Top

Published in:

01-05-2013 | Epidemiology

Association between a novel polymorphism (rs2046210) of the 6q25.1 locus and breast cancer risk

Authors: Ziang Yang, Juping Shen, Zhigang Cao, Biyun Wang

Published in: Breast Cancer Research and Treatment | Issue 1/2013

Abstract

The novel single nucleotide polymorphism (SNP), rs2046210, was identified in a breast cancer genome-wide association study of Chinese women. The SNP is located on 6q25.1 in proximity to the C6orf97 and estrogen receptor 1 (ESR1) genes. To replicate this susceptibility, a number of case–control studies have been conducted in various populations. However, some results were inconclusive due to the restriction of sample size or ethnic diversity. To derive a more precise estimation of the relationship between rs2046210 and genetic risk of breast cancer, we performed the first comprehensive meta-analysis which included 121,494 cases and 119,295 controls from 14 published studies. Overall, significant increased risk between the A allele of rs2046210 and breast cancer was found in the total population (allelic model: OR = 1.16, 95 %CI = 1.11–1.21, P _{heterogeneity} < 0.0001; dominant model: OR = 1.22, 95 %CI = 1.14–1.29, P _{heterogeneity} < 0.0001; recessive model: OR = 1.21, 95 %CI = 1.13–1.29, P _{heterogeneity} < 0.0001). When stratified by ethnicity, significant elevated risk was found among Europeans and Asians. However, no significant association was detected in African descent population. In the subgroup analyses according to estrogen receptor (ER) positive/negative status, our results suggested that this polymorphism tended to increase breast cancer risk in ER negative tumors by a greater magnitude compared to ER positive tumors. In addition, our subgroup analysis also indicated that this SNP was significantly associated with the risk of breast cancer for BRCA1 mutation carriers and exhibited weaker association with the risk for BRCA2 mutation carriers. Substantial heterogeneity was present in the overall analysis, but largely disappeared after stratification by ethnicity. Despite some limitations, this meta-analysis demonstrates that the rs2046210 polymorphism may be a risk factor associated with increased breast cancer risk. However, the association varies in different ethnicities.

Available only for authorised users

Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33(Suppl):238–244PubMedCrossRef

Nathanson KL, Wooster R, Weber BL (2001) Breast cancer genetics: what we know and what we need. Nat Med 7(5):552–556PubMedCrossRef

Peto J, Collins N, Barfoot R, Seal S, Warren W et al (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91(11):943–949PubMedCrossRef

Pharoah PD, Dunning AM, Ponder BA, Easton DF (2004) Association studies for finding cancer-susceptibility genetic variants. Nat Rev Cancer 4(11):850–860PubMedCrossRef

Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK et al (2009) Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nat Genet 41(5):585–590PubMedCrossRef

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(10):885–892PubMedCrossRef

Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093PubMedCrossRef

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(5):425–435PubMedCrossRef

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(7):870–874PubMedCrossRef

10.

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(7):865–869PubMedCrossRef

11.

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(6):703–706PubMedCrossRef

12.

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(5):579–584PubMedCrossRef

13.

Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A et al (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42(6):504–507PubMedCrossRef

14.

Zheng W, Long J, Gao YT, Li C, Zheng Y et al (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41(3):324–328PubMedCrossRef

15.

Figtree GA, Noonan JE, Bhindi R, Collins P (2009) Estrogen receptor polymorphisms: significance to human physiology, disease and therapy. Recent Pat DNA Gene Seq 3(3):164–171PubMedCrossRef

16.

Dunning AM, Healey CS, Baynes C, Maia AT, Scollen S et al (2009) Association of ESR1 gene tagging SNPs with breast cancer risk. Hum Mol Genet 18(6):1131–1139PubMedCrossRef

17.

Li N, Dong J, Hu Z, Shen H, Dai M (2010) Potentially functional polymorphisms in ESR1 and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 121(1):177–184PubMedCrossRef

18.

DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188PubMedCrossRef

19.

Woolf B (1955) On estimating the relation between blood group and disease. Ann Hum Genet 19(4):251–253PubMedCrossRef

20.

Antoniou AC, Kartsonaki C, Sinilnikova OM, Soucy P, McGuffog L et al (2011) Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 20(16):3304–3321PubMedCrossRef

21.

Cai Q, Wen W, Qu S, Li G, Egan KM et al (2011) Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of Chinese, Japanese, and European ancestry. Cancer Res 71(4):1344–1355PubMedCrossRef

22.

Campa D, Kaaks R, Le Marchand L, Haiman CA, Travis RC et al (2011) Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. J Natl Cancer Inst 103(16):1252–1263PubMedCrossRef

23.

Chan M, Ji SM, Liaw CS, Yap YS, Law HY et al (2012) Association of common genetic variants with breast cancer risk and clinicopathological characteristics in a Chinese population. Breast Cancer Res Treat 136(1):209–220PubMedCrossRef

24.

Han W, Woo JH, Yu JH, Lee MJ, Moon HG et al (2011) Common genetic variants associated with breast cancer in Korean women and differential susceptibility according to intrinsic subtype. Cancer Epidemiol Biomarkers Prev 20(5):793–798PubMedCrossRef

25.

Hein R, Maranian M, Hopper JL, Kapuscinski MK, Southey MC et al (2012) Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC). PLoS ONE 7(8):e42380PubMedCrossRef

26.

Jiang Y, Han J, Liu J, Zhang G, Wang L et al (2011) Risk of genome-wide association study newly identified genetic variants for breast cancer in Chinese women of Heilongjiang Province. Breast Cancer Res Treat 128(1):251–257PubMedCrossRef

27.

Kim HC, Lee JY, Sung H, Choi JY, Park SK et al (2012) A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study. Breast Cancer Res 14(2):R56PubMedCrossRef

28.

Mulligan AM, Couch FJ, Barrowdale D, Domchek SM, Eccles D et al (2011) Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2. Breast Cancer Res 13(6):R110PubMedCrossRef

29.

Ruiz-Narvaez EA, Rosenberg L, Yao S, Rotimi CN, Cupples AL et al (2012) Fine-mapping of the 6q25 locus identifies a novel SNP associated with breast cancer risk in African–American women. Carcinogenesis 34(2):287–291PubMedCrossRef

30.

Stacey SN, Sulem P, Zanon C, Gudjonsson SA, Thorleifsson G et al (2010) Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus. PLoS Genet 6(7):e1001029PubMedCrossRef

31.

Stevens KN, Vachon CM, Lee AM, Slager S, Lesnick T et al (2011) Common breast cancer susceptibility loci are associated with triple-negative breast cancer. Cancer Res 71(19):6240–6249PubMedCrossRef

32.

Sueta A, Ito H, Kawase T, Hirose K, Hosono S et al (2012) A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population. Breast Cancer Res Treat 132(2):711–721PubMedCrossRef

33.

Cancer CGoHFiB (2002) Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360(9328):187–195CrossRef

34.

Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedCrossRef

35.

Garcia-Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J et al (2008) Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet 4(4):e1000054PubMedCrossRef

36.

Long J, Shu XO, Cai Q, Gao YT, Zheng Y et al (2010) Evaluation of breast cancer susceptibility loci in Chinese women. Cancer Epidemiol Biomarkers Prev 19(9):2357–2365PubMedCrossRef

37.

Key T, Appleby P, Barnes I, Reeves G (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94(8):606–616PubMedCrossRef

38.

Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA et al (2008) Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 82(4):937–948PubMedCrossRef

39.

Antoniou AC, Sinilnikova OM, McGuffog L, Healey S, Nevanlinna H et al (2009) Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers. Hum Mol Genet 18(22):4442–4456PubMedCrossRef

40.

Antoniou AC, Beesley J, McGuffog L, Sinilnikova OM, Healey S et al (2010) Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 70(23):9742–9754PubMedCrossRef

Title: Association between a novel polymorphism (rs2046210) of the 6q25.1 locus and breast cancer risk
Authors: Ziang Yang
Juping Shen
Zhigang Cao
Biyun Wang
Publication date: 01-05-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-013-2494-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2013

Prevalence of germline TP53 mutations in HER2+ breast cancer patients

Improper use of “radioguided occult lesion localization” (ROLL) technique leads to misleading conclusions

Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis

Hotspot mutations in PIK3CA associate with first-line treatment outcome for aromatase inhibitors but not for tamoxifen

Fixed-dose capecitabine is feasible: results from a pharmacokinetic and pharmacogenetic study in metastatic breast cancer

The impact of breast cosmetic and functional outcomes on quality of life: long-term results from the St. George and Wollongong randomized breast boost trial

Keynote webinar | Spotlight on antibody–drug conjugates in cancer