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Mutations in DNA damage response genes and breast cancer susceptibility
Breast Cancer Research volume 4, Article number: 253 (2002)
The risk of breast cancer is greatly increased in women who carry a mutation in one of the breast cancer susceptibility genes BRCA1 or 2. In the years since these genes were first isolated, evidence of their function in DNA damage responses and the DNA repair mechanism has accumulated. The DNA damage resulting from ionising and UV irradiation activates the ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia- and RAD3-related (ATR) protein kinases, which in turn leads to the phosphorylation of BRCA proteins and other downstream targets such as CHEK2. It is known that the BRCA1 and 2 and CHEK2 gene products are cellular proteins that function to sense DNA damage, and to activate genes that both prevent cell cycle progression and initiate the DNA repair process. Several articles published over the last year have broadened our understanding of this pathway and its relevance to breast cancer risk and development.
BRCA1 and 2 mutations in women at increased risk of cancer are often predicted to lead to truncated proteins lacking the C-terminal region. Recently, the crystal structure of the functionally important BRCA1 C-terminal (BRCT) repeat region has been resolved by Williams and colleagues . The data demonstrate that BRCT repeats within the protein are similar in structure, and pack together in a head to tail alignment. Interestingly, BRCA1 missense mutations that increase susceptibility to breast cancer cluster at the predicted interface between these repeats and destabilise the structure. This supports the functional importance of the BRCT repeat domain in cellular responses to DNA damage and breast cancer susceptibility. Another report by Chiba and Parvin has identified 4 distinct, multi-protein, BRCA1-containing, cellular complexes . These include a complex with RAD50 (a molecule known to be involved in DNA damage response), a complex containing RNA Polymerase II, and a previously uncharacterised complex that forms in response to DNA replication inhibition, and contains the BRCA1-associated RING domain protein BARD1. Evidence continues to emerge of other links between DNA damage response genes, such as BRCA1, and DNA repair (for example, ). BRCA1 can, it turns out, trigger global genome repair independently of p53, and also induce expression of the nucleotide excision repair genes XPC, DDB2 and GADD45.
The search for gene mutations that explain why non-BRCA1/2 families can have high breast cancer penetrance has shown that other known proteins of the DNA damage response pathway are involved. Two papers report preliminary studies which showed that specific mis-sense but not truncating mutations of the ATM gene have dominant negative effects on ATM function and segregate with breast cancer cases in some non-BRCA1/2 families with multiple cases of breast cancer [4, 5]. Two other reports demonstrate that 1100delC, a specific CHEK2 truncating mutation, confers low penetrance susceptibility to breast cancer [6, 7]. The evidence indicates that the 1100delC mutation contributes to familial clustering of breast cancer cases and, in particular, increases the rates of male breast cancer.
Finally, in a landmark publication earlier this year in Nature, van 't Veer and colleagues from the Netherlands Cancer Institute and Rosetta Inpharmatics suggested that breast cancer recurrence could be predicted by a gene expression signature involving as few as 70 genes . The authors also analysed a group of tumours from germ-line BRCA1 mutation carriers and established a molecular signature of 100 genes whose expression levels identifies this group as a distinct subset of breast cancers.
These articles increase our knowledge of which genes function up- or down-stream of BRCA proteins and how mutations in these genes confer breast cancer susceptibility. This improved understanding may help us find novel strategies to prevent breast cancer through recognising those at risk. In addition, the finding that BRCA1 tumours have a specific molecular signature suggests that breast cancers caused by different germ-line gene mutations comprise separate subsets of tumours that can be targeted by specific therapies.
- ATR =:
ataxia-telangiectasia- and RAD3-related
- BRCT =:
- BARD =:
BRCA1-associated RING domain.
Williams RS, Green R, Glover JN: Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1. Nat Struct Biol. 2001, 8: 838-842. 10.1038/nsb1001-838. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr9_02.asp#williams
Chiba N, Parvin JD: Redistribution of BRCA1 among four different protein complexes following replication blockage. J Biol Chem. 2001, 276: 38549-38554. 10.1074/jbc.M105227200. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr9_02.asp#chiba
Hartman AR, Ford JM: BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nat Genet. 2002, 32: 180-184. 10.1038/ng953. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr9_02.asp#hartman
Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, Cummings M, Nyholt D, Jenkins MA, Scott C, Pupo GM, Dörk T, Bendix R, Kirk J, Tucker K, McCredie MR, Hopper JL, Sambrook J, Mann GJ, Khanna KK: Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst. 2002, 94: 205-215. 10.1093/jnci/94.3.205. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr9_02.asp#chenevix-trench
Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF: Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci U S A. 2002, 99: 925-930. 10.1073/pnas.012329699. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr9_02.asp#scott
Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002, 31: 55-59. 10.1038/ng879. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr9_02.asp#meijers-heijboer
Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomaki K, Heikkila P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H: A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002, 71: 432-438. 10.1086/341943. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr9_02.asp#vahteristo
van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsey PS, Bernards R, Friend SH: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002, 415: 530-536. 10.1038/415530a. For the Faculty of 1000 evaluation of this article please see http://breast-cancer-research.com/reports/bcr9_02.asp#Veer
This article is based on papers highlighted by Faculty of 1000 http://www.facultyof1000.com/start.asp a web-based literature awareness service. Faculty of 1000 evaluations available for articles cited in this report may be viewed at: http://breast-cancer-research.com/reports/bcr9_02.asp
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Clarke, R.B. Mutations in DNA damage response genes and breast cancer susceptibility. Breast Cancer Res 4, 253 (2002) doi:10.1186/bcr549
- Breast Cancer
- Breast Cancer Susceptibility
- Male Breast Cancer
- CHEK2 Gene
- Nucleotide Excision Repair Gene