Abstract PD05-02: Genome-Wide Associations of Breast Events and Functional Genomic Studies in High-Risk Women Receiving Tamoxifen or Raloxifene on NSABP P1 and P2 Prevention Trials. A Pharmacogenomics Research Network-RIKEN-NSABP Collaboration

Abstract

Background: NSABP P1 and P2 are the largest prevention trials of tamoxifen and raloxifene in women at high risk of developing breast cancer. Both agents have been shown to decrease, but not eliminate breast cancer risk in these women. The goal of our study was to identify single nucleotide polymorphisms (SNPs) associated with development of breast cancer in high-risk women treated with tamoxifen or raloxifene. Methods: We performed a nested matched case-control genome-wide association study (GWAS) in subjects entered on the P2, which included only postmenopausal women, and subjects at least 50 years old entered on the P1 phase III prevention trials who were treated with tamoxifen or raloxifene. Cases were defined as subjects who developed invasive breast cancer or ductal carcinoma in situ and each was matched to two controls based on trial (P1, P2), age at trial entry, Gail risk score, history of lobular carcinoma in situ, and time on study. The study was restricted to the 94% of subjects self-identified as Caucasian. Genotyping was performed with the Illumina Human610-Quad chip. Eigenstrat analyses were performed to control for population stratification. SNPs were imputed within 200 Kb on either side of regions containing SNPs with p ≤ 3E-05. CYP2D6 genotyping was performed on all subjects. Results: The GWAS included 592 cases and 1171 controls. 547,356 SNPs were used in the analyses after removing 14,019 for call rates less than 98%, 30,560 for minor allele frequencies <1%, and 301 with Hardy-Weinberg equilibrium p-value <1E-06. Eigenvectors did not alter the results when used as covariates. Eleven genotyped SNPs with p-values ranging from 2.12E-06 to 9.98E-06 (conditional logistic regression with eigenvector adjustment) were identified; and 22 SNPs with p < 4E-05 were identified by imputation around these SNPs on chromosomes (Chr) 4, 8, 9, 13, 16 and 22, which were then genotyped with the Invader platform. Following imputation and genotyping, initial functional genomic studies have focused on 8 SNPs on Chr 16 (p-values 1.81E-06 to 9.55E-06, with the lowest p-value for an imputed and fine mapped SNP), all of which were in ZNF423, a gene known to encode a protein that associates with SMAD family members. In lymphoblastoid cell lines genotyped for the 2 top SNPs in ZNF423 (rs8060157 and rs11076499) and stably transfected with estrogen receptor-α, the variant and wild type SNPs displayed striking differences in estradiol-induced expression of ZNF423, SMAD3, BRCA1, and BRCA2. Conclusions: This GWAS revealed SNPs associated with the development of breast cancer in high-risk women treated with tamoxifen or raloxifene. Genome-wide significance was not achieved, but SNPs in ZNF423 identified on Chr 16 were associated with differential expression of ZNF423, SMAD3, BRCA1, and BRCA2 in response to estradiol in vitro, providing direction for future research. (Supported in part by NIH grants U01GM61388, U01GM63173, P50CA116201, U10CA77202, U10CA37377, U10CA69974, U24CA114732, and the Biobank Japan Project funded by the Ministry of Education, Culture, Sports, Science and Technology, Japan) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-02.

Gemcitabine metabolic pathway genetic polymorphisms and response in patients with non-small cell lung cancer

“…Other confounding factors such as ATP levels and cell growth rates might also influence drug cytotoxicity assays [46, 47]. However, we have used this same system to successfully interpret SNP signals for other clinical studies and have also used this system to help identify and understand pharmacogenomic candidates [48, 49]. In addition, our functional genomic studies performed with lung cancer cell lines validated several of the candidate SNPs (Fig.…”

Two‐Phase Designs to Follow‐Up Genome‐Wide Association Signals With DNA Resequencing Studies

“…As described elsewhere [Ingle et al, ], a case‐control GWAS was conducted among women treated with either tamoxifen or raloxifene in randomized clinical trials of women at high risk for breast cancer: cases were women who experienced an invasive breast cancer or ductal carcinoma in situ (DCIS) and controls were women who did not experience an invasive breast cancer or DCIS. A total of 592 cases and 1,172 controls were genotyped by the Illumina Human610‐Quad platform, and 547,356 SNPs were analyzed for their association with case‐control status.…”

Using the gene ontology to scan multilevel gene sets for associations in genome wide association studies

“…Aromatase inhibitors are well‐established adjuvant therapies for postmenopausal women with early‐stage breast cancer, yet about half of the patients receiving these types of treatments have joint‐related musculoskeletal complaints, which likely contributes to decreased compliance. A GWAS was performed to identify SNPs associated with musculoskeletal adverse events (MSAEs) in women treated with aromatase inhibitors for early breast cancer [Ingle et al, ]. A nested case‐control design was used to select patients enrolled onto the MA.27 phase III trial that compared the aromatase inhibitors anastrozole and exemestane.…”

“…The gene closest to these four SNPs is the T‐cell leukemia 1A (TCL1A), 926–7,000 bp distance from the SNPs. Further details of the study design and main results can be found in the primary publication [Ingle et al, ]. The analyses presented here include only the SNPs measured on the Illumina platform.…”