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

  1. Author:
    Fu, Y. P.
    Kohaar, I.
    Rothman, N.
    Earl, J.
    Figueroa, J. D.
    Ye, Y.
    Malats, N.
    Tang, W.
    Liu, L.
    Garcia-Closas, M.
    Muchmore, B.
    Chatterjee, N.
    Tarway, M.
    Kogevinas, M.
    Porter-Gill, P.
    Baris, D.
    Mumy, A.
    Albanes, D.
    Purdue, M. P.
    Hutchinson, A.
    Carrato, A.
    Tardon, A.
    Serra, C.
    Garcia-Closas, R.
    Lloreta, J.
    Johnson, A.
    Schwenn, M.
    Karagas, M. R.
    Schned, A.
    Diver, W. R.
    Gapstur, S. M.
    Thun, M. J.
    Virtamo, J.
    Chanock, S. J.
    Fraumeni, J. F.
    Silverman, D. T.
    Wu, X. F.
    Real, F. X.
    Prokunina-Olsson, L.

  2. Author Address

    [Rothman, Nathaniel; Figueroa, Jonine D.; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Baris, Dalsu; Albanes, Demetrius; Purdue, Mark P.; Fraumeni, Joseph F., Jr.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fu, Yi-Ping; Kohaar, Indu; Tang, Wei; Liu, Luyang; Muchmore, Brian; Tarway, McAnthony; Porter-Gill, Patricia; Mumy, Adam; Chanock, Stephen J.; Prokunina-Olsson, Ludmila] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Earl, Julie; Real, Francisco X.] Ctr Nacl Invest Oncol, Epithelial Carcinogenesis Grp, Mol Pathol Programme, Madrid 28029, Spain. [Ye, Yuanqing] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Malats, Nuria] Spanish Natl Canc Res Ctr, Genet & Mol Epidemiol Grp, Madrid 28029, Spain. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. [Kogevinas, Manolis] Ctr Res Environm Epidemiol, Barcelona 08003, Spain. [Kogevinas, Manolis; Tardon, Adonina] Municipal Inst Med Res, Barcelona 08003, Spain. [Kogevinas, Manolis] Ctr Invest Biomed Red Epidemiol & Salud Publ, Barcelona 08003, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens 11521, Greece. [Hutchinson, Amy] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21702 USA. [Carrato, Alfredo] Ramon & Cajal Univ Hosp, Madrid 28034, Spain. [Tardon, Adonina] Univ Oviedo, Inst Univ Oncol, Oviedo 33003, Spain. [Serra, Consol; Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona 08003, Spain. [Lloreta, Josep] Univ Pompeu Fabra, Hosp del Mar, Inst Municipa Invest Med, Barcelona 08003, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna 38320, Spain. [Johnson, Alison] Vermont Canc Registry, Burlington, VT 05401 USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME 04333 USA. [Karagas, Margaret R.; Schned, Alan] Dartmouth Med Sch, Hanover, NH 03755 USA. [Diver, W. Ryan; Gapstur, Susan M.; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00271, Finland.;Fraumeni, JF (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA;fraumeni@nih.gov prokuninal@mail.nih.gov
    1. Year: 2012
    2. Date: Mar
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 109
    2. 13
    3. Pages: 4974-4979
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. Abstract:

    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 (r(2) = 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% confidence interval (CI) = 1.06-1.17, P = 5.8 x 10(-5)] for rs2294008 and OR = 1.07 (95% CI = 1.02-1.13, P= 9.7 x 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 x 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 different mechanisms that influence the control of mRNA expression and interaction with regulatory factors.

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  2. DOI: 10.1073/pnas.1202189109
  3. View record in Web of Science®
  4. WOS: 000302164200055

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  1. Fiscal Year: FY2011-2012
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