Human Molecular Genetics Advance Access originally published online on March 6, 2007
Human Molecular Genetics 2007 16(9):1051-1057; doi:10.1093/hmg/ddm050
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility
1 The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK, 2 Section of Cancer Genetics, 3 Cancer Research UK Epidemiology & Genetics Unit, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK, 4 Non Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK and 5 Genetic Susceptibility Group, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Lyon Cedex 08, France
* To whom correspondence should be addressed at: Non Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. Tel: +1 02079272455; Fax: +1 02075806897; Email: julian.peto{at}lshtm.ac.uk
Received January 8, 2007; Revised February 20, 2007; Accepted February 28, 2007
Rare inactivating mutations in BRCA1, BRCA2, ATM, TP53 and CHEK2 confer relative risks for breast cancer between about 2 and more than 10, but more common variants in these genes are generally considered of little or no clinical significance. Under the polygenic model for breast cancer carriers of multiple low-penetrance alleles are at high risk, but few such alleles have been reliably identified. We analysed 1037 potentially functional single nucleotide polymorphisms (SNPs) in candidate cancer genes in 473 women with two primary breast cancers and 2463 controls. Twenty-five of these SNPs were in BRCA1, BRCA2, ATM, TP53 and CHEK2. Among the 1037 SNPs there were a few significant findings, but hardly more than would be expected in this large experiment. There was, however, a significant trend in risk with increasing numbers of variant alleles for the 25 SNPs in BRCA1, BRCA2, ATM, TP53 and CHEK2 (Ptrend = 0.005). For the 21 of these with minor allele frequency <10% this trend was highly significant (Ptrend = 0.00004, odds ratio for 3 or more SNPs = 2.90, 95% CI 1.69–4.97). The individual effects of most of these risk alleles were undetectably small even in this well powered study, but the risk conferred by multiple variants is readily detectable and makes a substantial contribution to susceptibility. A risk score incorporating a suitably weighted sum of all potentially functional variants in these and a few other candidate genes may provide clinically useful identification of women at high genetic risk.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K.-D. Yu, G.-H. Di, W.-T. Yuan, L. Fan, J. Wu, Z. Hu, Z.-Z. Shen, Y. Zheng, W. Huang, and Z.-M. Shao Functional polymorphisms, altered gene expression and genetic association link NRH:quinone oxidoreductase 2 to breast cancer with wild-type p53 Hum. Mol. Genet., July 1, 2009; 18(13): 2502 - 2517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Li, H. Suzuki, B. Liu, J. Morris, J. Liu, T. Okazaki, Y. Li, P. Chang, and J. L. Abbruzzese DNA Repair Gene Polymorphisms and Risk of Pancreatic Cancer Clin. Cancer Res., January 15, 2009; 15(2): 740 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. R. Smith, E. A. Levine, R. I. Freimanis, S. A. Akman, G. O. Allen, K. N. Hoang, W. Liu-Mares, and J. J. Hu Polygenic model of DNA repair genetic polymorphisms in human breast cancer risk Carcinogenesis, November 1, 2008; 29(11): 2132 - 2138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Palles, N. Johnson, B. Coupland, C. Taylor, J. Carvajal, J. Holly, I. S. Fentiman, I. dos Santos Silva, A. Ashworth, J. Peto, et al. Identification of genetic variants that influence circulating IGF1 levels: a targeted search strategy Hum. Mol. Genet., May 15, 2008; 17(10): 1457 - 1464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Bethke, E. Webb, A. Murray, M. Schoemaker, M. Feychting, S. Lonn, A. Ahlbom, B. Malmer, R. Henriksson, A. Auvinen, et al. Functional Polymorphisms in Folate Metabolism Genes Influence the Risk of Meningioma and Glioma Cancer Epidemiol. Biomarkers Prev., May 1, 2008; 17(5): 1195 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Leng, C. A. Stidley, R. Willink, A. Bernauer, K. Do, M. A. Picchi, X. Sheng, M. A. Frasco, D. Van Den Berg, F. D. Gilliland, et al. Double-Strand Break Damage and Associated DNA Repair Genes Predispose Smokers to Gene Methylation Cancer Res., April 15, 2008; 68(8): 3049 - 3056. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Frank, M. Wiestler, S. Kropp, K. Hemminki, A. B. Spurdle, C. Sutter, B. Wappenschmidt, X. Chen, J. Beesley, J. L. Hopper, et al. Association of a Common AKAP9 Variant With Breast Cancer Risk: A Collaborative Analysis J Natl Cancer Inst, March 19, 2008; 100(6): 437 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Haiman, C. Hsu, P. I.W. de Bakker, M. Frasco, X. Sheng, D. Van Den Berg, J. T. Casagrande, L. N. Kolonel, L. Le Marchand, S. E. Hankinson, et al. Comprehensive association testing of common genetic variation in DNA repair pathway genes in relationship with breast cancer risk in multiple populations Hum. Mol. Genet., March 15, 2008; 17(6): 825 - 834. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-C. Hong, C. B. Ambrosone, J. Ahn, J.-Y. Choi, M. L. McCullough, V. L. Stevens, C. Rodriguez, M. J. Thun, and E. E. Calle Genetic Variability in Iron-Related Oxidative Stress Pathways (Nrf2, NQ01, NOS3, and HO-1), Iron Intake, and Risk of Postmenopausal Breast Cancer Cancer Epidemiol. Biomarkers Prev., September 1, 2007; 16(9): 1784 - 1794. [Abstract] [Full Text] [PDF]
|
|