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Grant Details

Grant Number: 5R01CA119069-05 Interpret this number
Primary Investigator: Xu, Jianfeng
Organization: Wake Forest University Health Sciences
Project Title: Qtl Mapping for Genes Regulating Apoptosis Capacity
Fiscal Year: 2010
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Abstract

DESCRIPTION (provided by applicant): Apoptosis is a highly conserved, continuous physiological process for non-inflammatory cell death, and the dysregulation of apoptosis has been shown to contribute to the initiation and progression of the tumorigenesis process. Variations in apoptosis capacity are expected to influence an individual's risk and progression of cancers, and an improved understanding of the variation in apoptosis capacity between individuals is likely to be beneficial in the prognosis and treatment of various diseases. However, apoptosis is a complex process that involves hundreds of proteins and is composed of multiple levels of redundancy, which makes it is difficult and tedious to dissect the major players that determine apoptosis capacity at the molecular level by in vitro experiments and animal models. Here we propose an alternative approach to pinpoint the major determinants of apoptosis through the identification of quantitative trait loci (QTL) that determine apoptosis capacity using a linkage analysis in a collection of informative families. These apoptosis QTL will then be followed up by a positional candidate gene approach that focuses only on the functionally relevant genes in the target chromosomal regions, thus quickly narrowing down the search to genes that contribute to variations in apoptosis capacity and are most directly relevant to human diseases in the general population. In this grant application, we propose to investigate the genetic variations and determinants of apoptosis capacity, using a large collection of 188 hereditary prostate cancer (HPC) families. Using an existing genome-wide scan marker dataset, we can systematically identify chromosomal regions likely to contain genes responsible for determining individuals' apoptosis capacity, in contrast to subjective selection of specific genes for evaluation. Furthermore, we can compare the results from genome-wide screens for apoptosis capacity with the results from our previous genome-wide screens for hereditary prostate cancer, clinically significant prostate cancer, and all types of cancers to identify apoptosis genes that have the greatest impact on cancer susceptibility. Our proposal describes a novel and efficient approach to identify apoptosis genes that are critical in cancer susceptibility.

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Publications

HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).
Authors: Xu J, Lange EM, Lu L, Zheng SL, Wang Z, Thibodeau SN, Cannon-Albright LA, Teerlink CC, Camp NJ, Johnson AM, Zuhlke KA, Stanford JL, Ostrander EA, Wiley KE, Isaacs SD, Walsh PC, Maier C, Luedeke M, Vogel W, Schleutker J, Wahlfors T, Tammela T, Schaid D, McDonnell SK, DeRycke MS, Cancel-Tassin G, Cussenot O, Wiklund F, Grönberg H, Eeles R, Easton D, Kote-Jarai Z, Whittemore AS, Hsieh CL, Giles GG, Hopper JL, Severi G, Catalona WJ, Mandal D, Ledet E, Foulkes WD, Hamel N, Mahle L, Moller P, Powell I, Bailey-Wilson JE, Carpten JD, Seminara D, Cooney KA, Isaacs WB, International Consortium for Prostate Cancer Genetics
Source: Hum Genet, 2013 Jan;132(1), p. 5-14.
EPub date: 2012 Oct 12.
PMID: 23064873
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Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG).
Authors: Jin G, Lu L, Cooney KA, Ray AM, Zuhlke KA, Lange EM, Cannon-Albright LA, Camp NJ, Teerlink CC, Fitzgerald LM, Stanford JL, Wiley KE, Isaacs SD, Walsh PC, Foulkes WD, Giles GG, Hopper JL, Severi G, Eeles R, Easton D, Kote-Jarai Z, Guy M, Rinckleb A, Maier C, Vogel W, Cancel-Tassin G, Egrot C, Cussenot O, Thibodeau SN, McDonnell SK, Schaid DJ, Wiklund F, Grönberg H, Emanuelsson M, Whittemore AS, Oakley-Girvan I, Hsieh CL, Wahlfors T, Tammela T, Schleutker J, Catalona WJ, Zheng SL, Ostrander EA, Isaacs WB, Xu J, International Consortium for Prostate Cancer Genetics
Source: Hum Genet, 2012 Jul;131(7), p. 1095-103.
EPub date: 2011 Dec 25.
PMID: 22198737
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Identification of novel CHD1-associated collaborative alterations of genomic structure and functional assessment of CHD1 in prostate cancer.
Authors: Liu W, Lindberg J, Sui G, Luo J, Egevad L, Li T, Xie C, Wan M, Kim ST, Wang Z, Turner AR, Zhang Z, Feng J, Yan Y, Sun J, Bova GS, Ewing CM, Yan G, Gielzak M, Cramer SD, Vessella RL, Zheng SL, Grönberg H, Isaacs WB, Xu J
Source: Oncogene, 2012 Aug 30;31(35), p. 3939-48.
EPub date: 2011 Dec 5.
PMID: 22139082
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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.
PMID: 19035483
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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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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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Assembly of inflammation-related genes for pathway-focused genetic analysis.
Authors: Loza MJ, McCall CE, Li L, Isaacs WB, Xu J, Chang BL
Source: PLoS One, 2007 Oct 17;2(10), p. e1035.
EPub date: 2007 Oct 17.
PMID: 17940599
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Association between Q551R IL4R genetic variants and atopic asthma risk demonstrated by meta-analysis.
Authors: Loza MJ, Chang BL
Source: J Allergy Clin Immunol, 2007 Sep;120(3), p. 578-85.
EPub date: 2007 Jun 21.
PMID: 17586032
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