Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study.
BACKGROUND
Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered.


METHODS
We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided.


RESULTS
We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)).


CONCLUSIONS
These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.
Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Olivia
O
Fletcher
Nichola
N
Johnson
Nick
N
Orr
Fay J
FJ
Hosking
Lorna J
LJ
Gibson
Kate
K
Walker
Diana
D
Zelenika
Ivo
I
Gut
Simon
S
Heath
Claire
C
Palles
Ben
B
Coupland
Peter
P
Broderick
Minouk
M
Schoemaker
Michael
M
Jones
Jill
J
Williamson
Sarah
S
Chilcott-Burns
Katarzyna
K
Tomczyk
Gemma
G
Simpson
Kevin B
KB
Jacobs
Stephen J
SJ
Chanock
David J
DJ
Hunter
Ian P
IP
Tomlinson
Anthony
A
Swerdlow
Alan
A
Ashworth
Gillian
G
Ross
Isabel
I
dos Santos Silva
Mark
M
Lathrop
Richard S
RS
Houlston
Julian
J
Peto
D000199:Actins / Q000235:genetics; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10; D002896:Chromosomes, Human, Pair 6; D002899:Chromosomes, Human, Pair 9; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D012307:Risk Factors; D011795:Surveys and Questionnaires; D006113:United Kingdom; D044465:White People / Q000235:genetics*
C120133:ACTL7A protein, human; D000199:Actins; D004268:DNA-Binding Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C513287:RAD23B protein, human; D045643:DNA Repair Enzymes