The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds

Tavtigian, Sean V.; Simard, Jacques; Rommens, Johanna M.; Couch, Fergus J.; Shattuck-Eidens, Donna; Neuhausen, Susan L.; Merajver, Sofía D.; Thorlacius, Steinunn; Offit, Kenneth; Stoppa‐Lyonnet, Dominique; Bélanger, Carole; Bell, Russell; Berry, Simon; Bogden, Robert; Chen, Q.; Davis, Thaylon; Dumont, Martine; Frye, Cheryl A.; Hattier, Thomas; Jammulapati, Srikanth; Janecki, Teresa; Ping, Jiang; Kehrer, Robert; Leblanc, J F; Mitchell, Jeffrey T.; Mcarthur-Morrison, Jodi; Nguyễn, Kim; Peng, Yi; Samson, C.; Schroeder, Mark E.; Snyder, Sarah C.; Steele, Linda; Stringfellow, Michael; Stroup, C.; Swedlund, Brad; Swense, J.; Teng, David H.‐F.; Thomas, Alun; Tran, Thao; Tranchant, Martine; Weaver-Feldhaus, Jane; Wong, Alexander; Shizuya, Hiroake; Eyfjörd, Jórunn E.; Cannon‐Albright, Lisa A.; Labrie, Fernand; Skolnick, Mark H.; Weber, Barbara; Kamb, Alexander; Goldgar, David E.

doi:10.1038/ng0396-333

Cited by 737 publications

(407 citation statements)

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“…Germline mutations in the breast-cancer susceptibility gene BRCA2 confer susceptibility to familial early-onset breast and ovarian cancers (Wooster et al, 1994(Wooster et al, , 1995Tavtigian et al, 1996;Brody and Biesecker, 1998;Rahman and Stratton, 1998). Extensive studies have indicated that BRCA2 has an important function in DNA repair (Connor et al, 1997;Mizuta et al, 1997;Sharan et al, 1997;Wong et al, 1997;Chen et al, 1998;Patel et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

DSS1 is required for the stability of BRCA2

et al. 2005

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DSS1 is an evolutionarily conserved acidic protein that binds to BRCA2. However, study of the function of DSS1 in mammalian cells has been hampered because endogenous DSS1 has not been detectable by Western blotting. Here, we developed a modified Western blotting protocol that detects endogenous DSS1 protein, and used it to study the function of DSS1 and its interaction with BRCA2 in mammalian cells. We found that essentially all BRCA2 in human cell lines is associated with DSS1. Importantly, we found that RNAi knockdown of DSS1 in human cell lines led to dramatic loss of BRCA2 protein, mainly due to its increased degradation. Furthermore, the stability of BRCA2 mutant devoid of the DSS1-binding domain is unaffected by the depletion of DSS1. Most notably, like BRCA2 depletion, DSS1 depletion also led to hypersensitivity to DNA damage. These results demonstrated that the stability of BRCA2 protein in mammalian cells depends on the presence of DSS1. Deletion or mutation of DSS1 or suppression of its expression by other mechanisms are therefore potential causative mechanisms for human breast and ovarian cancer. Such mechanisms may be relevant to sporadic as well as familiar breast cancer where BRCA1 and BRCA2 mutations are not present.

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Section: Introductionmentioning

confidence: 99%

DSS1 is required for the stability of BRCA2

et al. 2005

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“…Approximately, five to ten percent of all breast and ovarian cancers are due to genetic predisposition with autosomal dominant transmission (Newman et al, 1988;Claus et al, 1991;Schildkraut et al, 1989). Two major breast and ovarian cancer susceptibility genes, BRCA1 (MIM# 113705) and BRCA2 (MIM# 600185), have been identified (Miki et al, 1994;Wooster et al, 1995;Tavtigian et al, 1996). These genes are believed to be tumor suppressors whose function has not yet been completely elucidated.…”

Section: Introductionmentioning

confidence: 99%

Analysis of breast cancer susceptibility genesBRCA1 andBRCA2 in Thai familial and isolated early-onset breast and ovarian cancer

et al. 2002

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Here we report the study on BRCA1 and BRCA2 mutations in 12 Thai breast and/or ovarian cancer families and 6 early-onset breast or breast/ovarian cancer cases without a family history of cancer. Five distinct rare alterations were identified in each gene: four introducing premature stop codons, one in-frame deletion, two missense changes, two intronic alterations and one silent rare variant. The BRCA1 or BRCA2 truncating mutations were detected in four of seven patients with familial or personal history of breast and ovarian cancer, in one of four isolated early onset breast cancer cases and in none of seven breast cancer site specific families. The BRCA1 and BRCA2 mutation yield in Thai patients is consistent with that reported from Europe and North America in similar groups of patients, being particularly high in individuals with personal or family history of breast and ovarian cancer. The BRCA1 and BRCA2 alterations found in this series are different from those identified in other Asian studies, and all but two have never been reported before. We report at least three novel deleterious mutations, the BRCA1 3300delA, BRCA1 744ins20 and BRCA2 6382delT. One in-frame deletion was also found, the BRCA2 5527del9, which seggregated within family members of breast-only cancer patients and was thought to be a cancer-related mutation. BRCA1 3300delA and Asp67Glu alterations were detected each in at least two families and thus could represent founder mutations in Thais.

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“…A series of genes has been identi®ed linking breast cancer with inherited mutations (BRCA1, BRCA2) (Miki et al, 1994;Tavtigian et al, 1996) as well as acquired mutations or gene ampli®cations in a series of oncogenes including HER-2 (Szollosi et al, 1995), ras (Miyakis et al, 1998), and myc (Visscher et al, 1997). These oncogenes encode proteins that induce signals leading to cell transformation and proliferation.…”

Section: Introductionmentioning

confidence: 99%