|Grant Number:||5R01CA129435-03 Interpret this number|
|Primary Investigator:||Freedman, Matthew|
|Organization:||Dana-Farber Cancer Inst|
|Project Title:||Fine Mapping and Characterization of the 8q24 Prostate Cancer Risk Locus|
DESCRIPTION (provided by applicant): The ultimate objective of this proposal is to understand the genetic elements driving sporadic prostate cancer across multiple ethnic groups. Both somatic and, more recently, inherited genetic data highlight a 490 kilobase (kb) noncoding region on chromosome 8q24 as playing a major role in prostate cancer biology across multiple ethnic populations. At least 7 alleles are associated with prostate cancer risk. This finding represents the first validated genetic factor responsible for an appreciable amount of risk in the general population. Aim 1 intends to identify the actual causal alleles at 8q24 contributing to prostate cancer risk across five racial/ethnic populations. First, full characterization of common genetic variation in this 490 kilobase region will be determined by resequencing a multiethnic panel of 48 individuals. Second, all novel SNPs in this region will be genotyped in the well characterized HapMap samples to create a complete collection of all common genetic variation. Third, any newly discovered variants not adequately captured by our previous studies (as assessed by their correlations in HapMap) will be tested for association with prostate cancer in the MEC populations (2,788 incident prostate cancer cases and 2,613 controls). Aim 2 focuses on the intersection between inherited variation at 8q24 and the somatic phenotypes of gene expression and amplification. A total of 200 fresh frozen prostate tumor tissues will be analyzed (150 European American men and 50 African American men) for both projects. All of these samples will be genotyped for the known inherited risk alleles as well as any that are discovered during the course of this project. Since the risk alleles are noncoding, one hypothesis is that they are elevating risk by modulating expression levels of a gene in the vicinity. The expression study will take place in two stages. First, a comprehensive expression analysis covering 3.8 megabases of the 8q24 region will be assessed by tiling arrays to capture both annotated and unannotated transcribed sequences. Forty men representing the extremes of the risk allele distribution will be selected for this stage. Second, any candidate differentially expressed sequence will be validated in an independent sample of 160 men. Having identified a germline risk variant provides the unique opportunity to explore connections between the germline and somatic genomes. Amplification of the 8q region is one of the most frequent somatic lesions in prostate cancer. Tumors are often described as undergoing an evolutionary process of selection for tumor related traits. A new method based on this framework will be applied to evaluate if the risk allele resides on an amplified 8q chromosome more often than expected by chance. This observation would provide compelling evidence that the risk allele is selected for and, therefore, critical for tumor evolution. RELEVANCE TO PUBLIC HEALTH: Identifying the genetic factors underlying prostate cancer provides the opportunity to identify individuals at risk of developing disease as well as to lend insight into pathways that can be modulated for therapeutic benefit. Our proposal aims to pinpoint the causal changes in DNA sequence and the gene that it influences to better understand how this chromosomal region is responsible for an appreciable fraction of prostate cancer in the general population.
Integrative clinical genomics of advanced prostate cancer.
Authors: Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM
Source: Cell, 2015 May 21;161(5), p. 1215-28.
Integrative eQTL-based analyses reveal the biology of breast cancer risk loci.
Authors: Li Q, Seo JH, Stranger B, McKenna A, Pe'er I, Laframboise T, Brown M, Tyekucheva S, Freedman ML
Source: Cell, 2013 Jan 31;152(3), p. 633-41.
Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis.
Authors: Grisanzio C, Werner L, Takeda D, Awoyemi BC, Pomerantz MM, Yamada H, Sooriakumaran P, Robinson BD, Leung R, Schinzel AC, Mills I, Ross-Adams H, Neal DE, Kido M, Yamamoto T, Petrozziello G, Stack EC, Lis R, Kantoff PW, Loda M, Sartor O, Egawa S, Tewari AK, Hahn WC, Freedman ML
Source: Proc Natl Acad Sci U S A, 2012 Jul 10;109(28), p. 11252-7.
EPub date: 2012 Jun 22.
Cost-effective, high-throughput DNA sequencing libraries for multiplexed target capture.
Authors: Rohland N, Reich D
Source: Genome Res, 2012 May;22(5), p. 939-46.
EPub date: 2012 Jan 20.
The genetics of cancer risk.
Authors: Pomerantz MM, Freedman ML
Source: Cancer J, 2011 Nov-Dec;17(6), p. 416-22.
Chromosome 8q24-Associated Cancers and MYC.
Authors: Grisanzio C, Freedman ML
Source: Genes Cancer, 2010 Jun;1(6), p. 555-9.
Association of prostate cancer risk Loci with disease aggressiveness and prostate cancer-specific mortality.
Authors: Pomerantz MM, Werner L, Xie W, Regan MM, Lee GS, Sun T, Evan C, Petrozziello G, Nakabayashi M, Oh WK, Kantoff PW, Freedman ML
Source: Cancer Prev Res (Phila), 2011 May;4(5), p. 719-28.
EPub date: 2011 Mar 2.
Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis.
Authors: Pomerantz MM, Shrestha Y, Flavin RJ, Regan MM, Penney KL, Mucci LA, Stampfer MJ, Hunter DJ, Chanock SJ, Schafer EJ, Chan JA, Tabernero J, Baselga J, Richardson AL, Loda M, Oh WK, Kantoff PW, Hahn WC, Freedman ML
Source: PLoS Genet, 2010 Nov 11;6(11), p. e1001204.
EPub date: 2010 Nov 11.
Genome-wide association study of prostate cancer mortality.
Authors: Penney KL, Pyne S, Schumacher FR, Sinnott JA, Mucci LA, Kraft PL, Ma J, Oh WK, Kurth T, Kantoff PW, Giovannucci EL, Stampfer MJ, Hunter DJ, Freedman ML
Source: Cancer Epidemiol Biomarkers Prev, 2010 Nov;19(11), p. 2869-76.
EPub date: 2010 Oct 26.
8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC.
Authors: Ahmadiyeh N, Pomerantz MM, Grisanzio C, Herman P, Jia L, Almendro V, He HH, Brown M, Liu XS, Davis M, Caswell JL, Beckwith CA, Hills A, Macconaill L, Coetzee GA, Regan MM, Freedman ML
Source: Proc Natl Acad Sci U S A, 2010 May 25;107(21), p. 9742-6.
EPub date: 2010 May 7.
Exploring genetic susceptibility to cancer in diverse populations.
Authors: Haiman CA, Stram DO
Source: Curr Opin Genet Dev, 2010 Jun;20(3), p. 330-5.
EPub date: 2010 Mar 30.
A systematic approach to understand the functional consequences of non-protein coding risk regions.
Authors: Coetzee GA, Jia L, Frenkel B, Henderson BE, Tanay A, Haiman CA, Freedman ML
Source: Cell Cycle, 2010 Jan 15;9(2), p. 256-9.
EPub date: 2010 Jan 23.
Functional enhancers at the gene-poor 8q24 cancer-linked locus.
Authors: Jia L, Landan G, Pomerantz M, Jaschek R, Herman P, Reich D, Yan C, Khalid O, Kantoff P, Oh W, Manak JR, Berman BP, Henderson BE, Frenkel B, Haiman CA, Freedman M, Tanay A, Coetzee GA
Source: PLoS Genet, 2009 Aug;5(8), p. e1000597.
EPub date: 2009 Aug 14.
The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer.
Authors: Pomerantz MM, Ahmadiyeh N, Jia L, Herman P, Verzi MP, Doddapaneni H, Beckwith CA, Chan JA, Hills A, Davis M, Yao K, Kehoe SM, Lenz HJ, Haiman CA, Yan C, Henderson BE, Frenkel B, Barretina J, Bass A, Tabernero J, Baselga J, Regan MM, Manak JR, Shivdasani R, Coetzee GA, Freedman ML
Source: Nat Genet, 2009 Aug;41(8), p. 882-4.
EPub date: 2009 Jun 28.
Evaluation of the 8q24 prostate cancer risk locus and MYC expression.
Authors: Pomerantz MM, Beckwith CA, Regan MM, Wyman SK, Petrovics G, Chen Y, Hawksworth DJ, Schumacher FR, Mucci L, Penney KL, Stampfer MJ, Chan JA, Ardlie KG, Fritz BR, Parkin RK, Lin DW, Dyke M, Herman P, Lee S, Oh WK, Kantoff PW, Tewari M, McLeod DG, Srivastava S, Freedman ML
Source: Cancer Res, 2009 Jul 1;69(13), p. 5568-74.
EPub date: 2009 Jun 23.