Common genetic variants in the PSCA gene influence gene expression and bladder cancer risk

Yi Ping Fu, Indu Kohaar, Nathaniel Rothman, Julie Earl, Jonine D. Figueroa, Yuanqing Ye, Núria Malats, Wei Tang, Luyang Liu, Montserrat Garcia-Closas, Brian Muchmore, Nilanjan Chatterjee, McAnthony Tarway, Manolis Kogevinas, Patricia Porter-Gill, Dalsu Baris, Adam Mumy, Demetrius Albanes, Mark P. Purdue, Amy HutchinsonAlfredo Carrato, Adonina Tardón, Consol Serra, Reina García-Closas, Josep Lloreta, Alison Johnson, Molly Schwenn, Margaret R. Karagas, Alan Schned, W. Ryan Diver, Susan M. Gapstur, Michael J. Thun, Jarmo Virtamo, Stephen J. Chanock, Joseph F. Fraumeni*, Debra T. Silverman, Xifeng Wu, Francisco X. Real, Ludmila Prokunina-Olsson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


Genome-wide association studies have identified a SNP, rs2294008, on 8q24.3 within the prostate stem cell antigen (PSCA) gene, as a risk factor for bladder cancer. To fine-map this region, we imputed 642 SNPs within 100 Kb of rs2294008 in addition to 33 markers genotyped in one of the reported genome-wide association study in 8,652 subjects. A multivariable logistic regression model adjusted for rs2294008 revealed a unique signal, rs2978974 (r2 = 0.02,D′ = 0.19 with rs2294008). In the combined analysis of 5,393 cases and 7,324 controls, we detected a per-allele odds ratio (OR) = 1.11 [95% confi- dence interval (CI) = 1.06-1.17, P = 5.8 × 10-5] for rs2294008 and OR = 1.07 (95%CI = 1.02-1.13, P=9.7 × 10-3) for rs2978974. The effect was stronger in carriers of both risk variants (OR = 1.24, 95% CI = 1.08-1.41, P = 1.8 × 10-3) and there was a significant multiplicative interaction (P = 0.035) between these two SNPs, which requires replication in future studies. The T risk allele of rs2294008 was associated with increased PSCA mRNA expression in two sets of bladder tumor samples (n = 36, P = 0.0007 and n = 34, P = 0.0054) and in normal bladder samples (n = 35, P = 0.0155), but rs2978974 was not associated with PSCA expression. SNP rs2978974 is located 10 Kb upstream of rs2294008, within an alternative untranslated first exon of PSCA. The non-risk allele G of rs2978974 showed strong interaction with nuclear proteins from five cell lines tested, implying a regulatory function. In conclusion, a joint effect of two PSCA SNPs, rs2294008 and rs2978974, suggests that both variants may be important for bladder cancer susceptibility, possibly through differentmechanisms that influence the control of mRNA expression and interaction with regulatory factors.

Original languageEnglish
Pages (from-to)4974-4979
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number13
StatePublished - 27 Mar 2012
Externally publishedYes


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