Identification of the breast cancer susceptibility gene BRCA2

Wooster, Richard; Bignell, Graham R.; Lancaster, J; Swift, Sally; Seal, Sheila; Mangion, Jonathan; Collins, Nadine; Gregory, Simon; Gumbs, Curtis; Micklem, Gos; Barfoot, Rita; Hamoudi, Rifat; Patel, Sandeep; Rices, Catherine; Biggs, Patrick J.; Hashim, Yasmin; Smith, Amanda D.; Connor, Frances; Arason, Aðalgeir; Guðmundsson, Jūlı́us; Ficenec, D.; Kelsell, David P.; Ford, Deborah; Tonin, Patricia N.; Bishop, D. Timothy; Spurr, Nigel K.; Ponder, Bruce A.J.; Eeles, Rosalind; Peto, Julian; Devilee, Peter; Cornelisse, Cees J.; Lynch, Henry T.; Narod, Steven A.; Lenoir, Gilbert; Egilsson, V; Barkadottir, Rosa Bjork; Easton, Douglas F.; Bentley, David; Futreal, P. Andrew; Ashworth, Alan; Stratton, Michael R.

doi:10.1038/378789a0

Cited by 3,081 publications

(1,495 citation statements)

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“…Familial breast cancer (FBC) includes tumors from patients carrying mutations in the two known breast cancer susceptibility genes: BRCA1 (Miki et al, 1994) and BRCA2 (Wooster et al, 1995). However, most of FBC patients do not carry mutations in these genes, and are known as non-BRCA1/2 or BRCAX cases.…”

Section: Introductionmentioning

confidence: 99%

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

et al. 2007

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Five breast cancer subtypes have been described in sporadic breast cancer (SBC) using expression arrays: basal-like, ERBB2, normal breast-like, luminal A and B. These molecular subtypes show different genomic aberration patterns (GAPs). Recently, our group described these breast cancer subtypes in 50 non-BRCA1/2 familial tumors using immunohistochemistry assays. We extended this study to the other classes of familial breast cancer (FBC), including 62 tumors (18 BRCA1, 16 BRCA2 and 28 non-BRCA1/2), with the same panel of 25 immunohistochemical (IHC) markers and histological grade obtaining a similar classification. We combined these data with results generated by a 1 Mb BAC array-based CGH study to evaluate the genomic aberrations of each group. We found that BRCA1-related tumors are preferentially basal-like, whereas non-BRCA1/2 familial tumors are mainly luminal A subtype. We described distinct GAPs related to each IHC subtype. Basal tumors had a greater number of gains/losses, while luminal B tumors had more high-level DNA amplifications. Our data are similar to those obtained in SBC studies, highlighting the existence of distinct genetic pathways of tumor evolution, common to both SBC and FBC.

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Section: Introductionmentioning

confidence: 99%

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

et al. 2007

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“…In Western Europe and the United States, approximately one in every 12 women develop breast cancer (Wooster et al, 1995). As has been shown for the development of most cancers, breast cancer may arise through a multistep process involving multiple genetic alterations (Christofori and Hanahan, 1994;Devilee and Cornelisse, 1994;Fearon and Vogelstein, 1990).…”

Section: Introductionmentioning

confidence: 99%

Amplification of Ki-ras and elevation of MAP kinase activity during mammary tumor progression in C3(1)/SV40 Tag transgenic mice

et al. 1998

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We have previously documented that transgenic mice expressing SV40 Tag regulated by the rat prostatic steroid-binding protein C3(1) 5'-¯anking region display multistage mammary tumorigenesis. To delineate genetic changes associated with mammary tumor progression, comparative genomic hybridization (CGH) was performed. CGH revealed a consistent gain of the telomeric region of chromosome 6. This region contains the Ki-ras proto-oncogene. Analyses of genomic DNA by Southern blot demonstrated up to 40-fold ampli®cation of the Kiras gene. Ki-ras ampli®cation was detected in 12, 46 and 68% of tumors from 4, 5 and 6 month old mice, respectively, whereas no ampli®cations were found in any preneoplastic mammary tissues. Tumors bearing Ki-ras gene ampli®cation exhibited high levels of Ki-ras RNA and protein. The over-expressed Ki-Ras protein in these tumors appeared functionally active as indicated by the elevated MAP kinase activity. These data demonstrate that while Ki-ras ampli®cation might not be an early event, there is a strong association between Ki-ras ampli®cation and over-expression and mammary tumor progression in this model. This study also shows that CGH is a powerful and useful technique for identifying chromosomal copy number changes during tumor progression, and that this model may provide a predictable in vivo system for studying gene ampli®ca-tion.

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“…Inheritance of mutant alleles of the breast cancer susceptibility genes BRCA1 and BRCA2 confers a substantial risk of developing breast, ovarian and some other cancers (Mikki et al, 1994;Wooster et al, 1995). BRCA1 and BRCA2 have numerous similarities (Zhang et al, 1998).…”

Section: Introductionmentioning

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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Identification of the breast cancer susceptibility gene BRCA2

Cited by 3,081 publications

References 9 publications

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

Amplification of Ki-ras and elevation of MAP kinase activity during mammary tumor progression in C3(1)/SV40 Tag transgenic mice

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

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