Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95 %CI 1.02–13.84, P = 0.046) and 8.0 (95 %CI 2.20–29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28–1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.
Breast cancer Polymorphisms TOX3TNRC92q35 8q24
This is a preview of subscription content, log in to check access.
The authors thank the many families who participated in the research studies described in this article. We acknowledge the Breast Cancer Group of CONAC: Maria Teresa Barrios, Angelica Soto, Rossana Recabarren, Leticia Garcia, Karen Olmos and Paola Carrasco; and Lorena Seccia for her technical assistance.
Conflict of interest
Corporación Nacional del Cáncer.
The authors declare that they have no competing interests.
Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT). Grant number: 1110081.
Chen M, Wu X, Shen W, Wei M, Li C, Cai B et al (2011) Association between polymorphisms of trinucleotide repeat containing 9 gene and breast cancer risk: evidence from 62,005 subjects. Breast Cancer Res Treat 126:177–183. doi:10.1007/s10549-010-1114-6CrossRefPubMedGoogle Scholar
Ruiz-Narvaez EA, Rosenberg L, Rotimi CN, Cupples LA, Boggs DA, Adeyemo A et al (2010) Genetic variants on chromosome 5p12 are associated with risk of breast cancer in African American women: the black women’s health study. Breast Cancer Res Treat 123:525–530. doi:10.1007/s10549-010-0775-5PubMedCentralCrossRefPubMedGoogle Scholar
Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39:865–869. doi:10.1038/ng2064CrossRefPubMedGoogle Scholar
Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE 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/ng2075PubMedCentralCrossRefPubMedGoogle Scholar
Gorodnova TV, Kuligina ES, Yanus GA, Katanugina AS, Abysheva SN, Togo AV et al (2010) Distribution of FGFR2, TNRC9, MAP3K1, LSP1, and 8q24 alleles in genetically enriched breast cancer patients versus elderly tumor-free women. Cancer Genet Cytogenet 199:69–72. doi:10.1016/j.cancergencyto.2010.01.020CrossRefPubMedGoogle Scholar
Hemminki K, Müller-Myhsok B, Lichtner P, Engel C, Chen B, Burwinkel B et al (2010) Low-risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients. Int J Cancer 126:2858–2862. doi:10.1002/ijc.24986PubMedGoogle Scholar
Gonzalez-Hormazabal P, Gutierrez-Enriquez S, Gaete D, Reyes JM, Peralta O, Waugh E et al (2011) Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families. Breast Cancer Res Treat 126:705–716. doi:10.1007/s10549-010-1170-yCrossRefPubMedGoogle Scholar
Gonzalez-Hormazabal P, Reyes JM, Blanco R, Bravo T, Carrera I, Peralta O et al (2012) The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population. Mol Biol Rep 39:8091–8098. doi:10.1007/s11033-012-1656-2CrossRefPubMedGoogle Scholar
González-Hormazábal P, Castro VG, Blanco R, Gómez F, Peralta O, Waugh E et al (2008) Absence of CHEK2 1100delC mutation in familial breast cancer cases from a South American population. Breast Cancer Res Treat 110:543–545. doi:10.1007/s10549-007-9743-0CrossRefPubMedGoogle Scholar
Jara L, Dubois K, Gaete D, de Mayo T, Ratkevicius N, Bravo T et al (2010) Variants in dna double-strand break repair genes and risk of familial breast cancer in a South American population. Breast Cancer Res Treat 122:813–822. doi:10.1007/s10549-009-0709-2CrossRefPubMedGoogle Scholar
Jara L, Gonzalez-Hormazabal P, Cerceño K, Di Capua GA, Reyes JM, Blanco R et al (2013) Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population. Breast Cancer Res Treat 137:559–569. doi:10.1007/s10549-012-2359-zCrossRefPubMedGoogle Scholar
Riaz M, Berns EMJJ, Sieuwerts AM, Ruigrok-Ritstier K, de Weerd V, Groenewoud A et al (2012) Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes. Breast Cancer Res Treat 133:843–851. doi:10.1007/s10549-011-1663-3CrossRefPubMedGoogle Scholar
Lin C, Ho C, Bau D, Yang S, Liu S, Lin P et al (2012) Evaluation of breast cancer susceptibility loci on 2q35, 3p24, 17q23 and F2 genes in taiwanese women with breast cancer. Anticancer Res 32:475–482PubMedGoogle Scholar
Valenzuela C, Harb Z (1977) Socioeconomic assortative mating in santiago, chile: as demonstrated using stochastic matrices of mother-child relationships applied to abo blood groups. Soc Biol 24:225–233CrossRefPubMedGoogle Scholar
Valenzuela CY, Acuña MP, Harb Z (1987) sociogenetic gradient in the chilean population. Rev Med Chil 115:295–299PubMedGoogle Scholar