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Grant Details

Grant Number: 5R01CA106523-05 Interpret this number
Primary Investigator: Xu, Jianfeng
Organization: Wake Forest University Health Sciences
Project Title: Interaction of Pten and Cdkn1b in PCA Susceptibility
Fiscal Year: 2008
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Abstract

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer among men in the United States and genetic susceptibility is one of the strongest risk factors for this disease. Although the roles of tumor suppressor genes such as PTEN and CDKN1B in tumorigenesis have been well established in multiple cancers, including prostate, studies that examined the independent effect of germline mutations of PTEN and CDKN1B on prostate cancer risk have been limited and generally unsuccessful. Recently, a mouse study clearly demonstrated that combinations of genetic effects at both Pten and Cdknlb, rather than a single gene, cause prostate cancer in mice. In addition, the linkage results from our genome-wide screen also demonstrated a strong interaction between the chromosomal regions at 10q23 (PTEN) and 12pl 3 (CDKNIB). We therefore hypothesize that the interaction of germline mutations in two tumor suppressor genes (PTEN and CDKNIB) affects individual susceptibility to hereditary and non-hereditary prostate cancer. Four specific aims are proposed to test this hypothesis: 1) To sequence the entire transcript and promoter regions of CDKNIB and potentially important regions of PTEN to identify mutations and sequence variants among 188 high risk HPC probands and perform bioinformatic analysis to predict the biological significance of the identified variants; 2) To assess the main effect of each gene and the interaction effect of the two genes in hereditary prostate cancer by testing for linkage and association of the identified mutations/sequence variants with prostate cancer in all 188 HPC families using one-locus and two-locus linkage and association analyses; 3) To assess the main effect of each gene and the interaction effect of the two genes in non-hereditary prostate cancer by testing for association between the identified mutations/sequence variants and prostate cancer in a case-control population using single SNP, haplotype, and MDR approaches; and 4) To evaluate the functional impact of the mutations/sequence variants by measuring the expression of mRNA and protein levels, and alteration in protein functions, for a subset of mutations/sequence variants that are implicated in linkage and association analyses. The results from this study are likely to significant advance our knowledge of prostate cancer risk and begin to explore the underlying biological mechanisms for any observed differences.

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Publications

Genetic markers associated with early cancer-specific mortality following prostatectomy.
Authors: Liu W, Xie CC, Thomas CY, Kim ST, Lindberg J, Egevad L, Wang Z, Zhang Z, Sun J, Sun J, Koty PP, Kader AK, Cramer SD, Bova GS, Zheng SL, Grönberg H, Isaacs WB, Xu J
Source: Cancer, 2013 Jul 1;119(13), p. 2405-12.
EPub date: 2013 Apr 22.
PMID: 23609948
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Identification of new differentially methylated genes that have potential functional consequences in prostate cancer.
Authors: Kim JW, Kim ST, Turner AR, Young T, Smith S, Liu W, Lindberg J, Egevad L, Gronberg H, Isaacs WB, Xu J
Source: PLoS One, 2012;7(10), p. e48455.
EPub date: 2012 Oct 31.
PMID: 23119026
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Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families.
Authors: Bailey-Wilson JE, Childs EJ, Cropp CD, Schaid DJ, Xu J, Camp NJ, Cannon-Albright LA, Farnham JM, George A, Powell I, Carpten JD, Giles GG, Hopper JL, Severi G, English DR, Foulkes WD, Mæhle L, Møller P, Eeles R, Easton D, Guy M, Edwards S, Badzioch MD, Whittemore AS, Oakley-Girvan I, Hsieh CL, Dimitrov L, Stanford JL, Karyadi DM, Deutsch K, McIntosh L, Ostrander EA, Wiley KE, Isaacs SD, Walsh PC, Thibodeau SN, McDonnell SK, Hebbring S, Lange EM, Cooney KA, Tammela TL, Schleutker J, Maier C, Bochum S, Hoegel J, Grönberg H, Wiklund F, Emanuelsson M, Cancel-Tassin G, Valeri A, Cussenot O, Isaacs WB, International Consortium for Prostate Cancer Genetics
Source: BMC Med Genet, 2012 Jun 19;13, p. 46.
EPub date: 2012 Jun 19.
PMID: 22712434
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Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG.
Authors: Lu L, Cancel-Tassin G, Valeri A, Cussenot O, Lange EM, Cooney KA, Farnham JM, Camp NJ, Cannon-Albright LA, Tammela TL, Schleutker J, Hoegel J, Herkommer K, Maier C, Vogel W, Wiklund F, Emanuelsson M, Grönberg H, Wiley KE, Isaacs SD, Walsh PC, Helfand BT, Kan D, Catalona WJ, Stanford JL, FitzGerald LM, Johanneson B, Deutsch K, McIntosh L, Ostrander EA, Thibodeau SN, McDonnell SK, Hebbring S, Schaid DJ, Whittemore AS, Oakley-Girvan I, Hsieh CL, Powell I, Bailey-Wilson JE, Cropp CD, Simpson C, Carpten JD, Seminara D, Zheng SL, Xu J, Giles GG, Severi G, Hopper JL, English DR, Foulkes WD, Maehle L, Moller P, Badzioch MD, Edwards S, Guy M, Eeles R, Easton D, Isaacs WB, International Consortium for Prostate Cancer Genetics
Source: Prostate, 2012 Mar;72(4), p. 410-26.
EPub date: 2011 Jul 11.
PMID: 21748754
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Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women.
Authors: Ivansson EL, Juko-Pecirep I, Erlich HA, Gyllensten UB
Source: Genes Immun, 2011 Dec;12(8), p. 605-14.
EPub date: 2011 Jun 30.
PMID: 21716314
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Comparison of two methods for estimating absolute risk of prostate cancer based on single nucleotide polymorphisms and family history.
Authors: Hsu FC, Sun J, Zhu Y, Kim ST, Jin T, Zhang Z, Wiklund F, Kader AK, Zheng SL, Isaacs W, Grönberg H, Xu J
Source: Cancer Epidemiol Biomarkers Prev, 2010 Apr;19(4), p. 1083-8.
EPub date: 2010 Mar 23.
PMID: 20332264
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Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.
Authors: Xu J, Zheng SL, Isaacs SD, Wiley KE, Wiklund F, Sun J, Kader AK, Li G, Purcell LD, Kim ST, Hsu FC, Stattin P, Hugosson J, Adolfsson J, Walsh PC, Trent JM, Duggan D, Carpten J, Grönberg H, Isaacs WB
Source: Proc Natl Acad Sci U S A, 2010 Feb 2;107(5), p. 2136-40.
EPub date: 2010 Jan 11.
PMID: 20080650
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Association of 17 prostate cancer susceptibility loci with prostate cancer risk in Chinese men.
Authors: Zheng SL, Hsing AW, Sun J, Chu LW, Yu K, Li G, Gao Z, Kim ST, Isaacs WB, Shen MC, Gao YT, Hoover RN, Xu J
Source: Prostate, 2010 Mar 1;70(4), p. 425-32.
PMID: 19866473
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Estimation of absolute risk for prostate cancer using genetic markers and family history.
Authors: Xu J, Sun J, Kader AK, Lindström S, Wiklund F, Hsu FC, Johansson JE, Zheng SL, Thomas G, Hayes RB, Kraft P, Hunter DJ, Chanock SJ, Isaacs WB, Grönberg H
Source: Prostate, 2009 Oct 1;69(14), p. 1565-72.
PMID: 19562736
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Fine-mapping and family-based association analyses of prostate cancer risk variants at Xp11.
Authors: Lu L, Sun J, Isaacs SD, Wiley KE, Smith S, Pruett K, Zhu Y, Zhang Z, Wiklund F, Grönberg H, Walsh PC, Chang BL, Zheng SL, Isaacs WB, Xu J
Source: Cancer Epidemiol Biomarkers Prev, 2009 Jul;18(7), p. 2132-6.
EPub date: 2009 Jun 23.
PMID: 19549809
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Prostate cancer risk associated loci in African Americans.
Authors: Xu J, Kibel AS, Hu JJ, Turner AR, Pruett K, Zheng SL, Sun J, Isaacs SD, Wiley KE, Kim ST, Hsu FC, Wu W, Torti FM, Walsh PC, Chang BL, Isaacs WB
Source: Cancer Epidemiol Biomarkers Prev, 2009 Jul;18(7), p. 2145-9.
EPub date: 2009 Jun 23.
PMID: 19549807
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Two independent prostate cancer risk-associated Loci at 11q13.
Authors: Zheng SL, Stevens VL, Wiklund F, Isaacs SD, Sun J, Smith S, Pruett K, Wiley KE, Kim ST, Zhu Y, Zhang Z, Hsu FC, Turner AR, Johansson JE, Liu W, Kim JW, Chang BL, Duggan D, Carpten J, Rodriguez C, Isaacs W, Grönberg H, Xu J
Source: Cancer Epidemiol Biomarkers Prev, 2009 Jun;18(6), p. 1815-20.
PMID: 19505914
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Individual and cumulative effect of prostate cancer risk-associated variants on clinicopathologic variables in 5,895 prostate cancer patients.
Authors: Kader AK, Sun J, Isaacs SD, Wiley KE, Yan G, Kim ST, Fedor H, DeMarzo AM, Epstein JI, Walsh PC, Partin AW, Trock B, Zheng SL, Xu J, Isaacs W
Source: Prostate, 2009 Aug 1;69(11), p. 1195-205.
PMID: 19434657
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A novel prostate cancer susceptibility locus at 19q13.
Authors: Hsu FC, Sun J, Wiklund F, Isaacs SD, Wiley KE, Purcell LD, Gao Z, Stattin P, Zhu Y, Kim ST, Zhang Z, Liu W, Chang BL, Walsh PC, Duggan D, Carpten JD, Isaacs WB, Grönberg H, Xu J, Zheng SL
Source: Cancer Res, 2009 Apr 1;69(7), p. 2720-3.
EPub date: 2009 Mar 24.
PMID: 19318570
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Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer.
Authors: Liu W, Sun J, Li G, Zhu Y, Zhang S, Kim ST, Sun J, Wiklund F, Wiley K, Isaacs SD, Stattin P, Xu J, Duggan D, Carpten JD, Isaacs WB, Grönberg H, Zheng SL, Chang BL
Source: Cancer Res, 2009 Mar 15;69(6), p. 2176-9.
EPub date: 2009 Mar 3.
PMID: 19258504
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Genetic variants and family history predict prostate cancer similar to prostate-specific antigen.
Authors: Zheng SL, Sun J, Wiklund F, Gao Z, Stattin P, Purcell LD, Adami HO, Hsu FC, Zhu Y, Adolfsson J, Johansson JE, Turner AR, Adams TS, Liu W, Duggan D, Carpten JD, Chang BL, Isaacs WB, Xu J, Grönberg H
Source: Clin Cancer Res, 2009 Feb 1;15(3), p. 1105-11.
PMID: 19188186
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Fine mapping association study and functional analysis implicate a SNP in MSMB at 10q11 as a causal variant for prostate cancer risk.
Authors: Chang BL, Cramer SD, Wiklund F, Isaacs SD, Stevens VL, Sun J, Smith S, Pruett K, Romero LM, Wiley KE, Kim ST, Zhu Y, Zhang Z, Hsu FC, Turner AR, Adolfsson J, Liu W, Kim JW, Duggan D, Carpten J, Zheng SL, Rodriguez C, Isaacs WB, Grönberg H, Xu J
Source: Hum Mol Genet, 2009 Apr 1;18(7), p. 1368-75.
EPub date: 2009 Jan 19.
PMID: 19153072
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Sequence variants at 22q13 are associated with prostate cancer risk.
Authors: Sun J, Zheng SL, Wiklund F, Isaacs SD, Li G, Wiley KE, Kim ST, Zhu Y, Zhang Z, Hsu FC, Turner AR, Stattin P, Liu W, Kim JW, Duggan D, Carpten J, Isaacs W, Grönberg H, Xu J, Chang BL
Source: Cancer Res, 2009 Jan 1;69(1), p. 10-5.
PMID: 19117981
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Association of reported prostate cancer risk alleles with PSA levels among men without a diagnosis of prostate cancer.
Authors: Wiklund F, Zheng SL, Sun J, Adami HO, Lilja H, Hsu FC, Stattin P, Adolfsson J, Cramer SD, Duggan D, Carpten JD, Chang BL, Isaacs WB, Grönberg H, Xu J
Source: Prostate, 2009 Mar 1;69(4), p. 419-27.
PMID: 19116992
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Genetic and epigenetic inactivation of LPL gene in human prostate cancer.
Authors: Kim JW, Cheng Y, Liu W, Li T, Yegnasubramanian S, Zheng SL, Xu J, Isaacs WB, Chang BL
Source: Int J Cancer, 2009 Feb 1;124(3), p. 734-8.
PMID: 19004026
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Association of prostate cancer risk variants with clinicopathologic characteristics of the disease.
Authors: Xu J, Isaacs SD, Sun J, Li G, Wiley KE, Zhu Y, Hsu FC, Wiklund F, Turner AR, Adams TS, Liu W, Trock BJ, Partin AW, Chang B, Walsh PC, Grönberg H, Isaacs W, Zheng S
Source: Clin Cancer Res, 2008 Sep 15;14(18), p. 5819-24.
PMID: 18794092
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Family-based samples can play an important role in genetic association studies.
Authors: Lange EM, Sun J, Lange LA, Zheng SL, Duggan D, Carpten JD, Gronberg H, Isaacs WB, Xu J, Chang BL
Source: Cancer Epidemiol Biomarkers Prev, 2008 Sep;17(9), p. 2208-14.
PMID: 18768484
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Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12.
Authors: Sun J, Zheng SL, Wiklund F, Isaacs SD, Purcell LD, Gao Z, Hsu FC, Kim ST, Liu W, Zhu Y, Stattin P, Adami HO, Wiley KE, Dimitrov L, Sun J, Li T, Turner AR, Adams TS, Adolfsson J, Johansson JE, Lowey J, Trock BJ, Partin AW, Walsh PC, Trent JM, Duggan D, Carpten J, Chang BL, Grönberg H, Isaacs WB, Xu J
Source: Nat Genet, 2008 Oct;40(10), p. 1153-5.
EPub date: 2008 Aug 31.
PMID: 18758462
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Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer.
Authors: Liu W, Xie CC, Zhu Y, Li T, Sun J, Cheng Y, Ewing CM, Dalrymple S, Turner AR, Sun J, Isaacs JT, Chang BL, Zheng SL, Isaacs WB, Xu J
Source: Neoplasia, 2008 Aug;10(8), p. 897-907.
PMID: 18670647
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A multigenic approach to evaluating prostate cancer risk in a systematic replication study.
Authors: Hsu FC, Lindström S, Sun J, Wiklund F, Chen SH, Adami HO, Turner AR, Liu W, Bälter K, Kim JW, Stattin P, Chang BL, Isaacs WB, Xu J, Grönberg H, Zheng SL
Source: Cancer Genet Cytogenet, 2008 Jun;183(2), p. 94-8.
PMID: 18503826
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Cumulative effect of five genetic variants on prostate cancer risk in multiple study populations.
Authors: Sun J, Chang BL, Isaacs SD, Wiley KE, Wiklund F, Stattin P, Duggan D, Carpten JD, Trock BJ, Partin AW, Walsh PC, Grönberg H, Xu J, Isaacs WB, Zheng SL
Source: Prostate, 2008 Sep 1;68(12), p. 1257-62.
PMID: 18491292
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Association between sequence variants at 17q12 and 17q24.3 and prostate cancer risk in European and African Americans.
Authors: Sun J, Purcell L, Gao Z, Isaacs SD, Wiley KE, Hsu FC, Liu W, Duggan D, Carpten JD, Grönberg H, Xu J, Chang BL, Partin AW, Walsh PC, Isaacs WB, Zheng SL
Source: Prostate, 2008 May 15;68(7), p. 691-7.
PMID: 18361410
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Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer.
Authors: Gudmundsson J, Sulem P, Rafnar T, Bergthorsson JT, Manolescu A, Gudbjartsson D, Agnarsson BA, Sigurdsson A, Benediktsdottir KR, Blondal T, Jakobsdottir M, Stacey SN, Kostic J, Kristinsson KT, Birgisdottir B, Ghosh S, Magnusdottir DN, Thorlacius S, Thorleifsson G, Zheng SL, Sun J, Chang BL, Elmore JB, Breyer JP, McReynolds KM, Bradley KM, Yaspan BL, Wiklund F, Stattin P, Lindström S, Adami HO, McDonnell SK, Schaid DJ, Cunningham JM, Wang L, Cerhan JR, St Sauver JL, Isaacs SD, Wiley KE, Partin AW, Walsh PC, Polo S, Ruiz-Echarri M, Navarrete S, Fuertes F, Saez B, Godino J, Weijerman PC, Swinkels DW, Aben KK, Witjes JA, Suarez BK, Helfand BT, Frigge ML, Kristjansson K, Ober C, Jonsson E, Einarsson GV, Xu J, Gronberg H, Smith JR, Thibodeau SN, Isaacs WB, Catalona WJ, Mayordomo JI, Kiemeney LA, Barkardottir RB, Gulcher JR, Thorsteinsdottir U, Kong A, Stefansson K
Source: Nat Genet, 2008 Mar;40(3), p. 281-3.
EPub date: 2008 Feb 10.
PMID: 18264098
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Chromosome 8q24 risk variants in hereditary and non-hereditary prostate cancer patients.
Authors: Sun J, Lange EM, Isaacs SD, Liu W, Wiley KE, Lange L, Gronberg H, Duggan D, Carpten JD, Walsh PC, Xu J, Chang BL, Isaacs WB, Zheng SL
Source: Prostate, 2008 Apr 1;68(5), p. 489-97.
PMID: 18213635
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Cumulative association of five genetic variants with prostate cancer.
Authors: Zheng SL, Sun J, Wiklund F, Smith S, Stattin P, Li G, Adami HO, Hsu FC, Zhu Y, Bälter K, Kader AK, Turner AR, Liu W, Bleecker ER, Meyers DA, Duggan D, Carpten JD, Chang BL, Isaacs WB, Xu J, Grönberg H
Source: N Engl J Med, 2008 Feb 28;358(9), p. 910-9.
EPub date: 2008 Jan 16.
PMID: 18199855
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Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP.
Authors: Duggan D, Zheng SL, Knowlton M, Benitez D, Dimitrov L, Wiklund F, Robbins C, Isaacs SD, Cheng Y, Li G, Sun J, Chang BL, Marovich L, Wiley KE, Bälter K, Stattin P, Adami HO, Gielzak M, Yan G, Sauvageot J, Liu W, Kim JW, Bleecker ER, Meyers DA, Trock BJ, Partin AW, Walsh PC, Isaacs WB, Grönberg H, Xu J, Carpten JD
Source: J Natl Cancer Inst, 2007 Dec 19;99(24), p. 1836-44.
EPub date: 2007 Dec 11.
PMID: 18073375
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Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans.
Authors: Zheng SL, Sun J, Cheng Y, Li G, Hsu FC, Zhu Y, Chang BL, Liu W, Kim JW, Turner AR, Gielzak M, Yan G, Isaacs SD, Wiley KE, Sauvageot J, Chen HS, Gurganus R, Mangold LA, Trock BJ, Gronberg H, Duggan D, Carpten JD, Partin AW, Walsh PC, Xu J, Isaacs WB
Source: J Natl Cancer Inst, 2007 Oct 17;99(20), p. 1525-33.
EPub date: 2007 Oct 9.
PMID: 17925536
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Deletion of a small consensus region at 6q15, including the MAP3K7 gene, is significantly associated with high-grade prostate cancers.
Authors: Liu W, Chang BL, Cramer S, Koty PP, Li T, Sun J, Turner AR, Von Kap-Herr C, Bobby P, Rao J, Zheng SL, Isaacs WB, Xu J
Source: Clin Cancer Res, 2007 Sep 1;13(17), p. 5028-33.
PMID: 17785553
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