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Title: Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
Authors: Garcia-Closas M.
Hall P.
Nevanlinna H.
Pooley K.
Morrison J.
Richesson D.A.
Bojesen S.E.
Nordestgaard B.G.
Axelsson C.K.
Arias J.I.
Milne R.L.
Ribas G.
González-Neira A.
Benítez J.
Zamora P.
Brauch H.
Justenhoven C.
Hamann U.
Ko Y.-D.
Bruening T.
Haas S.
Dörk T.
Schürmann P.
Hillemanns P.
Bogdanova N.
Bremer M.
Karstens J.H.
Fagerholm R.
Aaltonen K.
Aittomäki K.
Von Smitten K.
Blomqvist C.
Mannermaa A.
Uusitupa M.
Eskelinen M.
Tengström M.
Kosma V.-M.
Kataja V.
Chenevix-Trench G.
Spurdle A.B.
Beesley J.
Chen X.
Devilee P.
Van Asperen C.J.
Jacobi C.E.
Tollenaar R.A.E.M.
Huijts P.E.A.
Klijn J.G.M.
Chang-Claude J.
Kropp S.
Slanger T.
Flesch-Janys D.
Mutschelknauss E.
Salazar R.
Wang-Gohrke S.
Couch F.
Goode E.L.
Olson J.E.
Vachon C.
Fredericksen Z.S.
Giles G.G.
Baglietto L.
Severi G.
Hopper J.L.
English D.R.
Southey M.C.
Haiman C.A.
Henderson B.E.
Kolonel L.N.
Le Marchand L.
Stram D.O.
Hunter D.J.
Hankinson S.E.
Cox D.G.
Tamimi R.
Kraft P.
Sherman M.E.
Chanock S.J.
Lissowska J.
Brinton L.A.
Peplonska B.
Hooning M.J.
Meijers-Heijboer H.
Collee J.M.
Van Den Ouweland A.
Uitterlinden A.G.
Liu J.
Low Y.L. 
Yuqing L.
Humphreys K.
Czene K.
Cox A.
Balasubramanian S.P.
Cross S.S.
Reed M.W.R.
Blows F.
Driver K.
Dunning A.
Tyrer J.
Ponder B.A.J.
Sangrajrang S.
Brennan P.
McKay J.
Odefrey F.
Gabrieau V.
Sigurdson A.
Doody M.
Struewing J.P.
Alexander B.
Easton D.F.
Pharoah P.D.
Keywords: estrogen receptor
fibroblast growth factor receptor 2
progesterone receptor
actin binding protein
FGFR2 protein, human
fibroblast growth factor receptor 2
LSP1 protein, human
MAP3K1 protein, human
mitogen activated protein kinase kinase kinase 1
progesterone receptor
TNRC9 protein, human
breast cancer
breast carcinogenesis
cancer genetics
cancer invasion
cancer risk
cancer survival
cancer susceptibility
chromosome 8q
clinical feature
controlled study
gene locus
genetic association
genetic heterogeneity
genetic susceptibility
genetic variability
major clinical study
overall survival
single nucleotide polymorphism
breast tumor
case control study
chromosome 8
gene linkage disequilibrium
genetic predisposition
middle aged
single nucleotide polymorphism
trinucleotide repeat
Breast Neoplasms
Case-Control Studies
Chromosomes, Human, Pair 8
Genetic Predisposition to Disease
Linkage Disequilibrium
MAP Kinase Kinase Kinase 1
Microfilament Proteins
Middle Aged
Odds Ratio
Polymorphism, Single Nucleotide
Receptor, Fibroblast Growth Factor, Type 2
Receptors, Progesterone
Trinucleotide Repeats
Issue Date: 2008
Citation: Garcia-Closas M., Hall P., Nevanlinna H., Pooley K., Morrison J., Richesson D.A., Bojesen S.E., Nordestgaard B.G., Axelsson C.K., Arias J.I., Milne R.L., Ribas G., González-Neira A., Benítez J., Zamora P., Brauch H., Justenhoven C., Hamann U., Ko Y.-D., Bruening T., Haas S., Dörk T., Schürmann P., Hillemanns P., Bogdanova N., Bremer M., Karstens J.H., Fagerholm R., Aaltonen K., Aittomäki K., Von Smitten K., Blomqvist C., Mannermaa A., Uusitupa M., Eskelinen M., Tengström M., Kosma V.-M., Kataja V., Chenevix-Trench G., Spurdle A.B., Beesley J., Chen X., Devilee P., Van Asperen C.J., Jacobi C.E., Tollenaar R.A.E.M., Huijts P.E.A., Klijn J.G.M., Chang-Claude J., Kropp S., Slanger T., Flesch-Janys D., Mutschelknauss E., Salazar R., Wang-Gohrke S., Couch F., Goode E.L., Olson J.E., Vachon C., Fredericksen Z.S., Giles G.G., Baglietto L., Severi G., Hopper J.L., English D.R., Southey M.C., Haiman C.A., Henderson B.E., Kolonel L.N., Le Marchand L., Stram D.O., Hunter D.J., Hankinson S.E., Cox D.G., Tamimi R., Kraft P., Sherman M.E., Chanock S.J., Lissowska J., Brinton L.A., Peplonska B., Hooning M.J., Meijers-Heijboer H., Collee J.M., Van Den Ouweland A., Uitterlinden A.G., Liu J., Low Y.L., Yuqing L., Humphreys K., Czene K., Cox A., Balasubramanian S.P., Cross S.S., Reed M.W.R., Blows F., Driver K., Dunning A., Tyrer J., Ponder B.A.J., Sangrajrang S., Brennan P., McKay J., Odefrey F., Gabrieau V., Sigurdson A., Doody M., Struewing J.P., Alexander B., Easton D.F., Pharoah P.D. (2008). Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genetics 4 (4) : e1000054. ScholarBank@NUS Repository.
Abstract: A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10-13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10-5, 10 -8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10-4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
Source Title: PLoS Genetics
ISSN: 15537390
DOI: 10.1371/journal.pgen.1000054
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