Risk of Estrogen Receptor–Positive and –Negative Breast Cancer and Single–Nucleotide Polymorphism 2q35-rs13387042

Milne, Roger L.; Benı́tez, Javier; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Arias, José Ignacio; Zamora, M. Pilar; Burwinkel, Barbara; Bartram, Claus R.; Meindl, Alfons; Schmutzler, Rita K.; Cox, Angela; Brock, Ian W.; Elliott, Graeme; Reed, Malcolm; Southey, Melissa C.; Smith, Letitia; Spurdle, Amanda B.; Hopper, John L.; Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu; Fredericksen, Zachary S.; Schürmann, Peter; Bremer, Michael; Hillemanns, Peter; Dörk, Thilo; Devilee, Peter; Asperen, C. J. van; Tollenaar, Rob A.E.M.; Seynaeve, Caroline; Hall, Per; Czene, Kamila; Li, Jianjun; Li, Yuqing; Ahmed, Shahana; Dunning, Alison M.; Maranian, Melanie; Pharoah, Paul D.P.; Chenevix-Trench, Georgia; Beesley, Jonathan; Investigators, kConFab; Bogdanova, Natalia; Antonenkova, Natalia; Zalutsky, Iosif V.; Anton‐Culver, Hoda; Ziogas, Argyrios; Brauch, Hiltrud; Justenhoven, Christina; Ko, Yon‐Dschun; Haas, Susanne; Fasching, Peter A.; Strick, Reiner; Ekici, Arif B.; Beckmann, Matthias W.; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; English, Dallas R.; Fletcher, Olivia; Johnson, Nichola; dos‐Santos‐Silva, Isabel; Peto, Julian; Turnbull, Clare; Hines, Sarah; Renwick, Anthony; Rahman, Nazneen; Nordestgaard, Børge G.; Bojesen, Stig E.; Flyger, Henrik; Kang, Daehee; Yoo, Keun-Young; Noh, Dong‐Young; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli‐Matti; García‐Closas, Montserrat; Chanock, Stephen J.; Lissowska, Jolanta; Brinton, Louise A.; Chang‐Claude, Jenny; Wang-Gohrke, Shan; Shen, Chen‐Yang; Wang, Hui‐Chun; Yu, Jyh‐Cherng; Chen, Sou-Tong; Bermisheva, Marina; Николаева, Т. Я.; Хуснутдинова, Э. К.; Humphreys, Manjeet K.; Morrison, Jonathan J.; Platte, Radka; Easton, Douglas F.

doi:10.1093/jnci/djp167

Cited by 99 publications

(73 citation statements)

References 7 publications

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“…However, the selection factors are unlikely to be related to the SNPs of interest. Furthermore, established susceptibility loci have shown the expected associations/odds ratios (ORs) in the GC-HBOC study population [Ahmed et al, 2009;Dunning et al, 2009;Frank et al, 2005;Milne et al, 2009;Shephard et al, 2009].…”

Section: Study Populationmentioning

confidence: 99%

Identification of aDMBT1polymorphism associated with increased breast cancer risk and decreased promoter activity

et al. 2010

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According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C>T, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A>C, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.

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Section: Study Populationmentioning

confidence: 99%

Identification of aDMBT1polymorphism associated with increased breast cancer risk and decreased promoter activity

et al. 2010

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“…Several genome wide association studies (GWAS) have identified the 2q35 region as associated with breast cancer risk (2)(3)(4)(5). Recent work has revealed the complexity of chromatin interactions in the 2q35 region (6) and its involvement in transcriptional regulation of neighbouring gene, IGFBP5 (MIM: 146734).…”

Section: Introductionmentioning

confidence: 99%

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Wyszynski¹,

Hong²,

Lam³

et al. 2016

Hum. Mol. Genet.

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Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERa binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR ¼ 0.68 95%CI 0.55-0.83, P ¼ 0.0002; replication OR ¼ 0.77 95% CI 0.73-0.82, P ¼ 2.1 Â 10 À19 ) and identify 13 additional linked variants (r 2 > 0.8) in the 20Kb linkage block containing the enCNV (P ¼ 3.2 Â 10 À15 À 5.6 Â 10 À17 ). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

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“…Stacey et al identifi ed a SNP on 2q35, a region with no known genes, as associated with breast cancer in Icelandic patients with ER + breast cancer [ 36 ]. Milne et al also found an association with ER − disease, although there was a stronger signal for ER+ [ 41 ]. Other breast cancer associations include signals on 3p24, potentially relating to the genes SLC4A7 or NEK10, and on 17q22, perhaps related to COX11.…”

Section: Common Low-penetrance Breast Cancer Genesmentioning

confidence: 99%

Breast Cancer Genomics

Kumar

2014

Omics Approaches in Breast Cancer

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Breast cancer is a complex disease caused by the progressive accumulation of multiple gene mutations combined with epigenetic dysregulation of critical genes and protein pathways. There is substantial interindividual variability in both the age at diagnosis and phenotypic expression of the disease. With an estimated 1,152,161 new breast cancer cases diagnosed worldwide per year, cancer-control efforts in the post-genome era should be focused at both population and individual levels to develop novel risk assessment and treatment strategies that will further reduce the morbidity and mortality associated with the disease.The discovery that mutations in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancers has radically transformed our understanding of the genetic basis of breast cancer, leading to improved management of high-risk women. A better understanding of tumor host biology has led to improvements in the multidisciplinary management of breast cancer, and traditional pathological evaluation is being complemented by more sophisticated genomic approaches. A number of genomic biomarkers have been developed for clinical use, and increasingly, pharmacogenetic end points are being incorporated into the clinical trial design.For women diagnosed with breast cancer, prognostic or predictive information is most useful when coupled with targeted therapeutic approaches, very few of which exist for women with triple-negative breast cancer or those with tumors resistant to chemotherapy. The immediate challenge is to learn how to use the molecular characteristics of an individual and their tumor to improve detection and treatment and, ultimately, to prevent the development of breast cancer.

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Risk of Estrogen Receptor–Positive and –Negative Breast Cancer and Single–Nucleotide Polymorphism 2q35-rs13387042

Abstract: The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.

Cited by 99 publications

References 7 publications

Identification of aDMBT1polymorphism associated with increased breast cancer risk and decreased promoter activity

Identification of aDMBT1polymorphism associated with increased breast cancer risk and decreased promoter activity

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Breast Cancer Genomics

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