Aneuploidy and polyploidy associated with chromosomal instability are hallmarks of many breast cancers and have been implicated as some of the earliest steps in tumor formation. Recent evidence has established that aneuploidy/polyploidy can even predispose to breast cancer. While much is already known about the molecular mechanisms leading to aneuploidy/polyploidy, little is understood at the genetic and epidemiological level. We hypothesize that inherited variation in genes involved in regulating cell division contribute to the development of aneuploidy/polyploidy and subsequently to breast cancer. We propose a comprehensive multi stage approach to the study of genes involved in regulation of cell division using single variants and haplotypes. We will identify candidate variants and haplotypes associated with breast cancer risk in the Mayo Clinic Breast Cancer case-control Study and validate the associations in the Anglican Breast Cancer (ABC) Study. The genes containing the variants will be resequenced and haplotyped tagging variants representing small haplotype blocks will be selected and re-genotyped in an expanded Mayo Clinic Breast Cancer Study to identify the specific variants or haplotype blocks that account for the association with breast cancer risk. These variants and haplotypes will be validated in an expanded ABC study and the influence of these SNPs on gene expression and function will be characterized.
Our specific aims are:
Aim #1 : To identify and confirm associations between Single Nucleotide Polymorphisms (SNPs) and haplotypes in genes that regulate cell division and breast cancer risk.
Specific Aim #2 : To characterize all genetic variation in the genes displaying association with breast cancer risk in the Mayo Clinic Breast Cancer Study population.
Specific Aim #3 : To identify the variants in these genes that account for the modified risk of cancer.
Specific Aim #4 : To characterize the functional significance of inherited variation in mitotic regulation genes that is associated with breast cancer risk. This study will address the contribution of the under-evaluated area of regulation of cell division to breast cancer etiology. The study will go beyond identification of risk markers to the characterization of the variants that actually cause the modification of breast cancer risk. The results will provide information for improved risk assessment and could provide targets for breast cancer prevention and therapeutic agents.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Epidemiology of Cancer Study Section (EPIC)
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Martin, Damali
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Mayo Clinic, Rochester
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Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2 (see original citation for additional authors) (2016) No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer. Gynecol Oncol 141:386-401
Shi, Jiajun; Zhang, Yanfeng; Zheng, Wei et al. (2016) Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer. Int J Cancer 139:1303-1317
Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki et al. (2016) Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry. Cancer Causes Control 27:679-93
Dunning, Alison M (see original citation for additional authors) (2016) Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170. Nat Genet 48:374-86
Mavaddat, Nasim; Pharoah, Paul D P; Michailidou, Kyriaki et al. (2015) Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst 107:
Stone, Jennifer; Thompson, Deborah J; Dos Santos Silva, Isabel et al. (2015) Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures. Cancer Res 75:2457-67
Guo, Qi; Schmidt, Marjanka K; Kraft, Peter et al. (2015) Identification of novel genetic markers of breast cancer survival. J Natl Cancer Inst 107:
Pirie, Ailith; Guo, Qi; Kraft, Peter et al. (2015) Common germline polymorphisms associated with breast cancer-specific survival. Breast Cancer Res 17:58
Guo, Xingyi; Long, Jirong; Zeng, Chenjie et al. (2015) Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk. Cancer Epidemiol Biomarkers Prev 24:1680-91
Milne, Roger L; Herranz, Jesús; Michailidou, Kyriaki et al. (2014) A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46,450 cases and 42,461 controls from the breast cancer association consortium. Hum Mol Genet 23:1934-46

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