Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility

被引:89
作者
Johnson, Nichola
Fletcher, Olivia
Palles, Claire
Rudd, Matthew
Webb, Emily
Sellick, Gabrielle
Silva, Isabel Dos Santos
McCormack, Valerie
Gibson, Lorna
Fraser, Agnes
Leonard, Angela
Gilham, Clare
Tavtigian, Sean V.
Ashworth, Alan
Houlston, Richard
Peto, Julian
机构
[1] Univ London London Sch Hyg & Trop Med, Non Communicable Dis Epidemiol Unit, London WC1E 7HT, England
[2] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England
[3] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England
[4] Inst Canc Res, Canc Res UK Epidemiol & Genet Unit, Sutton SM2 5NG, Surrey, England
[5] Int Agcy Res Canc, Genet Susceptibil Grp, F-69372 Lyon 08, France
关键词
D O I
10.1093/hmg/ddm050
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (P-trend = 0.005). For the 21 of these with minor allele frequency < 10% this trend was highly significant (P-trend = 0.00004, odds ratio for 3 or more SNPs = 2.90, 95% Cl 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.
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收藏
页码:1051 / 1057
页数:7
相关论文
共 37 条
[1]   Polygenic inheritance of breast cancer: Implications for design of association studies [J].
Antoniou, AC ;
Easton, DF .
GENETIC EPIDEMIOLOGY, 2003, 25 (03) :190-202
[2]   Gene Ontology: tool for the unification of biology [J].
Ashburner, M ;
Ball, CA ;
Blake, JA ;
Botstein, D ;
Butler, H ;
Cherry, JM ;
Davis, AP ;
Dolinski, K ;
Dwight, SS ;
Eppig, JT ;
Harris, MA ;
Hill, DP ;
Issel-Tarver, L ;
Kasarskis, A ;
Lewis, S ;
Matese, JC ;
Richardson, JE ;
Ringwald, M ;
Rubin, GM ;
Sherlock, G .
NATURE GENETICS, 2000, 25 (01) :25-29
[3]   A common coding variant in CASP8 is associated with breast cancer risk [J].
Cox, Angela ;
Dunning, Alison M. ;
Garcia-Closas, Montserrat ;
Balasubramanian, Sabapathy ;
Reed, Malcolm W. R. ;
Pooley, Karen A. ;
Scollen, Serena ;
Baynes, Caroline ;
Ponder, Bruce A. J. ;
Chanock, Stephen ;
Lissowska, Jolanta ;
Brinton, Louise ;
Peplonska, Beata ;
Southey, Melissa C. ;
Hopper, John L. ;
McCredie, Margaret R. E. ;
Giles, Graham G. ;
Fletcher, Olivia ;
Johnson, Nichola ;
dos Santos Silva, Isabel ;
Gibson, Lorna ;
Bojesen, Stig E. ;
Nordestgaard, Borge G. ;
Axelsson, Christen K. ;
Torres, Diana ;
Hamann, Ute ;
Justenhoven, Christina ;
Brauch, Hiltrud ;
Chang-Claude, Jenny ;
Kropp, Silke ;
Risch, Angela ;
Wang-Gohrke, Shan ;
Schuermann, Peter ;
Bogdanova, Natalia ;
Doerk, Thilo ;
Fagerholm, Rainer ;
Aaltonen, Kirsimari ;
Blomqvist, Carl ;
Nevanlinna, Heli ;
Seal, Sheila ;
Renwick, Anthony ;
Stratton, Michael R. ;
Rahman, Nazneen ;
Sangrajrang, Suleeporn ;
Hughes, David ;
Odefrey, Fabrice ;
Brennan, Paul ;
Spurdle, Amanda B. ;
Chenevix-Trench, Georgia ;
Beesley, Jonathan .
NATURE GENETICS, 2007, 39 (03) :352-358
[4]  
Easton D, 2004, AM J HUM GENET, V74, P1175, DOI 10.1086/421251
[5]   BRCA1 mutations in southern England [J].
Eccles, DM ;
Englefield, P ;
Soulby, MA ;
Campbell, IG .
BRITISH JOURNAL OF CANCER, 1998, 77 (12) :2199-2203
[6]   Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas [J].
Fearnhead, NS ;
Wilding, JL ;
Winney, B ;
Tonks, S ;
Bartlett, S ;
Bicknell, DC ;
Tomlinson, IPM ;
Mortensen, NJM ;
Bodmer, WF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (45) :15992-15997
[7]   Inconsistent association between the STK15 f31I genetic polymorphism and breast cancer risk [J].
Fletcher, Olivia ;
Johnson, Nichola ;
Palles, Claire ;
dos Santos, Isabel ;
McCormack, Valerie ;
Whittaker, John ;
Ashworth, Alan ;
Peto, Julian .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2006, 98 (14) :1014-1018
[8]   Identification of single nucleotide polymorphisms in human DNA repair genes [J].
Ford, BN ;
Ruttan, CC ;
Kyle, VL ;
Brackley, ME ;
Glickman, BW .
CARCINOGENESIS, 2000, 21 (11) :1977-1981
[9]   AMINO-ACID DIFFERENCE FORMULA TO HELP EXPLAIN PROTEIN EVOLUTION [J].
GRANTHAM, R .
SCIENCE, 1974, 185 (4154) :862-864
[10]   Replication validity of genetic association studies [J].
Ioannidis, JPA ;
Ntzani, EE ;
Trikalinos, TA ;
Contopoulos-Ioannidis, DG .
NATURE GENETICS, 2001, 29 (03) :306-309