Common variation in EMSY and risk of breast and ovarian cancer: a case-control study using HapMap tagging SNPs.
BACKGROUND
EMSY could be involved in low-level susceptibility to breast and ovarian cancer. Gene amplification is seen in a proportion of breast and ovarian tumours and correlates with poor prognosis in breast cancer patients. Furthermore, the EMSY protein silences a transcription activation domain in BRCA2 exon 3.


METHODS
We used a genetic association study design to determine if common genetic variation (frequency > or = 5%) in EMSY was associated with breast or ovarian cancer risk in the British population. Haplotype tagging single-nucleotide polymorphisms (htSNPs) were selected from the HapMap database and genotyped using Taqman in two large study sets of white British women (n [breast set] = 2343 cases and 2284 controls, n [ovarian set] = 864 cases and 864 controls). HapMap data might be insufficient to tag genetic variation in EMSY comprehensively. We therefore screened the gene promoter and coding sequences with denaturing high performance liquid chromatography in order to identify additional SNPs that are most likely to be functional.


RESULTS
HapMap data on 22 SNPs show that 4 htSNPs tag 4 common haplotypes: rs2282611 (5'up t > g), rs4245443 (IVS7 g > a), rs2513511 (IVS16 a > g), rs2155220 (3'down c > t). We observed no association between any of the genotypes or associated haplotypes and breast or ovarian cancer risk. Seventeen out of the 18 remaining HapMap polymorphisms (94%) were well tagged by the 4 selected htSNPs (r2s > 0.8). Genotype frequencies for two further SNPs identified by screening and located near exon-intron boundaries, rs2508740 (IVS9 a > g) and rs11600501 (IVS10 c > t), were also similar in cases and controls. In order to simulate unidentified SNPs, we performed the leave-one-out cross-validation procedure on the HapMap data; over 95% of the common genetic variation was well represented by tagging polymorphisms. We are therefore likely to have tagged any common, functional variants present in our population.


CONCLUSIONS
We found no association between common genetic variation in EMSY and risk of breast or ovarian cancer in two large study sets of white British women.
Benusiglio
Patrick R
PR
Strangeways Research Laboratory, Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK. pbenusiglio@yahoo.com
Lesueur
Fabienne
F
Luccarini
Craig
C
McIntosh
Joan
J
Luben
Robert N
RN
Smith
Paula
P
Dunning
Alison
A
Easton
Douglas F
DF
Ponder
Bruce A J
BA
Pharoah
Paul D
PD
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D012306:Risk; D015533:Transcriptional Activation
C480344:EMSY protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins