|Grant Number:||5R01CA095052-05 Interpret this number|
|Primary Investigator:||Xu, Jianfeng|
|Organization:||Wake Forest University Health Sciences|
|Project Title:||Mapping Prostate Cancer Susceptibility Genes at 8p22-23|
DESCRIPTION (provided by applicant): A gene or genes on chromosome arm 8p have been implicated in prostate carcinogenesis since the original observation of frequent deletions of this arm in prostate cancer cells was described over 10 years ago. However, no definitive prostate cancer gene on 8p has been identified. Recently, a series of new observations from our laboratory and other groups implicate germ line variations of 8p as an important genetic component of prostate carcino genesis, including: 1) demonstration of linkage at 8p22-23 in families with hereditary prostate cancer (HPC) in multiple studies; 2) observation of germ line rearrangements (inversions, duplications) involving 8p22-23 in HPC patients; 3) the most recent finding by our group that the MSR1 (macrophage scavenger receptor 1) gene is associated with prostate cancer risk; and 4) evidence for additional prostate cancer genes at 8p22-23 as positive linkage remains and shifts to the telomeric side of the 8p22-23 region in families without MSR1 mutations. We therefore hypothesize that additional germline sequence variants in genes on 8p22-23 increase individual susceptibility to prostate cancer, as well as that MSR1 is a major prostate cancer susceptibility gene. To test these hypotheses, we propose to use a combination of linkage, sequencing, family-based association studies, and functional studies in a large and unique collection of 206 HPC families with at least three men with prostate cancer. We have the following three specific aims: 1) Obtain further evidence for MSR1 as a major prostate cancer susceptibility gene by screening for known and novel MSR1 mutations and assessing their co-segregation with prostate cancer in the 47 newly collected families and additional family members of the 11 families with MSR1 mutations. 2) Identify mutations/sequence variants in other genes at the tetomeric side of the 8p22-23 linkage region using direct sequencing in probands of the families without MSR1 mutations. 3) Assess the association between the identified mutations/sequence variants and prostate cancer risk by performing family-based association tests. 4) Begin to evaluate the functional changes of the mutations/sequence variants by measuring the expression of mRNA and protein levels for a subset of mutations/sequence variants that are associated with prostate cancer risk. Successful identification of prostate cancer genes will have a significant impact on understanding the etiology, prevention, diagnosis, and treatment of prostate cancer.
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.
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.
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.
Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study.
Authors: Cheng Y, Liu W, Kim ST, Sun J, Lu L, Sun J, Zheng SL, Isaacs WB, Xu J
Source: Cancer Genet, 2011 Jul;204(7), p. 375-81.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Genetic and epigenetic inactivation of TNFRSF10C in human prostate cancer.
Authors: Cheng Y, Kim JW, Liu W, Dunn TA, Luo J, Loza MJ, Kim ST, Zheng SL, Xu J, Isaacs WB, Chang BL
Source: Prostate, 2009 Feb 15;69(3), p. 327-35.