Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

TY - JOUR

T1 - Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

AU - Garcia-Closas, Montserrat

AU - Hall, Per

AU - Nevanlinna, Heli

AU - Pooley, Karen

AU - Morrison, Jonathan

AU - Richesson Douglas, A

AU - Bojesen Stig, E

AU - Nordestgaard Børge, G

AU - Axelsson Christen, K

AU - Arias Jose, I

AU - Milne Roger, L

AU - Ribas, Gloria

AU - González-Neira, Anna

AU - Benítez, Javier

AU - Zamora, Pilar

AU - Brauch, Hiltrud

AU - Justenhoven, Christina

AU - Hamann, Ute

AU - Ko, Yon-Dschun

AU - Bruening, Thomas

AU - Haas, Susanne

AU - Dörk, Thilo

AU - Schürmann, Peter

AU - Hillemanns, Peter

AU - Bogdanova, Natalia

AU - Bremer, Michael

AU - Karstens, Johann Hinrich

AU - Fagerholm, Rainer

AU - Aaltonen, Kirsimari

AU - Aittomäki, Kristiina

AU - von Smitten, Karl

AU - Blomqvist, Carl

AU - Mannermaa, Arto

AU - Uusitupa, Matti

AU - Eskelinen, Matti

AU - Tengström, Maria

AU - Kosma, Veli-Matti

AU - Kataja, Vesa

AU - Chenevix-Trench, Georgia

AU - Spurdle Amanda, B

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Group, Australian Ovarian Cancer Management

AU - Cancer, Kathleen Cuningham Foundation Consortium For Research Into Familial Breast

AU - Devilee, Peter

AU - van Asperen Christi, J

AU - Jacobi, Catharina E

AU - Tollenaar Rob, A E M

AU - Huijts, Petra E A

AU - Klijn, Jan G M

AU - Chang-Claude, Jenny

AU - Kropp, Silke

AU - Slanger, Tracy

AU - Flesch-Janys, Dieter

AU - Mutschelknauss, Elke

AU - Salazar, Ramona

AU - Wang-Gohrke, Shan

AU - Couch, Fergus

AU - Goode, Ellen L

AU - Olson, Janet E

AU - Vachon, Celine

AU - Fredericksen Zachary, S

AU - Giles Graham, G

AU - Baglietto, Laura

AU - Severi, Gianluca

AU - Hopper, John L

AU - English Dallas, R

AU - Southey, Melissa C

AU - Haiman, Christopher A

AU - Henderson Brian, E

AU - Kolonel, Laurence N

AU - Loic, Le Marchand

AU - Stram, Daniel O

AU - Hunter, David J

AU - Hankinson, Susan E

AU - Cox, David G

AU - Tamimi, Rulla

AU - Kraft, Peter

AU - Sherman, Mark E

AU - Chanock Stephen, J

AU - Lissowska, Jolanta

AU - Brinton, Louise A

AU - Peplonska, Beata

AU - Hooning Maartje, J

AU - Meijers-Heijboer, Han

AU - Collee, J Margriet

AU - van den Ouweland, Ans

AU - Uitterlinden, Andre G

AU - Liu, Jianjun

AU - Lin, Low Yen

AU - Yuqing, Li

AU - Humphreys, Keith

AU - Czene, Kamila

AU - Cox, Angela

AU - Balasubramanian Sabapathy, P

AU - Cross, Simon S

AU - Reed Malcolm, W R

AU - Blows, Fiona

AU - Driver, Kristy

AU - Dunning, Alison

AU - Tyrer, Jonathan

AU - Ponder Bruce, A J

AU - Sangrajrang, Suleeporn

AU - Brennan, Paul

AU - McKay, James

AU - Odefrey, Fabrice

AU - Gabrieau, Valerie

AU - Sigurdson, Alice

AU - Doody, Michele

AU - Struewing Jeffrey, P

AU - Alexander, Bruce

AU - Easton Douglas, F

AU - Pharoah, Paul D

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1000054

DO - 10.1371/journal.pgen.1000054

M3 - SCORING: Zeitschriftenaufsatz

VL - 4

SP - 1000054

JO - PLOS GENET

JF - PLOS GENET

SN - 1553-7404

IS - 4

M1 - 4

ER -