The 6q22.33 locus and breast cancer susceptibility.
Recently, we identified a novel breast cancer susceptibility locus at 6q22.33 following a genome-wide association study in the Ashkenazi Jewish genetic isolate. To replicate these findings, we did a case-control association analysis on 6q22.33 (rs2180341) in an additional 487 Ashkenazi Jewish breast cancer cases and in an independent non-Jewish, predominantly European American, population of 1,466 breast cancer cases and 1,467 controls. We confirmed the 6q22.33 association with breast cancer risk in the replication cohorts [per-allele odds ratio (OR), 1.18; 95% confidence interval (95% CI), 1.04-1.33; P = 0.0083], with the strongest effect in the aggregate meta-analysis of 3,039 breast cancer cases and 2,616 Ashkenazi Jewish and non-Jewish controls (per-allele OR, 1.24; 95% CI, 1.13-1.36; P = 3.85 x 10(-7)). We also showed that the association was slightly stronger with estrogen receptor-positive tumors (per-allele OR, 1.35; 95% CI, 1.20-1.51; P = 2.2 x 10(-5)) compared with estrogen receptor-negative tumors (per-allele OR, 1.19; 95% CI, 0.97-1.47; P = 0.1). Furthermore, this study provides a novel insight into the functional significance of 6q22.33 in breast cancer susceptibility. Due to the stronger association of 6q22.33 with estrogen receptor-positive breast cancer, we examined the effect of candidate genes on estrogen receptor response elements. Upon transfection of overexpressed RNF146 in the MCF-7 breast cancer cell line, we observed diminished expression of an estrogen receptor response element reporter construct. This study confirms the association of 6q22.33 with breast cancer, with slightly stronger effect in estrogen receptor-positive tumors. Further functional studies of candidate genes are in progress, and a large replication analysis is being completed as part of an international consortium.
Kirchhoff
Tomas
T
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. kirchhot@mskcc.org
Chen
Zhang-qun
ZQ
Gold
Bert
B
Pal
Prodipto
P
Gaudet
Mia M
MM
Kosarin
Kristi
K
Levine
Douglas A
DA
Gregersen
Peter
P
Spencer
Sara
S
Harlan
Megan
M
Robson
Mark
M
Klein
Robert J
RJ
Hudis
Clifford A
CA
Norton
Larry
L
Dean
Michael
M
Offit
Kenneth
K
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002896:Chromosomes, Human, Pair 6; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D007585:Jews; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000096:biosynthesis; D012307:Risk Factors; D017421:Sequence Analysis
D011960:Receptors, Estrogen
Int J Mol Med. 2005 Jan;15(1):33-40
15583825
Breast Cancer Res Treat. 2008 Jan;107(2):195-210
17377839
Stat Med. 2007 Sep 10;26(20):3722-34
17139701
Hum Mol Genet. 2005 Feb 15;14(4):555-63
15649950
J Natl Cancer Inst. 1999 Jun 2;91(11):943-9
10359546
J Urban Health. 2004 Jun;81(2):301-10
15136663
Nature. 2007 Jun 28;447(7148):1087-93
17529967
Nat Genet. 2007 Jul;39(7):870-4
17529973
N Engl J Med. 2008 Jun 26;358(26):2796-803
18579814
J Biol Chem. 2006 Mar 17;281(11):7452-7
16421098
Clin Cancer Res. 2004 May 1;10(9):2918-21
15131025
Mol Cancer Res. 2006 Oct;4(10):695-707
17050664
Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2766-72
18843021
Expert Opin Ther Targets. 2008 Jul;12(7):855-70
18554154
Cancer Res. 2003 Nov 1;63(21):7330-7
14612531
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4340-5
18326623
N Engl J Med. 2000 Jul 13;343(2):78-85
10891514
Clin Cancer Res. 2000 May;6(5):1796-803
10815900
EMBO Rep. 2005 Jun;6(6):538-44
15891768
Nat Genet. 2008 Jun;40(6):703-6
18438407
PLoS Genet. 2008 Apr 25;4(4):e1000054
18437204
Nat Genet. 2007 Jul;39(7):865-9
17529974
J Clin Oncol. 2005 Jul 20;23(21):4776-89
16034054
Cancer Epidemiol Biomarkers Prev. 1999 Mar;8(3):271-4
10090306
EMBO J. 2006 Dec 13;25(24):5742-53
17139257
Mol Cells. 2008 Apr 30;25(2):289-93
18414007
J Natl Cancer Inst. 1997 Feb 19;89(4):287-93
9048832
Br J Cancer. 2002 Jan 7;86(1):76-83
11857015
Genomics. 2000 Nov 15;70(1):113-22
11087668