Mapping Prostate Cancer Susceptibility Genes At 8p22-23
Jianfeng Xu, Professor
Wake Forest University Health Sciences Medical Center Blvd Winston-salem, Nc 27157
Grant 5R01CA095052-05 from National Cancer Institute IRG: EDC
Abstract: 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.
Keywords: cancer risk, chromosome, genetic susceptibility, linkage disequilibrium, neoplasm /cancer genetics, prostate neoplasm, chromosome movement, functional /structural genomics, gene mutation, genetic disorder diagnosis, genetic polymorphism, genetic screening, genotype, macrophage, nucleic acid sequence, scavenger receptor, clinical research, gel mobility shift assay, human subject, microarray technology, polymerase chain reaction
Project start date: 2003-09-10
Project end date: 2008-06-30
5R01CA095052-05 (2007): $264602
Sponsored Links Excellgen http://Excellgen.com
Mapping Prostate Cancer Susceptibility Genes At 8p22-23
Jianfeng Xu, Professor
Wake Forest University Health Sciences Medical Center Blvd Winston-salem, Nc 27157
Grant 5R01CA095052-04 from National Cancer Institute IRG: EDC
Abstract: 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.
Keywords: cancer risk, chromosome, genetic susceptibility, linkage disequilibrium, neoplasm /cancer genetics, prostate neoplasm, chromosome movement, functional /structural genomics, gene mutation, genetic disorder diagnosis, genetic polymorphism, genetic screening, genotype, macrophage, nucleic acid sequence, scavenger receptor, clinical research, gel mobility shift assay, human subject, microarray technology, polymerase chain reaction
Project start date: 2003-09-10
Project end date: 2008-06-30
5R01CA095052-04 (2006): $273649
5R01CA095052-03 (2005): $281372
5R01CA095052-02 (2004): $282476
Grants awarded to Jianfeng Xu
Targeting Therapeutic Gene Vectors To Reactive Glia
Jianfeng Xu
Beth Israel Deaconess Medical Center
Grant 5F32NS054453-03 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: The objective of this proposal is to generate a novel set of targeted gene vectors with specificity for reactive glial cells, which will serve as valuable tools for basic research into the mechanisms underlying multiple brain disorders as well as vehicles for potential therapy, and test them in a specific first application to a standard animal model of ischemia
Keywords: gene, glia astrocyte, brain disorder, capsid, model
Project start date: 2007-03-26
Project end date: 2010-03-25
1F32NS054453-01A1 (2006): $58036
Interaction Of PTEN And CDKN1B In Pca Susceptibility
Jianfeng Xu, Professor
Public Health Sciences (phs)wake Forest University Health Sciences
medical Center Blvd
winston-salem, Nc 27157
Grant 5R01CA106523-05 from National Cancer Institute IRG: GNM
Abstract: 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
Keywords: cancer risk, family genetics, gene interaction, genetic screening, genetic susceptibility, prostate neoplasm, tumor suppressor gene gene expression, gene mutation, genetic marker, genetic promoter element, genotype, linkage mapping, messenger RNA, neoplasm /cancer genetics, protein structure function, single nucleotide polymorphism bioinformatics, clinical research, gel mobility shift assay, high throughput technology, human subject, immunocytochemistry, patient oriented research, polymerase chain reaction, questionnaire
Project start date: 2004-09-30
Project end date: 2009-06-30
5R01CA106523-05 (2008): $302779
5R01CA106523-04 (2007): $381746
5R01CA106523-03 (2006): $294543
5R01CA106523-02 (2005): $270765
1R01CA106523-01A1 (2004): $312684
Association Of Inflammatory Genes And Prostate Cancer
Jianfeng Xu, Professor
Public Health Sciences (phs)wake Forest University Health Sciences
medical Center Blvd
winston-salem, Nc 27157
Grant 5R01CA105055-05 from National Cancer Institute IRG: ZRG1
Abstract: Prostate cancer is of significant public health importance because it is the most common cancer and the second leading cause of cancer death among men in the United States. Although the etiology of prostate cancer remains unknown, epidemiologic studies have consistently demonstrated genetic susceptibility to this disease. To date, efforts to identify susceptibility genes have primarily focused on genes involved in androgen biosynthesis and growth factors. However, there remain several candidate pathways that have yet to be adequately studied. Chronic or recurrent inflammation is known to play a causative role in the development of many human cancers. Inflammatory changes have been recognized in prostate tissues for many years, leading to speculation that inflammation might contribute to prostate cancer development. The exact mechanism by which inflammation might act in tumor development and progression remains to be elucidated and is likely to be complex. Inflammation-associated DNA damage, decreased apoptosis (bypassing p53), growth and survival factors, angiogenesis, invasion and metastasis may all play a role in the development and progression of prostate cancer. We hypothesize that sequence variants in a number of inflammatory genes are associated with prostate cancer risk. To test this hypothesis, we propose to 1) perform exploratory tests for association of Prostate cancer risk with inflammatory gene sequence variants in an established Prostate cancer case-control population that was collected in Sweden, 2) perform confirmatory tests for association of Prostate cancer risk with a subset of inflammatory gene sequence variants that have been implicated in the first population in a second newly collected Swedish Prostate cancer case-control population and 3) explore the functional impact of htSNPs and htSNP-haplotypes on the corresponding protein levels in serum and/or prostate tissue for a subset of inflammatory genes that have been implicated in both study populations. Answers to these questions will significantly improve our knowledge of the role of inflammation in prostate cancer and will guide our efforts in identifying additional prostate cancer genes
Keywords: European, cancer risk, gene expression, inflammation, linkage mapping, pathologic process, prostate neoplasm, single nucleotide polymorphism cell proliferation, cytokine, genetic transcription, genotype, homeobox gene, neoplastic process, p53 gene /protein Scandinavian country, biotechnology, human genetic material tag, human subject, male, microarray technology, polymerase chain reaction, questionnaire, serology /serodiagnosis
Project start date: 2004-09-24
Project end date: 2009-06-30
5R01CA105055-05 (2008): $441199
5R01CA105055-04 (2007): $437498
5R01CA105055-03 (2006): $449348
Sponsored Links Excellgen http://Excellgen.com
5R01CA105055-02 (2005): $503814
1R01CA105055-01A1 (2004): $522927
CLINICAL VALIDITY AND UTILITY OF GENOMIC TARGETED CHEMOPREVENTION OF PCA
Jianfeng Xu
Wake Forest University Health Sciences, Winston-salem, Nc 27157
Grant 5RC2CA148463-02 from Office Of The Director, National Institutes Of Health
Abstract: Prostate cancer (PCa) is the most common cancer among men in the U.S. One important strategy to address this public health concern is to prevent the disease. Two large randomized clinical trials, The Prostate Cancer Prevention Trial (PCPT) and The Reduction by Dutasteride of Prostate Cancer Events (REDUCE), have demonstrated a 23-25% reduction in PCa risk with the use of 5 alpha reductase inhibitors (5ARIs finasteride and dutasteride). However, 5ARIs have not been widely adopted due, in part, to poor cost-effectiveness. We hypothesize that targeted chemoprevention, based on 1) overall genetic risk [family history (FH) and PCa risk associated genetic variants], and 2) polymorphisms that interact with 5ARIs, may be more efficacious and cost effective, and thus more likely to be employed by physicians and their patients. The effectiveness of this genomic-targeted approach needs to be systematically evaluated and compared to non-genomic approaches using evidence-based methods such as those recommended by the EGAPP (Evaluation of Genomic Applications in Practice and Prevention) working group. We have assembled a multidisciplinary research team to address an overarching question of whether a genomic-targeted approach improves outcomes related to chemoprevention of PCa using 5ARIs compared to a non-targeted approach. We will evaluate and compare the efficacy, perception, decision making, and cost-effectiveness of genomic and non-genomic approaches in two existing large randomized clinical trials (REDUCE and PCPT), two new study populations of men at risk for PCa, and in a survey of physicians. The unique study design of REDUCE and PCPT, with end-of-study prostate biopsies, allows us to address two critical questions in this study PSA detection-bias of PCa risk associated SNPs and efficacy of genomic-targeted chemoprevention of PCa using 5ARIs. We have the following specific aims 1) assess the clinical validity of PCa risk prediction models using a panel of non PSA detection biased PCa risk-associated Single Nucleotide Polymorphisms (SNPs). 2) identify and assess the clinical validity of novel polymorphisms that interact with 5ARIs in reducing PCa diagnosis using both genome-wide and candidate gene approaches, 3) assess the clinical utility of a genomic-targeted approach by comparing its reduction in rates of PCa with non-targeted chemoprevention, 4) compare perception and decision making of physicians and patients for genomic and non-genomic-targeted chemoprevention of PCa, and 5) Compare the cost-effectiveness of genomic and non-genomic-targeted chemoprevention of PCa. Results from this study will provide comprehensive data for evidence-based evaluation by the Center for Disease Control´s EGAPP working group, provide a proof of principle study of comparative effectiveness research (CER), and will help build a road map for future genomic and personalized medicine (GPM) in the 21st century. We will evaluate whether targeting groups of men based on genetic markers and family history of prostate cancer may improve the effectiveness of chemoprevention for prostate cancer. This would lead to a significant decrease in prostate cancer diagnoses and greatly reduce the burden to the individual and society
Keywords: 17beta-N-(2, 5-bis(trifluoromethyl))phenyl-carbamoyl-4-aza-5alpha-androst-1-en-3-one; 4-Azaandrost-1-ene-17-carboxamide, N-(1, 1-dimethylethyl)-3-oxo-, (5alpha, 17beta)-; 5 Alpha-Reductase Inhibitor; Active Follow-up; Address; Adopted; Affect; Behavioral; Biopsy; CDC; CP33; CP34; CYP3; CYP3A; CYP3A13; CYP3A3; CYP3A4; CYP3A4 gene; CYPIIIA4; Calibration; Cancer of Prostate; Cancers; Candidate Disease Gene; Candidate Gene; Centers for Disease Control; Centers for Disease Control (U.S.); Centers for Disease Control and Prevention; Centers for Disease Control and Prevention (U.S.); Chemoprevention; Clinic; Clinical; Cognitive Discrimination; Collaborations; Cost Effective Analyses; Cost Effectiveness Analysis; Data; Decision Making; Detection; Discrimination; Discrimination (Psychology); Disease; Disorder; Dutasteride; Effectiveness; Epidemiology, Family Medical History; Evaluation; Event; Family Medical History; Family history of; Finasteride; Future; GWAS; Gene Family; Gene Targeting; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Risk; Genetic screening method; Genital System, Male, Prostate; Genome; Genomics; HLP; Human Prostate; Human Prostate Gland; Individual; Intention; Interdisciplinary Research; Interdisciplinary Study; Investigators; Lead; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Maps; Medicine; Methods; Modeling; Multidisciplinary Collaboration; Multidisciplinary Research; NF-25; Outcome; P450-PCN1; P450C3; P450PCN1; PSA level; Patients; Pb element; Perception; Physicians; Polymorphism (Genetics); Polymorphism, Genetic; Population; Population Study; Prevention; Primary Care; Primary Care Physician; Primary Health Care; Primary Healthcare; Prostate; Prostate CA; Prostate Cancer; Prostate Cancer Prevention Trial; Prostate Gland; Prostatic Cancer; Prostatic Gland; Public Health; Randomized; Randomized Clinical Trials; Recommendation; Recruitment Activity; Reporting; Research Design; Research Personnel; Researchers; Risk; Risk Estimate; Science of Medicine; Societies; Staging; Study Type; Study, Interdisciplinary; Survey Instrument; Surveys; Targetings, Gene; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Urologist; Variant; Variation; Work; ing; application in practice; base; cancer diagnosis; cancer risk; case control; comparative effectiveness; comparative efficacy; cost; cost effective; cost effectiveness; cost efficient analysis; design; designing; disease/disorder; effectiveness research; ethical legal social implication; ethical, legal, and social; evidence base; follow-up; genetic testing; genetic variant; genome wide association scan; genome wide association studies; genome wide association study; genome-wide; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; heavy metal Pb; heavy metal lead; high risk men; improved; male group; malignancy; men; men at high risk; men`s; men`s group; neoplasm/cancer; non-genomic; nongenomic; novel; polymorphism; practical application; prevent; preventing; prevention evaluation; public health medicine (field); randomisation; randomization; randomly assigned; recruit; response; risk perception; study design; uptake; whole genome association studies; whole genome association study; willingness; working group
Relevance: Narrative We will evaluate whether targeting groups of men based on genetic markers and family history of prostate cancer may improve the effectiveness of chemoprevention for prostate cancer. This would lead to a significant decrease in prostate cancer diagnoses and greatly reduce the burden to the individual and society
Project start date: 2009-09-29
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-OD-09-004
5RC2CA148463-02 (2010): $2006440
1RC2CA148463-01 (2009): $1972330
GENETIC PROFILING IN PCPT: PROSTATE CANCER RISK, PSA LEVELS, AND CHEMOPREVENTION
Jianfeng Xu, Professor
Wake Forest University Health Sciences, Winston-salem, Nc 27157
Grant 5R01CA140262-02 from National Cancer Institute
Abstract: More than a dozen SNPs have been found to be associated with prostate cancer (PCa) risk by genome-wide association studies (GWAS). These reported PCa risk associated SNPs, if not driven by PSA detection bias or not completely correlated with PSA, could be used to improve PSA and other existing clinical variables in predicting positive prostate biopsy (i.e. PCa). These two important questions, however, cannot be addressed by most PCa case-control studies because some cases were diagnosed on the basis of elevated PSA levels. Only studies such as the Prostate Cancer Prevention Trial (PCPT) where men at the end of the trial were biopsied regardless of PSA levels can be used to dissect these two questions. The overall hypothesis of the study is that multiple genetic variants, when combined, can be used to predict men at increased risk for PCa. Specifically, we hypothesize that 1) a subset of genetic variants are associated with PCa risk and are not solely due to PSA detection bias, 2) these genetic variants, when combined, are strongly associated with PCa risk, 3) genetic variants can supplement PSA and other existing clinical variables to improve the predictive performance for PCa and aggressive PCa, and 4) the chemoprevention effect of finasteride is different among men with different genetic risks and the reduction in PCa diagnosis by finasteride is larger for men with higher genetic risk. To test these hypotheses, we will use data and samples from the PCPT study, a phase III randomized, double-blind, placebo-controlled trial of finasteride in the prevention of prostate cancer. We have three specific aims. Aim 1 is to test whether reported prostate cancer risk associated variants from GWAS are associated with PCa risk, free of PSA detection bias. Aim 2 is to estimate the joint predictive performance for prostate cancer diagnosis, overall PCa and aggressive PCa, using genetic variants as well as PSA and other existing clinical variables. Aim 3 is to assess the differential chemoprevention effect of finasteride on prostate cancer diagnosis among men with higher or lower genetic risk for PCa. Results from this study may potentially benefit millions men. Men at highest risk for PCa could be identified at an early age for intensive screening and chemoprevention such as finasteride. Genetic variants could also be used in combination with PSA and other existing clinical variables to considerably improve their predictive accuracy for positive prostate biopsy. Dozens of prostate cancer risk associated variants, when combined, could be used to identify men at highest risk for prostate cancer. Such men could be identified at an early age for intensive screening and chemoprevention. Prostate cancer risk associated variants could also be used in combination with PSA and other existing clinical variables to considerably improve their predictive accuracy for positive prostate biopsy. 1
Keywords: 21+ years old; 4-Azaandrost-1-ene-17-carboxamide, N-(1, 1-dimethylethyl)-3-oxo-, (5alpha, 17beta)-; Address; Adult; Adverse effects; Affect; Age; Alleles; Allelomorphs; Area Under Curve; Arm; Articulation; Biology; Biopsy; Boxing; Cancer of Prostate; Case-Base Studies; Case-Comparison Studies; Case-Compeer Studies; Case-Control Studies; Case-Referent Studies; Case-Referrent Studies; Chemoprevention; Clinic; Clinical; Collaborations; Complement; Complement Proteins; Cross-Product Ratio; Data; Detection; Diagnosis; Diagnostic; Diet; Disease; Disorder; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Environment; Epidemiologist; Epidemiology, Family Medical History; European; Family Medical History; Family history of; Finasteride; Future; GWAS; General Population; General Public; Genetic; Genetic Risk; Genetic screening method; Genital System, Male, Prostate; Genotype; Gleason Grade; Gleason Grade for Prostate Cancer; Gleason Score; Gleason Score for Prostate Cancer; Gleason Sum; Gleason-SC; Goals; History; Human Prostate; Human Prostate Gland; Human, Adult; Incidence; Individual; Investigators; Joints; Letters; Life Style; Lifestyle; Logistic Regressions; Logistics; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Measures; Modeling; Mortality; Mortality Vital Statistics; Nature; Odds Ratio; Oncologist; PBO; PSA level; PSA screening; Paper; Performance; Phase; Placebo Control; Placebos; Population; Population Study; Prevention; Prevention of Prostate CA; Prevention of Prostate Cancer; Prostate; Prostate Adenocarcinoma; Prostate CA; Prostate CA Prevention; Prostate Cancer; Prostate Cancer Prevention; Prostate Cancer Prevention Trial; Prostate Gland; Prostate Gland Adenocarcinoma; Prostatic Cancer; Prostatic Gland; Race; Racial Group; Randomized; Receiver Operating Characteristics; Recording of previous events; Relative Odds; Reporting; Research; Research Personnel; Researchers; Risk; Risk Ratio; Risk Reduction; Sampling; Science of Statistics; Screening for Prostate Cancer; Screening procedure; Sham Treatment; Staging; Statistics; Stocks, Racial; Stratification; Testing; Treatment Cost; Treatment Side Effects; Upper arm; Variant; Variation; Work; adult human (21+); association test; base; cancer diagnosis; cancer genetics; cancer risk; cohort; design; designing; disease/disorder; double-blind placebo controlled trial; double-masked controlled study; double-masked controlled trial; experience; genetic association; genetic profiling; genetic testing; genetic variant; genome wide association scan; genome wide association studies; genome wide association study; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; high risk men; improved; innovate; innovation; innovative; interest; male group; member; men; men at high risk; men`s; men`s group; prevent; preventing; prospective; prostate cancer early detection; prostate cancer prevention; prostatic adenocarcinoma; public health relevance; randomisation; randomization; randomly assigned; screening; screenings; sham therapy; side effect; statistics; therapy adverse effect; treatment adverse effect; urologic; urological; whole genome association studies; whole genome association study
Relevance: Narrative Dozens of prostate cancer risk associated variants, when combined, could be used to identify men at highest risk for prostate cancer. Such men could be identified at an early age for intensive screening and chemoprevention. Prostate cancer risk associated variants could also be used in combination with PSA and other existing clinical variables to considerably improve their predictive accuracy for positive prostate biopsy. 1
Project start date: 2009-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-07-070
5R01CA140262-02 (2010): $629341
QTL MAPPING FOR GENES REGULATING APOPTOSIS CAPACITY
Jianfeng Xu, Professor
Wake Forest University Health Sciences, Winston-salem, Nc 27157
Grant 5R01CA119069-05 from National Cancer Institute
Abstract: 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
Keywords: Accounting; Active Follow-up; Affect; Alleles; Allelomorphs; Animal Model; Animal Models and Related Studies; Apoptosis; Apoptosis Pathway; Apoptosis Promoter; Applications Grants; Articulation; Assay; Bioassay; Biologic Assays; Biological; Biological Assay; Biological Function; Biological Process; Blotting, Western; Cancer Family; Cancer Induction; Cancer of Prostate; Cancers; Candidate Disease Gene; Candidate Gene; Cell Death; Cell Death, Programmed; Characteristics; Chromosome Mapping; Collection; Complement; Complement Proteins; Complex; Data; Data Set; Databases, Genetic; Dataset; Demethyl Epipodophyllotoxin Ethylidine Glucoside; Disease; Disorder; EPEG; Eposide; Etoposide; Evaluation; Event; Family; Forecast of outcome; Frequencies (time pattern); Frequency; GWAS; Gene Localization; Gene Mapping; Gene Mapping, Total Human and Non-Human; Gene variant; General Population; General Public; Genes; Genetic; Genetic Data Banks; Genetic Data Bases; Genetic Databanks; Genetic Databases; Genetic Diversity; Genetic Information Databases; Genetic Predisposition; Genetic Predisposition to Disease; Genetic Susceptibility; Genetic Variation; Genetics, Gene Mapping; Genome; Genotype; Goals; Grant Proposals; Grants, Applications; Guidelines; Haplotypes; Hereditary; Heritability; Heterozygote; High-Risk Cancer; Homozygote; Human; Human, General; In Vitro; Individual; Inducer of Apoptosis; Induction of Apoptosis; Inflammatory; Inherited; Inherited Predisposition; Inherited Susceptibility; International; Investigators; Joints; Lastet; Linkage Analysis; Linkage Mapping; Location; Lod Score; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Man (Taxonomy); Man, Modern; Maps; Measures; Messenger RNA; Microsatellite Markers; Microsatellite Repeats; Microsatellites; Minor; Molecular; Oncogenesis; Organism-Level Process; Organismal Process; Outcome; Phenotype; Physiologic Processes; Physiological Processes; Population; Population Study; Position; Positioning Attribute; Predisposition; Process; Prognosis; Prostate CA; Prostate Cancer; Prostatic Cancer; Proteins; QTL; Quantitative Trait Loci; RNA, Messenger; Research Design; Research Personnel; Researchers; Resolution; Risk; Study Type; Susceptibility; Testing; Time; Variant; Variation; Variation (Genetics); Vepesid; Western Blotting; Western Blottings; Western Immunoblotting; allelic variant; anticancer research; base; cancer genetics; cancer progression; cancer research; cancer type; carcinogenesis; case control; clinical significance; clinically significant; disease/disorder; established cell line; experiment; experimental research; experimental study; family based linkage study; follow-up; gene product; genetic etiology; genetic linkage analyses; genetic linkage analysis; genetic mapping; genetic mechanism of disease; genetic variant; genetic vulnerability; genome wide association scan; genome wide association studies; genome wide association study; genome-wide; genome-wide analysis; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; human disease; improved; linkage analyses; lymphoblastoid cell line; mRNA; mRNA Expression; malignancy; meetings; model organism; necrocytosis; neoplasm progression; neoplasm/cancer; neoplastic progression; novel; outcome forecast; protein blotting; protein protein interaction; research study; study design; tumor progression; tumorigenesis; whole genome association studies; whole genome association study
Project start date: 2006-09-01
Project end date: 2011-07-31
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
5R01CA119069-05 (2010): $247921
5R01CA119069-04 (2009): $223171
5R01CA119069-03 (2008): $222836
Mapping Prostate Cancer Susceptibility Genes At 8p22-23
Jianfeng Xu, Professor
Wake Forest University Health Sciences Medical Center Blvd Winston-salem, Nc 27157
Grant 1R01CA095052-01A2 from National Cancer Institute IRG: EDC
Abstract: 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.
Keywords: cancer risk, chromosome, genetic susceptibility, linkage disequilibrium, neoplasm /cancer genetics, prostate neoplasm, chromosome movement, functional /structural genomics, gene mutation, genetic disorder diagnosis, genetic polymorphism, genetic screening, genotype, macrophage, nucleic acid sequence, scavenger receptor, clinical research, gel mobility shift assay, human subject, microarray technology, polymerase chain reaction
Project start date: 2003-09-10
Project end date: 2008-08-31
1R01CA095052-01A2 (2003): $296552
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CONFIRMATION OF SNPS ASSOCIATED WITH AGGRESSIVE PCA IN A GWA STUDY
Jianfeng Xu, Professor
Wake Forest University Health Sciences, Winston-salem, Nc 27157
Grant 5R01CA129684-03 from National Cancer Institute
Keywords: Active Follow-up; Affect; Articulation; Base of Human Prostate; Base of the Prostate; Cancer Genes; Cancer Patient; Cancer of Prostate; Cancer-Promoting Gene; Cancers; Candidate Disease Gene; Candidate Gene; Case-Base Studies; Case-Comparison Studies; Case-Compeer Studies; Case-Control Studies; Case-Referent Studies; Case-Referrent Studies; Causality; Characteristics; Classification; Data; Diagnosis; Diathesis; Disease; Disease Association; Disease Progression; Disease susceptibility; Disorder; Etiology; Follow-Up Studies; Followup Studies; Frequencies (time pattern); Frequency; Funding; GWAS; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Predisposition; Genetic Predisposition to Disease; Genetic Susceptibility; Genome; Genomics; Genotype; Grant; HOSP; Hereditary; Hospitals; Inherited; Inherited Predisposition; Inherited Susceptibility; Investigators; Joints; Lead; Linkage Disequilibrium; Linkage Disequilibriums; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Maps; Methods; NIH RFA; Nature; Oncogenes; Pathway interactions; Pb element; Phenotype; Polymorphism (Genetics); Polymorphism, Genetic; Polymorphism, Single Base; Population; Population Study; Prevention; Probability; Prostate CA; Prostate Cancer; Prostatic Cancer; Request for Applications; Research Design; Research Personnel; Researchers; Risk; Role; SNP; SNPs; Sample Size; Single Nucleotide Polymorphism; Staging; Stratification; Structure of base of prostate; Study Subject; Study Type; Sweden; Systematics; Testing; Time; Transforming Genes; Universities; Variant; Variation; Work; association test; cancer genome; cancer risk; case control; clinical relevance; clinically relevant; design; designing; disease causation; disease etiology; disease risk; disease/disorder; disease/disorder etiology; disease/disorder proneness/risk; disorder etiology; disorder risk; experience; follow-up; forest; genetic association; genetic etiology; genetic mechanism of disease; genetic vulnerability; genome wide association scan; genome wide association studies; genome wide association study; genome-wide; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; genotyping technology; heavy metal Pb; heavy metal lead; improved; liability to disease; malignancy; men; men`s; neoplasm/cancer; new approaches; novel; novel approaches; novel strategies; novel strategy; pathway; polymorphism; population based; social role; study design; success; whole genome association studies; whole genome association study
Project start date: 2008-04-04
Project end date: 2012-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01CA129684-03 (2010): $600462