receptor (TGF β IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21(Waf1) was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21(Waf1). These data do not support, therefore, the simple model based on studies of BRCA-/- embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21(Waf1) expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.EnglishBRCA1BRCA2BreastFamilialMutation(s)P53TumourBeta globinBrca1 proteinBrca2 proteinProtein baxProtein p16Protein p21Protein p53Transforming growth factor beta receptorBreast tumorCodonControlled studyHumanHuman tissueMutation rateMutator geneOncogenePriority journalTumor suppressor geneBRCA1 proteinBRCA2 proteinBreast neoplasmsCodonCyclin-Dependent kinase inhibitor p21CyclinsFemaleGene ExpressionHumansMitosisMutationNeoplasm proteinsPhenotypeTranscription factorsTumor suppressor Protein p53Article