Abstract 2852: Variation in centrosome-related genes and risk of breast cancer
Authors: Olson Janet E. , Wang Xianshu , Pankratz V. Shane , Fredericksen Zachary S. , Vierkant Robert A. , Cerhan James R. , Rider David N. , Vachon Celine M. , Couch Fergus J. 
Published: February 2011

INTRODUCTION: The centrosome is the primary microtubule organizing center of the cell. Numerical or functional defects of the centrosome can result in improper chromosome segregation, leading to aneuploidy and polyploidy. Because many cancer cells have aberrant numbers of chromosomes, many have suggested a link between centrosomes and cancer. We conducted an association study to determine whether common genetic variations in 100 genes involved in maintaining and regulating centrosome structure and function account in part for the contribution of the pathway to breast cancer risk.

METHODS: Incident cases of BC were identified at the Mayo Clinic in Rochester, MN from 2001 through 2005. Controls (N=843) were frequency matched to cases (N=798) on age and region of residence. Seven hundred-eighty-two tagging and candidate functional SNPs were selected from 100 genes involved in the structure and/or function of the centrosome. Genotyping was performed on an Illumina BeadLab using the Illumina GoldenGate genotyping assay. Logistic regression was used to calculate odds ratios and 95% confidence intervals for BC. Women having two copies of the most common allele were defined as the referent category. Linear regression was used to estimate mean and 95% CI for PD for each additional copy of the variant allele. All models were adjusted for age, residence, and confounding factors.

RESULTS: Forty-eight SNPs from 29 genes (out of 782 SNPs examined) showed evidence of significant associations with breast cancer risk in our population in the log-additive (1 degree of freedom (d.f.)) model (Ptrend&lt; 0.05). One SNP, rs1374468 SNP in TACC3, displayed the most significant association with risk in the overall analyses (Ptrend = 0.001). Two SNPs from each of seven genes (AJUBA, CHUK, MCPH1, NEK7, PAK1, PIK3CB, and PINS) were significantly associated with risk of breast cancer (Ptrend &lt; 0.05). Three genes, AXIN2, NIN, NUMA1, had four or more SNPs that were significantly associated with breast cancer risk (Ptrend &lt; 0.05). All of the SNPs in these four genes were in strong linkage disequilibrium (r2&gt;0.6). No single SNP association was significant after adjustment for multiple comparisons via permutation testing.

Haplotype analyses showed 20 genes for which global haplotypes were significantly associated with breast cancer risk. Of these, haplotype blocks in six genes (14-3-3 Epsilon, CDC16, CD-TOG, KIF2, NEK9, NPM2) were significantly associated with risk (global P&lt;0.05), although none of the individual SNPs in these six genes displayed significant associations. This suggests that the associations of these specific combinations of alleles with risk were not due to the effects of individual SNPs.

CONCLUSION: These analyses provide some evidence to support an association between genetic variation in centrosomal genes and risk of breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2852.