Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation

Gayther, Simon A.; Warren, William; Mazoyer, Sylvie; Russell, Paul; Harrington, Patricia; Chiano, Mathias; Seal, Sheila; Hamoudi, Rifat; Rensburg, Elizabeth J. van; Dunning, Alison M.; Love, Richard R.; Evans, D. Gareth; Easton, Doug; Clayton, David; Stratton, Michael R.; Ponder, Bruce A.J.

doi:10.1038/ng1295-428

Cited by 452 publications

(264 citation statements)

References 17 publications

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“…The germ-line mutations in these families have been described previously (Gayther et al, 1995(Gayther et al, , 1997. To control for a potentially biasing e ect of grade, a series of sporadic grade 3 breast tumours, previously characterized by the Breast Cancer Linkage Consortium (1997), was analysed in parallel.…”

Section: Resultsmentioning

confidence: 99%

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

et al. 1998

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The 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 (P50.05). 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 b-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not re¯ect 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 b type II receptor (TGF b 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 BRCA7/7 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.

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Section: Resultsmentioning

confidence: 99%

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

et al. 1998

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“…Germ-line alterations of BRCA1 are more frequently localized in the 3' one-third of the gene (Gayther et al, 1995) and only one case of alteration at the exons 6 and 8 has been reported (The Breast Cancer Information Core). Therefore, in order to amplify BRCA1 transcripts in a large panel of samples, primers were chosen in these two di erent exons together with a chimeric RNA derived from the same sequence but containing an insert of 48 bp, which was used as a competitor (Ribieras et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region

et al. 1998

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Germ-line alterations of BRCA1 are responsible for about 50% of familial breast cancers. Although its biological function (s) has not yet been fully determined, it has been suggested that it may act as a tumor suppressor gene in breast and ovarian cancers. In sporadic breast cancers alterations of BRCA1 have not been detected and in vitro experiments have indicated that BRCA1 negatively regulates cellular proliferation. The present study was designed to identify and quantify, the BRCA1 mRNA levels, in normal and neoplasic human breast tissue. BRCA1 mRNA molecules were quanti®ed using competitive reverse transcriptase PCR assays. DNA methylation patterns of this gene have been analysed by Southern blot experiments using methylation sensitive restriction enzymes. We found that BRCA1 mRNA levels were signi®cantly lower in sporadic breast cancers (37 cases analysed, 24 cases of invasive ductal carcinomas not otherwise speci®ed (NOS), two lobular carcinomas in situ two medullary carcinomas, four invasive lobular carcinomas, two invasive mucinous carcinomas and three invasive ductal carcinomas with predominantly in situ component) compared with normal breast tissues (P=0.0003). This down-regulation of BRCA1 is observed in all histologic types analysed. In invasive ductal carcinomas NOS, this down-regulation does not correlate with any of the prognostic factors studied (tumor size, node status, histologic grade, hormone receptor status). In the samples analysed, alterations of DNA methylation patterns were not dectected in the vicinity of the major transcription start site. These data suggest the involvement of BRCA1 in the carcinogenesis of these histologic types.

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“…The risk of ovarian cancer is increased by 1.9 times for mutations within this region and the risk of breast cancer appears to be decreased (Thompson and Easton, 2001). Among BRCA1 mutation carriers, the relative proportion of ovarian cancer compared with breast cancer seems to be greater for mutations within the 5 0 two-thirds of the gene (Gayther et al, 1995). Allelic variation can explain differences in penetrance among families and among countries.…”

Section: Introductionmentioning

confidence: 99%

Modifiers of risk of hereditary breast cancer

Narod

2006

Oncogene

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Mutations in the BRCA1 and BRCA2 genes confer a high lifetime risk of breast and ovarian cancer. The risk varies from individual to individual, and it appears that the risk has increased in recent generations. These observations imply that non-genetic factors may modify the inherited risk. To date, the factors that appear most strongly to modify the risk include reproductive histories and exogenous hormones. Oral contraceptives are associated with a profound reduction in the risk of ovarian cancer, and with little or no increase in the risk of breast cancer. Other modifying factors include age of menarche, parity, breastfeeding and oophorectomy. The effect of parity is different in BRCA1 and BRCA2 carriers. Multiparity appears to be protective in BRCA1 carriers, but is associated with an increase in risk in BRCA2 carriers. Oophorectomy has been associated with reductions in both the risk of breast and ovarian cancer. Knowledge of these risk factors will be useful for managing risk and for developing prevention strategies.

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Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype–phenotype correlation

Cited by 452 publications

References 17 publications

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region

Modifiers of risk of hereditary breast cancer

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