Wu, Lang

Abstract Introduction: Laboratory studies have demonstrated that zinc and zinc transporters play important roles in the development of urological cancers, including prostate, bladder, and renal cell cancer. To date however, there have been no efforts to evaluate whether germline variation in zinc transporter genes alter the risk of developing these cancers. Motivated by this, we evaluated associations of known variants in zinc transporter genes with risk of prostate, bladder, and renal cell cancer using three NCI Genome Wide Association Study (GWAS) data sets downloaded from dbGaP. Methods: Data consisted of GWAS data from the PLCO Screening Trial (prostate; 1172 cases, 1157 controls); Bladder Cancer study (3527 cases, 5119 controls); and Renal Cancer study (1453 cases, 3531 controls). All genotyped variants in 10 ZNT family genes (ZNT1-ZNT10) and 14 ZIP family genes (ZIP1-ZIP14) in each data set were analyzed by logistic regression models to evaluate the association of each variant with risk of developing prostate, bladder, and renal cancer, respectively. We evaluated these associations in a univariable setting, after adjusting for available covariates, such as age and gender. Correction for multiple comparisons used Max T permutation tests. Results: One variant in ZIP11, rs8081059, was associated with increased risk of renal cancer (OR=1.28, 95% CI= 1.13-1.45; corrected p= 0.049). Another ZIP11 variant, rs11871756, was associated with an increased risk of bladder cancer risk (OR=1.43, 95% CI 1.24-1.63; corrected p=0.0002). We also found three variants in ZIP11 associated with a decreased risk of bladder cancer: rs11077654 (OR=0.76, 95% CI 0.68-0.85; corrected p=0.001), rs9913017 (OR=0.76, 95% CI= 0.68-0.85; corrected p=0.002), and rs4969054 (OR=0.78, 95% CI 0.69-0.88; corrected p=0.02). Interestingly, these three protective variants are within the same LD block. There were no associations between zinc transporter variants and prostate cancer risk. Conclusion: We report for the first time that specific genetic variants of a zinc transporter gene, ZIP11, are associated with risk of renal and bladder cancer. If validated in larger, more focused studies, further investigations are warranted to explore the functional significance of ZIP11 in these two cancers. Citation Format: Lang Wu, Kari G. Rabe, Alexander S. Parker, Gloria M. Petersen. ZIP11 and susceptibility to renal and bladder cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A52.

Abstract Background: Large-scale genome-wide association studies (GWAS) have identified ~35 loci associated with epithelial ovarian cancer risk. However, these genetic loci together explain only a small portion of the heritability of this malignancy. The large majority of the GWAS-identified variants are located in non-coding regions, thus possible causal genes in these loci remain largely unknown. We performed a transcriptome-wide association study (TWAS) to search for novel genetic loci for ovarian cancer risk and plausible causal genes at GWAS-identified loci. Method: Transcriptome data from normal ovarian tissue samples (n=68) and all tissue samples (n = 369), along with their high-density genotyping data, obtained from only European descendants included in the Genotype-Tissue Expression Project (GTEx), were used to build ovarian linear prediction models and cross-tissue models (to increase statistical power) using the elastic net method. Based on model performance, we evaluated 17,121 genes for their cis-predicted gene expressions in relation to ovarian cancer risk using summary statistics data generated in GWAS of ovarian cancer from 25,509 cases and 40,941 controls. MetaXcan was used to integrate gene expression prediction model with summary statistics. Results: We identified 35 genes with predicted expression levels associated with ovarian cancer risk at P value < 2.2 × 10-6, the Bonferroni corrected significance level for multiple comparisons. Of these, 12 genes at 4 genetic loci are located ≥500kb away from risk SNPs previously reported in GWAS, representing potential novel genetic loci for ovarian cancer risk. The remaining 23 genes at 12 loci are located within known ovarian cancer risk loci. Fifteen of these genes at the 12 loci have not been reported in previous studies. Analyses by ovarian cancer histological subtypes showed that the majority of these 35 genes are associated with serous invasive carcinoma. Several new associations were identified in histological subtype analyses. Conclusion: In this TWAS we identified multiple genes with predicted expressions related to ovarian cancer risk and provide substantial new information to enhance the understanding of ovarian cancer biology and genetics. Citation Format: Yingchang Lu, Joellen M. Schildkraut, Thomas A. Sellers, Lang Wu, Xingyi Guo, Bingshan Li, Y. Ann Chen, Jennifer B. Doherty, Simon Gayther, Ellen L. Goode, Hae Kyung Im, Siddhartha Kar, Kate Lawrenson, Ani W. Manichaikul, Jennifer B. Permuth, Brett M. Reid, Jamie K. Teer, Paul Pharoah, Wei Zheng, Jirong Long. Transcriptome-wide association study among 66,450 women to identify candidate susceptible genes for ovarian cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1308. doi:10.1158/1538-7445.AM2017-1308