Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10？10; P-het for ILC vs IDC ER+ tumors = 1.8×10？4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.
Yoder BJ, Wilkinson EJ, Massoll NA (2007) Molecular and morphologic distinctions between infiltrating ductal and lobular carcinoma of the breast. Breast J 13 (2) 172–79. doi: 10.1111/j.1524-4741.2007.00393.x
Reeves GK, Beral V, Green J, Gathani T (2006) Bull D (2006) Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 7: 910–918. doi: 10.1016/s1470-2045(06)70911-1
Kotsopoulos J, Chen WY, Gates MA, Tworoger SS, Hankinson SE, et al. (2010) Risk factors for ductal and lobular breast cancer: results from the nurses' health study. Breast Cancer Res 12: R106. doi: 10.1186/bcr2790
Pestalozzi BC, Zahrieh D, Mallon E, Gusterson BA, Price KN, et al. (2008) Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol 26 (18) 3006–3014. doi: 10.1200/jco.2007.14.9336
Tubiana-Hulin M, Stevens D, Lasry S, Guinebretière JM, Bouita L, et al. (2006) Response to neoadjuvant chemotherapy in lobular and ductal breast carcinomas:. Ann Oncol 17 (8) 1228–1233. doi: 10.1093/annonc/mdl114
Chuba PJ, Hamre MR, Yap J, Severson RK, Lucas D, et al. (2005) Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of surveillance, epidemiology, and end results data. J Clin Oncol 23 (24) 5534–5541. doi: 10.1200/jco.2005.04.038
Fisher ER, Land SR, Fisher B, Mamounas E, Gilarski L, et al. (2004) Pathologic findings from the NSABBP: twelve-year observations concerning lobular carcinoma in situ. Cancer 15;100 (2) 238–244. doi: 10.1002/cncr.11883
Sasson AR, Fowble B, Hanlon AL, Torosian MH, Freedman G, et al. (2001) Lobular carcinoma in situ increases the risk of local recurrence in selected patients with stages I and II breast carcinoma treated with conservative surgery and radiation. Cancer 91: 1862–1869. doi: 10.1002/1097-0142(20010515)91:10<1862::aid-cncr1207>3.0.co;2-#
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, et al. (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39: 870–874. doi: 10.1038/ng2075
Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, et al. (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer. Nat Genet 39: 865–869 (2007). doi: 10.1038/ng2064
Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA, et al. (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor–positive breast cancer. Nat Genet 40: 703–706. doi: 10.1038/ng.131
Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, et al. (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41: 579–584. doi: 10.1038/ng.353
Antoniou AC, Wang X, Fredericksen ZS, McGuffog L, Tarrell R, et al. (2010) A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population. Nat Genet 42: 885–892.
Fletcher O, Johnson N, Orr N, Hosking FJ, Gibson LJ, et al. (2011) Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst 103: 425–435. doi: 10.1093/jnci/djq563
Siddiq A, Couch FJ, Chen GK, Lindstr？m S, Eccles D, et al. (2012) A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. Hum Mol Genet 21: 5373–5384.
Figueroa JD, Garcia-Closas M, Humphreys M, Platte R, Hopper JL, et al. (2011) Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium. Hum Mol Genet 20 (23) 4693–706. doi: 10.1158/1538-7445.am2011-5614
Ibrahim SA, Yip GW, Stock C, Pan JW, Neubauer C, et al. (2012) Targeting of syndecan-1 by microRNA miR-10b promotes breast cancer cell motility and invasiveness via a Rho-GTPase- and E-cadherin-dependent mechanism. Int J Cancer 131 (6) E884–896. doi: 10.1002/ijc.27629
Pharoah PD, Guilford P, Caldas C (2001) International Gastric Cancer Linkage Consortium (2001) Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121 (6) 1348–53. doi: 10.1053/gast.2001.29611
Xie ZM, Li LS, Laquet C, Penault-Llorca F, Uhrhammer N, et al. (2011) Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. Cancer 117 (14) 3112–3117. doi: 10.1002/cncr.25876
Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, et al. (2008) Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol 216 (2) 141–150. doi: 10.1002/path.2407
Milne RL, Goode EL, García-Closas M, Couch FJ, Severi G, et al. (2011) Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer. Cancer Epidemiol Biomarkers Prev 10: 2222–2231.
Swann R, Perkins KA, Velentzis LS, Ciria C, Dutton SJ, et al. (2013) The DietCompLyf study: A prospective cohort study of breast cancer survival and phytoestrogen consumption. Maturitas 3: 232–240. doi: 10.1016/j.maturitas.2013.03.018