title: Association of genetic variation in genes implicated in the beta-catenin destruction complex with risk of breast cancer.
abstract: Aberrant Wnt/beta-catenin signaling leading to nuclear accumulation of the oncogene product beta-catenin is observed in a wide spectrum of human malignancies. The destruction complex in the Wnt/beta-catenin pathway is critical for regulating the level of beta-catenin in the cytoplasm and in the nucleus. Here, we report a comprehensive study of the contribution of genetic variation in six genes encoding the beta-catenin destruction complex (APC, AXIN1, AXIN2, CSNK1D, CSNK1E, and GSK3B) to breast cancer using a Mayo Clinic Breast Cancer Case-Control Study. A total of 79 candidate functional and tagging single nucleotide polymorphisms (SNP) were genotyped in 798 invasive cases and 843 unaffected controls. Of these, rs454886 in the APC tumor suppressor gene was associated with increased breast cancer risk (per allele odds ratio, 1.23; 95% confidence intervals, 1.05-1.43; P(trend) = 0.01). In addition, five SNPs in AXIN2 were associated with increased risk of breast cancer (P(trend) < 0.05). Haplotype-based tests identified significant associations between specific haplotypes in APC and AXIN2 (P < or = 0.03) and breast cancer risk. Further characterization of the APC and AXIN2 variants suggested that AXIN2 rs4791171 was significantly associated with risk in premenopausal (P(trend) = 0.0002) but not in postmenopausal women. The combination of our findings and numerous genetic and functional studies showing that APC and AXIN2 perform crucial tumor suppressor functions suggest that further investigation of the contribution of AXIN2 and APC SNPs to breast cancer risk are needed.
authors: Department of Laboratory Medicine and Pathology, Mayo Clinic, Stabile 2-42, 200 First Street Southwest, Rochester, MN 55905, USA.
authors: Xianshu
authors: X
authors: Wang
authors: Ellen L
authors: EL
authors: Goode
authors: Zachary S
authors: ZS
authors: Fredericksen
authors: Robert A
authors: RA
authors: Vierkant
authors: V Shane
authors: VS
authors: Pankratz
authors: Wen
authors: W
authors: Liu-Mares
authors: David N
authors: DN
authors: Rider
authors: Celine M
authors: CM
authors: Vachon
authors: James R
authors: JR
authors: Cerhan
authors: Janet E
authors: JE
authors: Olson
authors: Fergus J
authors: FJ
authors: Couch
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D009361:Neoplasm Invasiveness; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012306:Risk; D051176:beta Catenin / Q000235:genetics*
chemical_list: D011518:Proto-Oncogene Proteins; D051176:beta Catenin