|Grant Number:||3U01CA136792-03S1 Interpret this number|
|Primary Investigator:||Henderson, Brian|
|Organization:||University Of Southern California|
|Project Title:||A Genome-Wide Association Study of Prostate Cancer in African Americans|
DESCRIPTION (provided by applicant): Prostate cancer is one of the leading causes of morbidity and mortality among men. We do not have an understanding of the underlying etiology of prostate cancer, or why different groups such as African Americans have higher rates of this disease. Risk factors for prostate cancer have remained elusive, other than age, having a family history of the disease and African ancestry, until recently with the discovery of multiple disease risk loci utilizing Genome Wide Association Studies( GWAS ). The first such loci were discovered in a gene " desert " in 8q24, and now the total number of loci number at least 30. Many of the allelic loci identified since those in 8q24, lie within introns or nearby known gene regions. Given the SNP density of the current tools used for GWAS, virtually all the risk loci identified have been found to be common allelic variants and the relative risk of prostate cancer from each such risk locus tends to be modest, e.g. 1.1-1.3. While differences in the frequency of such individual risk alleles, particularly in the 8q24 region, can partially account for the higher risk in populations of African ancestry, all the risk loci detected to date account for no more than 20-25% of the familial risk of prostate cancer. It has been hypothesized that less common or rare functional risk alleles might be identifiable in those loci located within or near to known functional candidate gene regions, and that such less common or rare alleles might explain both the " signal " identified by a more common allele in LD and a somewhat greater familial and/ or population attributable risk. In this application we have assembled a multi- institutional team of investigators with experience in prostate cancer research in minority populations who are willing to pool resources for a large scale attempt to identify such less common or rare alleles. We propose to collaborate with David Reich at Harvard who has the capability to bar code and pool large numbers of DNA samples for deep sequencing across the risk regions where the common allelic variants have been discovered. To optimize our ability to identify these less common and rare variants we propose to include 4500 prostate cases and controls from the Multiethnic Cohort ( Japanese, African American, European American, Latino and Native Hawaiian ) as well as 500 African American prostate cancer cases with a family history of prostate cancer from among those populations currently participating in the collaborative GWAS of African Americans being conducted at USC. We expect this effort to significantly advance knowledge of the genetic risk factors for sporadic and familial prostate cancer among a variety of different racial/ethnic groups, including the highest risk population of African ancestry. The specific identification of the functional genetic variants in the risk loci that have been discovered by GWAS should guide the development of future preventive, early detection, prognostic and even therapeutic measures. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify less common and rare risk alleles for prostate cancer in the approximately 30 allelic loci that have been discovered by genome wide association studies. For this effort, we will utilize the resources of the Multiethnic Cohort Study populations (African American, Japanese, Latino, European American, and Native Hawaiian) as well as several of the key populations of African Americans who are part of the funded African American prostate cancer genome wide association study. More specifically we propose to sequence 4500 individuals with prostate cancer and 4500 controls from the Multiethnic Cohort Study and an additional 500 African American prostate cancer cases with a family history of prostate cancer.
A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.
Authors: Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, Benlloch S, Hazelett DJ, Wang Z, Saunders E, Leongamornlert D, Lindstrom S, Jugurnauth-Little S, Dadaev T, Tymrakiewicz M, Stram DO, Rand K, Wan P, Stram A, Sheng X, Pooler LC, Park K, Xia L, Tyrer J, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Goh C, Ahmed M, Govindasami K, Guy M, Tammela TL, Auvinen A, Wahlfors T, Schleutker J, Visakorpi T, Leinonen KA, Xu J, Aly M, Donovan J, Travis RC, Key TJ, Siddiq A, Canzian F, Khaw KT, Takahashi A, Kubo M, Pharoah P, Pashayan N, Weischer M, Nordestgaard BG, Nielsen SF, Klarskov P, Rřder MA, Iversen P, Thibodeau SN, McDonnell SK, Schaid DJ, Stanford JL, Kolb S, Holt S, Knudsen B, Coll AH, Gapstur SM, Diver WR, Stevens VL, Maier C, Luedeke M, Herkommer K, Rinckleb AE, Strom SS, Pettaway C, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Cannon-Albright L, Cybulski C, Woko?orczyk D, Klu?niak W, Park J, Sellers T, Lin HY, Isaacs WB, Partin AW, Brenner H, Dieffenbach AK, Stegmaier C, Chen C, Giovannucci EL, Ma J, Stampfer M, Penney KL, Mucci L, John EM, Ingles SA, Kittles RA, Murphy AB, Pandha H, Michael A, Kierzek AM, Blot W, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske C, Wu SY, Hennis A, Kibel AS, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Batra J, Clements J, Spurdle A, Teixeira MR, Paulo P, Maia S, Slavov C, Kaneva R, Mitev V, Witte JS, Casey G, Gillanders EM, Seminara D, Riboli E, Hamdy FC, Coetzee GA, Li Q, Freedman ML, Hunter DJ, Muir K, Gronberg H, Neal DE, Southey M, Giles GG, Severi G, Breast and Prostate Cancer Cohort Consortium (BPC3), PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, COGS (Collaborative Oncological Gene-environment Study) Consortium, GAME-ON/ELLIPSE Consortium, Cook MB, Nakagawa H, Wiklund F, Kraft P, Chanock SJ, Henderson BE, Easton DF, Eeles RA, Haiman CA
Source: Nat Genet, 2014 Oct;46(10), p. 1103-9.
EPub date: 2014 Sep 14.
Generalizability of established prostate cancer risk variants in men of African ancestry.
Authors: Han Y, Signorello LB, Strom SS, Kittles RA, Rybicki BA, Stanford JL, Goodman PJ, Berndt SI, Carpten J, Casey G, Chu L, Conti DV, Rand KA, Diver WR, Hennis AJ, John EM, Kibel AS, Klein EA, Kolb S, Marchand LL, Leske MC, Murphy AB, Neslund-Dudas C, Park JY, Pettaway C, Rebbeck TR, Gapstur SM, Zheng SL, Wu SY, Witte JS, Xu J, Isaacs W, Ingles SA, Hsing A, The PRACTICAL Consortium, The ELLIPSE GAME-ON Consortium, Easton DF, Eeles RA, Schumacher FR, Chanock S, Nemesure B, Blot WJ, Stram DO, Henderson BE, Haiman CA
Source: Int J Cancer, 2014 Jul 8;null, p. null.
EPub date: 2014 Jul 8.
Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study.
Authors: Kocarnik JM, Pendergrass SA, Carty CL, Pankow JS, Schumacher FR, Cheng I, Durda P, Ambite JL, Deelman E, Cook NR, Liu S, Wactawski-Wende J, Hutter C, Brown-Gentry K, Wilson S, Best LG, Pankratz N, Hong CP, Cole SA, Voruganti VS, B??kova P, Jorgensen NW, Jenny NS, Wilkens LR, Haiman CA, Kolonel LN, Lacroix A, North K, Jackson R, Le Marchand L, Hindorff LA, Crawford DC, Gross M, Peters U
Source: Circ Cardiovasc Genet, 2014 Apr;7(2), p. 178-88.
EPub date: 2014 Mar 12.
Pleiotropy of cancer susceptibility variants on the risk of non-Hodgkin lymphoma: the PAGE consortium.
Authors: Lim U, Kocarnik JM, Bush WS, Matise TC, Caberto C, Park SL, Carlson CS, Deelman E, Duggan D, Fesinmeyer M, Haiman CA, Henderson BE, Hindorff LA, Kolonel LN, Peters U, Stram DO, Tiirikainen M, Wilkens LR, Wu C, Kooperberg C, Le Marchand L
Source: PLoS One, 2014;9(3), p. e89791.
EPub date: 2014 Mar 5.
Replication of associations between GWAS SNPs and melanoma risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study.
Authors: Kocarnik JM, Park SL, Han J, Dumitrescu L, Cheng I, Wilkens LR, Schumacher FR, Kolonel L, Carlson CS, Crawford DC, Goodloe RJ, Dilks H, Baker P, Richardson D, Ambite JL, Song F, Quresh AA, Zhang M, Duggan D, Hutter C, Hindorff LA, Bush WS, Kooperberg C, Le Marchand L, Peters U
Source: J Invest Dermatol, 2014 Jul;134(7), p. 2049-52.
EPub date: 2014 Jan 30.
No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population.
Authors: Dumitrescu L, Carty CL, Franceschini N, Hindorff LA, Cole SA, B??ková P, Schumacher FR, Eaton CB, Goodloe RJ, Duggan DJ, Haessler J, Cochran B, Henderson BE, Cheng I, Johnson KC, Carlson CS, Love SA, Brown-Gentry K, Nato AQ, Quibrera M, Shohet RV, Ambite JL, Wilkens LR, Le Marchand L, Haiman CA, Buyske S, Kooperberg C, North KE, Fornage M, Crawford DC
Source: Hum Genet, 2013 Dec;132(12), p. 1427-31.
EPub date: 2013 Oct 8.
Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.
Authors: Carlson CS, Matise TC, North KE, Haiman CA, Fesinmeyer MD, Buyske S, Schumacher FR, Peters U, Franceschini N, Ritchie MD, Duggan DJ, Spencer KL, Dumitrescu L, Eaton CB, Thomas F, Young A, Carty C, Heiss G, Le Marchand L, Crawford DC, Hindorff LA, Kooperberg CL, PAGE Consortium
Source: PLoS Biol, 2013 Sep;11(9), p. e1001661.
EPub date: 2013 Sep 17.
Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Fesinmeyer MD, Meigs JB, North KE, Schumacher FR, B??ková P, Franceschini N, Haessler J, Goodloe R, Spencer KL, Voruganti VS, Howard BV, Jackson R, Kolonel LN, Liu S, Manson JE, Monroe KR, Mukamal K, Dilks HH, Pendergrass SA, Nato A, Wan P, Wilkens LR, Le Marchand L, Ambite JL, Buyske S, Florez JC, Crawford DC, Hindorff LA, Haiman CA, Peters U, Pankow JS
Source: BMC Med Genet, 2013 Sep 25;14, p. 98.
EPub date: 2013 Sep 25.
Genetic variation in the inflammation and innate immunity pathways and colorectal cancer risk.
Authors: Wang H, Taverna D, Stram DO, Fortini BK, Cheng I, Wilkens LR, Burnett T, Makar KW, Lindor NM, Hopper JL, Gallinger S, Baron JA, Haile R, Kolonel LN, Henderson BE, Newcomb PA, Casey G, Duggan D, Ulrich CM, Le Marchand L
Source: Cancer Epidemiol Biomarkers Prev, 2013 Nov;22(11), p. 2094-101.
EPub date: 2013 Sep 17.
Variants at IRX4 as prostate cancer expression quantitative trait loci.
Authors: Xu X, Hussain WM, Vijai J, Offit K, Rubin MA, Demichelis F, Klein RJ
Source: Eur J Hum Genet, 2014 Apr;22(4), p. 558-63.
EPub date: 2013 Sep 11.
Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia.
Authors: Cheng I, Kocarnik JM, Dumitrescu L, Lindor NM, Chang-Claude J, Avery CL, Caberto CP, Love SA, Slattery ML, Chan AT, Baron JA, Hindorff LA, Park SL, Schumacher FR, Hoffmeister M, Kraft P, Butler AM, Duggan DJ, Hou L, Carlson CS, Monroe KR, Lin Y, Carty CL, Mann S, Ma J, Giovannucci EL, Fuchs CS, Newcomb PA, Jenkins MA, Hopper JL, Haile RW, Conti DV, Campbell PT, Potter JD, Caan BJ, Schoen RE, Hayes RB, Chanock SJ, Berndt SI, Küry S, Bézieau S, Ambite JL, Kumaraguruparan G, Richardson DM, Goodloe RJ, Dilks HH, Baker P, Zanke BW, Lemire M, Gallinger S, Hsu L, Jiao S, Harrison TA, Seminara D, Haiman CA, Kooperberg C, Wilkens LR, Hutter CM, White E, Crawford DC, Heiss G, Hudson TJ, Brenner H, Bush WS, Casey G, Le Marchand L, Peters U
Source: Gut, 2014 May;63(5), p. 800-7.
EPub date: 2013 Aug 9.
Association of the FTO obesity risk variant rs8050136 with percentage of energy intake from fat in multiple racial/ethnic populations: the PAGE study.
Authors: Park SL, Cheng I, Pendergrass SA, Kucharska-Newton AM, Lim U, Ambite JL, Caberto CP, Monroe KR, Schumacher F, Hindorff LA, Oetjens MT, Wilson S, Goodloe RJ, Love SA, Henderson BE, Kolonel LN, Haiman CA, Crawford DC, North KE, Heiss G, Ritchie MD, Wilkens LR, Le Marchand L
Source: Am J Epidemiol, 2013 Sep 1;178(5), p. 780-90.
EPub date: 2013 Jul 2.
Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Dumitrescu L, Carty CL, Franceschini N, Hindorff LA, Cole SA, B??ková P, Schumacher FR, Eaton CB, Goodloe RJ, Duggan DJ, Haessler J, Cochran B, Henderson BE, Cheng I, Johnson KC, Carlson CS, Love SA, Brown-Gentry K, Nato AQ Jr, Quibrera M, Anderson G, Shohet RV, Ambite JL, Wilkens LR, Marchand LL, Haiman CA, Buyske S, Kooperberg C, North KE, Fornage M, Crawford DC
Source: Ann Hum Genet, 2013 Sep;77(5), p. 416-25.
EPub date: 2013 Jun 28.
Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Zhang L, Buzkova P, Wassel CL, Roman MJ, North KE, Crawford DC, Boston J, Brown-Gentry KD, Cole SA, Deelman E, Goodloe R, Wilson S, Heiss G, Jenny NS, Jorgensen NW, Matise TC, McClellan BE Jr, Nato AQ Jr, Ritchie MD, Franceschini N, Kao WH
Source: Atherosclerosis, 2013 Jun;228(2), p. 390-9.
EPub date: 2013 Mar 13.
Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.
Authors: Wu Y, Waite LL, Jackson AU, Sheu WH, Buyske S, Absher D, Arnett DK, Boerwinkle E, Bonnycastle LL, Carty CL, Cheng I, Cochran B, Croteau-Chonka DC, Dumitrescu L, Eaton CB, Franceschini N, Guo X, Henderson BE, Hindorff LA, Kim E, Kinnunen L, Komulainen P, Lee WJ, Le Marchand L, Lin Y, Lindström J, Lingaas-Holmen O, Mitchell SL, Narisu N, Robinson JG, Schumacher F, Stan?áková A, Sundvall J, Sung YJ, Swift AJ, Wang WC, Wilkens L, Wilsgaard T, Young AM, Adair LS, Ballantyne CM, B??ková P, Chakravarti A, Collins FS, Duggan D, Feranil AB, Ho LT, Hung YJ, Hunt SC, Hveem K, Juang JM, Kesäniemi AY, Kuusisto J, Laakso M, Lakka TA, Lee IT, Leppert MF, Matise TC, Moilanen L, Njřlstad I, Peters U, Quertermous T, Rauramaa R, Rotter JI, Saramies J, Tuomilehto J, Uusitupa M, Wang TD, Boehnke M, Haiman CA, Chen YD, Kooperberg C, Assimes TL, Crawford DC, Hsiung CA, North KE, Mohlke KL
Source: PLoS Genet, 2013 Mar;9(3), p. e1003379.
EPub date: 2013 Mar 21.
Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.
Authors: Carty CL, Spencer KL, Setiawan VW, Fernandez-Rhodes L, Malinowski J, Buyske S, Young A, Jorgensen NW, Cheng I, Carlson CS, Brown-Gentry K, Goodloe R, Park A, Parikh NI, Henderson B, Le Marchand L, Wactawski-Wende J, Fornage M, Matise TC, Hindorff LA, Arnold AM, Haiman CA, Franceschini N, Peters U, Crawford DC
Source: Hum Reprod, 2013 Jun;28(6), p. 1695-706.
EPub date: 2013 Mar 18.