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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095052-02
Application #
6800132
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Seminara, Daniela
Project Start
2003-09-10
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$282,476
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Liu, Wennuan; Xie, Chunmei C; Thomas, Christopher Y et al. (2013) Genetic markers associated with early cancer-specific mortality following prostatectomy. Cancer 119:2405-12
Bailey-Wilson, Joan E; Childs, Erica J; Cropp, Cheryl D et al. (2012) Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families. BMC Med Genet 13:46
Kim, Jin W; Kim, Seong-Tae; Turner, Aubrey R et al. (2012) Identification of new differentially methylated genes that have potential functional consequences in prostate cancer. PLoS One 7:e48455
Lu, Lingyi; Cancel-Tassin, Geraldine; Valeri, Antoine et al. (2012) Chromosomes 4 and 8 implicated in a genome wide SNP linkage scan of 762 prostate cancer families collected by the ICPCG. Prostate 72:410-26
Cheng, Yu; Liu, Wennuan; Kim, Seong-Tae et al. (2011) Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study. Cancer Genet 204:375-81
Ivansson, E L; Juko-Pecirep, I; Erlich, H A et al. (2011) Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women. Genes Immun 12:605-14
Xie, Chunmei C; Lu, Lingyi; Sun, Jielin et al. (2011) Germ-line sequence variants of PTEN do not have an important role in hereditary and non-hereditary prostate cancer susceptibility. J Hum Genet 56:496-502
Xu, Jianfeng; Zheng, Siqun Lilly; Isaacs, Sarah D et al. (2010) Inherited genetic variant predisposes to aggressive but not indolent prostate cancer. Proc Natl Acad Sci U S A 107:2136-40
Hsu, Fang-Chi; Sun, Jielin; Zhu, Yi et al. (2010) Comparison of two methods for estimating absolute risk of prostate cancer based on single nucleotide polymorphisms and family history. Cancer Epidemiol Biomarkers Prev 19:1083-8
Zheng, Siqun Lilly; Hsing, Ann W; Sun, Jielin et al. (2010) Association of 17 prostate cancer susceptibility loci with prostate cancer risk in Chinese men. Prostate 70:425-32

Showing the most recent 10 out of 55 publications