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; Michlem, Gos; Barfoot, Rita; Hamoudi, Rifat; Patel, Sandeep; Rice, Catherine M.; Biggs, Patrick J.; Hashim, Yasmin; Smith, Amanda; Connor, Frances; Arason, Adelgeir; Guðmundsson, Jūlı́us; Ficenec, D.; Kelsell, David P.; Ford, Deborah; Tonin, Patricia N.; Bishop, D. Timothy; Spurr, Nigel K.; Ponder, Bruce A.J.; Eeles, Rosalind A.; Peto, Julian; Devilee, Peter; Cornelisse, Cees J.; Lynch, Henry T.; Narod, Steven A.; Lenoir, Gilbert; Egilsson, V; Barkadottir, Rosa Bjork; Easton, Douglas F.; Futreal, P. Andrew; Ashworth, Alan; Stratton, Michael R.

doi:10.1038/379749a0

Cited by 484 publications

(551 citation statements)

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“…BRCA1 and BRCA2 are two major early onset breast cancer (BC) and ovarian cancer (OvC) predisposing genes (Miki et al, 1994;Wooster et al, 1995). The penetrance of these genes varies greatly.…”

Section: Introductionmentioning

confidence: 99%

Impact of a paternal origin of germline BRCA1/2 mutations on the age at breast and ovarian cancer diagnosis in a Southern Swedish cohort

Ellberg

Jernström

Broberg

et al. 2014

Genes Chromosomes & Cancer

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Three studies have reported that BRCA1/2 mutations of paternal origin confer an earlier age at breast cancer diagnosis compared with maternal origin. The primary aim of this study was to investigate the impact of parental origin of BRCA1/2 mutations on age at breast and ovarian cancer diagnosis. This study included 577 female BRCA1/2 mutation carriers. All BRCA1/2 mutation carriers belonged to families registered between 1993 and 2011 at the Oncogenetic Clinic at Skånes University Hospital, Lund, Sweden. Cox proportional hazard ratios were used to analyze time to breast or ovarian cancer diagnosis. A novel finding was that carriers of BRCA1 mutations of paternal origin were 4 years older at age of ovarian cancer (P = 0.009) compared with those carrying a BRCA1 mutation of maternal origin. BRCA1 carriers with mutations of paternal origin were 4 years younger at breast cancer diagnosis (P = 0.017) compared with those carrying a BRCA1 mutation of maternal origin, which is in agreement with three previous studies. Both findings were adjusted for of year of inclusion, birth date, and oral contraceptive pill use. No associations between parental origin of BRCA2 mutations and time to breast or ovarian cancer diagnosis were found. An attempt to handle a potential selection bias regarding use of oral contraceptives was made using multiple imputations by chained equations. The observed age difference may allow a greater understanding of mechanisms associated with the differences in cancer penetrance in BRCA1/2 mutation carriers, some of which may depend on paternal origin.

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Section: Introductionmentioning

confidence: 99%

Impact of a paternal origin of germline BRCA1/2 mutations on the age at breast and ovarian cancer diagnosis in a Southern Swedish cohort

Ellberg

Jernström

Broberg

et al. 2014

Genes Chromosomes & Cancer

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“…Germ-line mutations in the BRCA2 gene are associated with hereditary breast cancer in humans (Wooster et al, 1995;Scully and Livingston, 2000). Although accumulated data suggest that the Brca2 protein plays a role in the control of genome stability, its exact function remains unclear (Jasin, 2002;West, 2003).…”

Section: Introductionmentioning

confidence: 99%

Brca2 is involved in meiosis in Arabidopsis thaliana as suggested by its interaction with Dmc1

Siaud¹,

Dray²,

Gy³

et al. 2004

EMBO J

159

193

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Two BRCA2-like sequences are present in the Arabidopsis genome. Both genes are expressed in flower buds and encode nearly identical proteins, which contain four BRC motifs. In a yeast two-hybrid assay, the Arabidopsis Brca2 proteins interact with Rad51 and Dmc1. RNAi constructs aimed at silencing the BRCA2 genes at meiosis triggered a reproducible sterility phenotype, which was associated with dramatic meiosis alterations. We obtained the same phenotype upon introduction of RNAi constructs aimed at silencing the RAD51 gene at meiosis in dmc1 mutant plants. The meiotic figures we observed strongly suggest that homologous recombination is highly disturbed in these meiotic cells, leaving aberrant recombination events to repair the meiotic double-strand breaks. The ‘brca2' meiotic phenotype was eliminated in spo11 mutant plants. Our experiments point to an essential role of Brca2 at meiosis in Arabidopsis. We also propose a role for Rad51 in the dmc1 context

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“…To our knowledge, only one segregation analysis was carried out in African-American women that showed evidence for the segregation of a recessive major gene (MG) [Amos et al, 1991]. The identification of two breast cancer genes, BRCA1 and BRCA2 [Miki et al, 1994;Wooster et al, 1995], has led to an extensive search for mutations worldwide. BRCA1 mutations appeared to be less common among African-American than among white patients with BC [Newman et al, 1998].…”

Section: Introductionmentioning

confidence: 99%

Interactions between genetic and reproductive factors in breast cancer risk in a population‐based sample of African‐American families

Chaudru¹,

Laing²,

Dunston³

et al. 2002

Genetic Epidemiology

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Incidence of breast cancer (BC) varies among ethnic groups, with higher rates in white than in African-American women. Until now, most epidemiological and genetic studies have been carried out in white women. To investigate whether interactions between genetic and reproductive risk factors may explain part of the ethnic disparity in BC incidence, a genetic epidemiology study was conducted, between 1989 and 1994, at the Howard University Cancer Center (Washington, DC), which led to the recruitment of 245 AfricanAmerican families. Segregation analysis of BC was performed by use of the class D regressive logistic model that allows for censored data to account for a variable age of onset of disease, as implemented in the REGRESS program. Segregation analysis of BC was consistent with a putative dominant gene effect (P < 0.000001) and residual sister-dependence (P < 0.0001). This putative gene was found to interact significantly with age at menarche (P = 0.048), and an interaction with a history of spontaneous abortions was suggested (P = 0.08). A late age at menarche increased BC risk in gene carriers but had a protective effect in non-gene carriers. A history of spontaneous abortions had a protective effect in gene carriers and increased BC risk in non-gene carriers. Our findings agree partially with a similar analysis of French families showing a significant gene × parity interaction and a suggestive gene ×

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Identification of the breast cancer susceptibility gene BRCA2

Cited by 484 publications

References 0 publications

Impact of a paternal origin of germline BRCA1/2 mutations on the age at breast and ovarian cancer diagnosis in a Southern Swedish cohort

Impact of a paternal origin of germline BRCA1/2 mutations on the age at breast and ovarian cancer diagnosis in a Southern Swedish cohort

Brca2 is involved in meiosis in Arabidopsis thaliana as suggested by its interaction with Dmc1

Interactions between genetic and reproductive factors in breast cancer risk in a population‐based sample of African‐American families

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