Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P =2.01 × 10-29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10-143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor-positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10-22) but less strongly, if at all, with ER-negative (ER+) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; Phet = 1.16 × 10-6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of theGallele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. ©2012 AACR.
9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium / Warren H.; Dudbridge F.; Fletcher O.; Orr N.; Johnson N.; Hopper J.L.; Apicella C.; Southey M.C.; Mahmoodi M.; Schmidt M.K.; Broeks A.; Cornelissen S.; Braaf L.M.; Muir K.R.; Lophatananon A.; Chaiwerawattana A.; Wiangnon S.; Fasching P.A.; Beckmann M.W.; Ekici A.B.; Schulz-Wendtland R.; Sawyer E.J.; Tomlinson I.; Kerin M.; Burwinkel B.; Marme F.; Schneeweiss A.; Sohn C.; Guenel P.; Truong T.; Laurent-Puig P.; Mulot C.; Bojesen S.E.; Nielsen S.F.; Flyger H.; Nordestgaard B.G.; Milne R.L.; Benitez J.; Arias-Perez J.-I.; Zamora M.P.; Anton-Culver H.; Ziogas A.; Bernstein L.; Dur C.C.; Brenner H.; Muller H.; Arndt V.; Langheinz A.; Meindl A.; Golatta M.; Bartram C.R.; Schmutzler R.K.; Brauch H.; Justenhoven C.; Bruning T.; Chang-Claude J.; Wang-Gohrke S.; Eilber U.; Dork T.; Schurmann P.; Bremer M.; Hillemanns P.; Nevanlinna H.; Muranen T.A.; Aittomaki K.; Blomqvist C.; Bogdanova N.; Antonenkova N.; Rogov Y.; Bermisheva M.; Prokofyeva D.; Zinnatullina G.; Khusnutdinova E.; Lindblom A.; Margolin S.; Mannermaa A.; Kosma V.-M.; Hartikainen J.M.; Kataja V.; Chenevix-Trench G.; Beesley J.; Chen X.; Lambrechts D.; Smeets A.; Paridaens R.; Weltens C.; Flesch-Janys D.; Buck K.; Behrens S.; Peterlongo P.; Bernard L.; Manoukian S.; Radice P.; Couch F.J.; Vachon C.; Wang X.; Olson J.; Giles G.; Baglietto L.; McLean C.A.; Severi G.; John E.M.; Miron A.; Winqvist R.; Pylkas K.; Jukkola-Vuorinen A.; Grip M.; Andrulis I.L.; Knight J.A.; Mulligan A.M.; Weerasooriya N.; Devilee P.; Tollenaar R.A.E.M.; Martens J.W.M.; Seynaeve C.M.; Hooning M.J.; Hollestelle A.; Jager A.; Tilanus-Linthorst M.M.A.; Hall P.; Czene K.; Liu J.; Li J.; Cox A.; Cross S.S.; Brock I.W.; Reed M.W.R.; Pharoah P.; Blows F.M.; Dunning A.M.; Ghoussaini M.; Ashworth A.; Swerdlow A.; Jones M.; Schoemaker M.; Easton D.F.; Humphreys M.; Wang Q.; Peto J.; Dos-Santos-Silva I.. - In: CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION. - ISSN 1055-9965. - STAMPA. - 21:(2012), pp. 1783-1791. [10.1158/1055-9965.EPI-12-0526]
9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: Evidence from the Breast Cancer Association Consortium
Severi G.;Wang Q.;
2012
Abstract
Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P =2.01 × 10-29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10-143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor-positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10-22) but less strongly, if at all, with ER-negative (ER+) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; Phet = 1.16 × 10-6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of theGallele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. ©2012 AACR.
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