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Grant Details

Grant Number: 5R01CA104682-08 Interpret this number
Primary Investigator: Skibola, Christine
Organization: University Of California Berkeley
Project Title: Genetic Susceptibility to Non-Hodgkin Lymphoma
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): Genetic Susceptibility to Non-Hodgkin Lymphoma - Renewal: Dramatic increases worldwide in the incidence of non-Hodgkin lymphoma (NHL) have stimulated considerable efforts to identify factors that may aid in the prevention and treatment of this disease and to further our understanding of the biological mechanisms that initiate and sustain a lymphoid malignancy. As a continuation of grant R01 CA 104682-01, the overall goal of this proposal is to identify genetic variants that are causally related to risk of NHL using DNA from two large case-control studies based in the San Francisco Bay Area: SF Bay Area NHL1 (400 cases, 800 controls) and SF Bay Area NHL2 (1,800 cases, 1,800 controls). We have made considerable contributions to the field to date in identifying genetic risk factors of NHL in multiple studies. We have identified nearly thirty genes strongly associated with NHL during the previous grant period, from a recent genome scan and through collaborations within the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). These genes lie in the obesity, inflammation, hormone production and innate immunity pathways. Now, using the Illumina genotyping platform, under Aim#1, we will fine map these genes to identify true NHL risk alleles. Under Aim#2, as part of ongoing replication studies within InterLymph, we will lead the fine mapping of genes associated with NHL based on a large pooled genetic study currently underway that is being spearheaded by Dr. Skibola. Using data from a recent genome scan, in Aim#3, we will assess the influence of copy number variation on risk of NHL, which will then be confirmed in our additional NHL cases and controls. Finally, we will test the function of putatively causal polymorphisms identified through Aims 1 and 2 and perform mechanistic studies of risk alleles to gain further insights that will enhance our current understanding of mechanisms involved in lymphomagenesis. Results from these studies 1) can be translated into prevention and treatment programs aimed at reducing the public health burden of NHL worldwide; 2) use already existing DNA from two NHL case-control studies; 3) use already existing data from our genome scan; 4) will be the first to report genetic susceptibility of NHL based on copy number variation in population studies; and 5) will support major efforts to perform replication, fine mapping and pooled analyses within the InterLymph consortium. PUBLIC HEALTH RELEVANCE: In 2008, non-Hodgkin lymphoma (NHL) will account for over 63,000 newly diagnosed cases and 20,000 associated deaths in the U.S. and over 300,000 cases and 172,000 deaths worldwide. Incidence and mortality rates have steadily increased over the last several decades, making NHL the fifth most common cancer in the U.S. An important role for family genetics has been established in causing lymphoma and common genetic variants may influence disease susceptibility. These studies will use genetics to increase our understanding of how lymphoma develops in the body and provide clues about environmental agents and lifestyle exposures that contribute to disease risk that may be translated to NHL screening, prevention and treatment programs.

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Publications

Follicular lymphoma-protective HLA class II variants correlate with increased HLA-DQB1 protein expression.
Authors: Sillé FC, Conde L, Zhang J, Akers NK, Sanchez S, Maltbaek J, Riby JE, Smith MT, Skibola CF
Source: Genes Immun, 2014 Mar;15(2), p. 133-6.
EPub date: 2013 Dec 5.
PMID: 24304973
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Non-Hodgkin lymphoma risk and variants in genes controlling lymphocyte development.
Authors: Schuetz JM, Daley D, Leach S, Conde L, Berry BR, Gallagher RP, Connors JM, Gascoyne RD, Bracci PM, Skibola CF, Spinelli JJ, Brooks-Wilson AR
Source: PLoS One, 2013;8(9), p. e75170.
EPub date: 2013 Sep 30.
PMID: 24098683
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X chromosome-wide association study of follicular lymphoma.
Authors: Conde L, Foo JN, Riby J, Liu J, Darabi H, Hjalgrim H, Bracci PM, Smedby KE, Skibola CF
Source: Br J Haematol, 2013 Sep;162(6), p. 858-62.
EPub date: 2013 Jun 25.
PMID: 23795672
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Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk.
Authors: Foo JN, Smedby KE, Akers NK, Berglund M, Irwan ID, Jia X, Li Y, Conde L, Darabi H, Bracci PM, Melbye M, Adami HO, Glimelius B, Khor CC, Hjalgrim H, Padyukov L, Humphreys K, Enblad G, Skibola CF, de Bakker PI, Liu J
Source: Am J Hum Genet, 2013 Jul 11;93(1), p. 167-72.
EPub date: 2013 Jun 20.
PMID: 23791106
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia.
Authors: Berndt SI, Skibola CF, Joseph V, Camp NJ, Nieters A, Wang Z, Cozen W, Monnereau A, Wang SS, Kelly RS, Lan Q, Teras LR, Chatterjee N, Chung CC, Yeager M, Brooks-Wilson AR, Hartge P, Purdue MP, Birmann BM, Armstrong BK, Cocco P, Zhang Y, Severi G, Zeleniuch-Jacquotte A, Lawrence C, Burdette L, Yuenger J, Hutchinson A, Jacobs KB, Call TG, Shanafelt TD, Novak AJ, Kay NE, Liebow M, Wang AH, Smedby KE, Adami HO, Melbye M, Glimelius B, Chang ET, Glenn M, Curtin K, Cannon-Albright LA, Jones B, Diver WR, Link BK, Weiner GJ, Conde L, Bracci PM, Riby J, Holly EA, Smith MT, Jackson RD, Tinker LF, Benavente Y, Becker N, Boffetta P, Brennan P, Foretova L, Maynadie M, McKay J, Staines A, Rabe KG, Achenbach SJ, Vachon CM, Goldin LR, Strom SS, Lanasa MC, Spector LG, Leis JF, Cunningham JM, Weinberg JB, Morrison VA, Caporaso NE, Norman AD, Linet MS, De Roos AJ, Morton LM, Severson RK, Riboli E, Vineis P, Kaaks R, Trichopoulos D, Masala G, Weiderpass E, Chirlaque MD, Vermeulen RC, Travis RC, Giles GG, Albanes D, Virtamo J, Weinstein S, Clavel J, Zheng T, Holford TR, Offit K, Zelenetz A, Klein RJ, Spinelli JJ, Bertrand KA, Laden F, Giovannucci E, Kraft P, Kricker A, Turner J, Vajdic CM, Ennas MG, Ferri GM, Miligi L, Liang L, Sampson J, Crouch S, Park JH, North KE, Cox A, Snowden JA, Wright J, Carracedo A, Lopez-Otin C, Bea S, Salaverria I, Martin-Garcia D, Campo E, Fraumeni JF Jr, de Sanjose S, Hjalgrim H, Cerhan JR, Chanock SJ, Rothman N, Slager SL
Source: Nat Genet, 2013 Aug;45(8), p. 868-76.
EPub date: 2013 Jun 16.
PMID: 23770605
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Rare variant association testing under low-coverage sequencing.
Authors: Navon O, Sul JH, Han B, Conde L, Bracci PM, Riby J, Skibola CF, Eskin E, Halperin E
Source: Genetics, 2013 Jul;194(3), p. 769-79.
EPub date: 2013 May 1.
PMID: 23636738
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Integrating GWAS and expression data for functional characterization of disease-associated SNPs: an application to follicular lymphoma.
Authors: Conde L, Bracci PM, Richardson R, Montgomery SB, Skibola CF
Source: Am J Hum Genet, 2013 Jan 10;92(1), p. 126-30.
EPub date: 2012 Dec 13.
PMID: 23246294
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PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium.
Authors: Nieters A, Conde L, Slager SL, Brooks-Wilson A, Morton L, Skibola DR, Novak AJ, Riby J, Ansell SM, Halperin E, Shanafelt TD, Agana L, Wang AH, De Roos AJ, Severson RK, Cozen W, Spinelli J, Butterbach K, Becker N, de Sanjose S, Benavente Y, Cocco P, Staines A, Maynadié M, Foretova L, Boffetta P, Brennan P, Lan Q, Zhang Y, Zheng T, Purdue M, Armstrong B, Kricker A, Vajdic CM, Grulich A, Smith MT, Bracci PM, Chanock SJ, Hartge P, Cerhan JR, Wang SS, Rothman N, Skibola CF
Source: Blood, 2012 Nov 29;120(23), p. 4645-8.
EPub date: 2012 Oct 9.
PMID: 23047821
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A meta-analysis of genome-wide association studies of follicular lymphoma.
Authors: Skibola CF, Conde L, Foo JN, Riby J, Humphreys K, Sillé FC, Darabi H, Sanchez S, Hjalgrim H, Liu J, Bracci PM, Smedby KE
Source: BMC Genomics, 2012 Oct 1;13, p. 516.
EPub date: 2012 Oct 1.
PMID: 23025665
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Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and, potentially, other non-Hodgkin lymphoma subtypes.
Authors: Slager SL, Camp NJ, Conde L, Shanafelt TD, Achenbach SJ, Rabe KG, Kay NE, Novak AJ, Call TG, Bracci PM, Sille FM, Sanchez S, Akers NK, Cunningham JM, Serie DJ, McDonnell SK, Leis JF, Wang AH, Weinberg JB, Glenn M, Link B, Vachon CM, Lanasa MC, Skibola CF, Cerhan JR
Source: Br J Haematol, 2012 Dec;159(5), p. 572-6.
EPub date: 2012 Oct 1.
PMID: 23025533
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Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia.
Authors: Slager SL, Skibola CF, Di Bernardo MC, Conde L, Broderick P, McDonnell SK, Goldin LR, Croft N, Holroyd A, Harris S, Riby J, Serie DJ, Kay NE, Call TG, Bracci PM, Halperin E, Lanasa MC, Cunningham JM, Leis JF, Morrison VA, Spector LG, Vachon CM, Shanafelt TD, Strom SS, Camp NJ, Weinberg JB, Matutes E, Caporaso NE, Wade R, Dyer MJ, Dearden C, Cerhan JR, Catovsky D, Houlston RS
Source: Blood, 2012 Jul 26;120(4), p. 843-6.
EPub date: 2012 Jun 13.
PMID: 22700719
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Multi-locus HLA class I and II allele and haplotype associations with follicular lymphoma.
Authors: Skibola CF, Akers NK, Conde L, Ladner M, Hawbecker SK, Cohen F, Ribas F, Erlich HA, Goodridge D, Trachtenberg EA, Smith MT, Bracci PM
Source: Tissue Antigens, 2012 Apr;79(4), p. 279-86.
EPub date: 2012 Feb 2.
PMID: 22296171
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Self-reported history of infections and the risk of non-Hodgkin lymphoma: an InterLymph pooled analysis.
Authors: Becker N, Falster MO, Vajdic CM, de Sanjose S, Martínez-Maza O, Bracci PM, Melbye M, Smedby KE, Engels EA, Turner J, Vineis P, Costantini AS, Holly EA, Spinelli JJ, La Vecchia C, Zheng T, Chiu BC, Montella M, Cocco P, Maynadié M, Foretova L, Staines A, Brennan P, Davis S, Severson R, Cerhan JR, Breen EC, Birmann B, Cozen W, Grulich AE, Newton R
Source: Int J Cancer, 2012 Nov 15;131(10), p. 2342-8.
EPub date: 2012 Aug 12.
PMID: 22266776
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Post-GWAS functional characterization of susceptibility variants for chronic lymphocytic leukemia.
Authors: Sillé FC, Thomas R, Smith MT, Conde L, Skibola CF
Source: PLoS One, 2012;7(1), p. e29632.
EPub date: 2012 Jan 3.
PMID: 22235315
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The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma.
Authors: Carvalho A, Cunha C, Almeida AJ, Osório NS, Saraiva M, Teixeira-Coelho M, Pedreiro S, Torrado E, Domingues N, Gomes-Alves AG, Marques A, Lacerda JF, da Silva MG, Gomes M, Pinto AC, Torres F, Rendeiro P, Tavares P, Di Ianni M, Medeiros R, Heutink P, Bracci PM, Conde L, Ludovico P, Pedrosa J, Maciel P, Pitzurra L, Aversa F, Marques H, Paiva A, Skibola CF, Romani L, Castro AG, Rodrigues F
Source: Genes Immun, 2012 Feb;13(2), p. 197-201.
EPub date: 2011 Aug 25.
PMID: 21866115
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Multiplexed, ligation-dependent probe amplification for rapid and inexpensive HLA-DQB1 allelotyping.
Authors: Akers NK, Curry JD, Smith MT, Bracci PM, Skibola CF
Source: Tissue Antigens, 2011 Oct;78(4), p. 275-80.
EPub date: 2011 Jul 18.
PMID: 21762399
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A search for overlapping genetic susceptibility loci between non-Hodgkin lymphoma and autoimmune diseases.
Authors: Conde L, Bracci PM, Halperin E, Skibola CF
Source: Genomics, 2011 Jul;98(1), p. 9-14.
EPub date: 2011 Mar 23.
PMID: 21439368
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SNP rs6457327 in the HLA region on chromosome 6p is predictive of the transformation of follicular lymphoma.
Authors: Wrench D, Leighton P, Skibola CF, Conde L, Cazier JB, Matthews J, Iqbal S, Carlotti E, Bödör C, Montoto S, Calaminici M, Gribben JG, Lister TA, Fitzgibbon J
Source: Blood, 2011 Mar 17;117(11), p. 3147-50.
EPub date: 2011 Jan 13.
PMID: 21233317
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Association of HLA-DQB1 alleles with risk of follicular lymphoma.
Authors: Akers NK, Curry JD, Conde L, Bracci PM, Smith MT, Skibola CF
Source: Leuk Lymphoma, 2011 Jan;52(1), p. 53-8.
EPub date: 2010 Dec 6.
PMID: 21133715
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A generic coalescent-based framework for the selection of a reference panel for imputation.
Authors: Pa?aniuc B, Avinery R, Gur T, Skibola CF, Bracci PM, Halperin E
Source: Genet Epidemiol, 2010 Dec;34(8), p. 773-82.
PMID: 21058333
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Birth order and risk of non-hodgkin lymphoma--true association or bias?
Authors: Grulich AE, Vajdic CM, Falster MO, Kane E, Smedby KE, Bracci PM, de Sanjose S, Becker N, Turner J, Martinez-Maza O, Melbye M, Engels EA, Vineis P, Costantini AS, Holly EA, Spinelli JJ, La Vecchia C, Zheng T, Chiu BC, Franceschi S, Cocco P, Maynadié M, Foretova L, Staines A, Brennan P, Davis S, Severson RK, Cerhan JR, Breen EC, Birmann B, Cozen W
Source: Am J Epidemiol, 2010 Sep 15;172(6), p. 621-30.
EPub date: 2010 Aug 18.
PMID: 20720098
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Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32.
Authors: Conde L, Halperin E, Akers NK, Brown KM, Smedby KE, Rothman N, Nieters A, Slager SL, Brooks-Wilson A, Agana L, Riby J, Liu J, Adami HO, Darabi H, Hjalgrim H, Low HQ, Humphreys K, Melbye M, Chang ET, Glimelius B, Cozen W, Davis S, Hartge P, Morton LM, Schenk M, Wang SS, Armstrong B, Kricker A, Milliken S, Purdue MP, Vajdic CM, Boyle P, Lan Q, Zahm SH, Zhang Y, Zheng T, Becker N, Benavente Y, Boffetta P, Brennan P, Butterbach K, Cocco P, Foretova L, Maynadié M, de Sanjosé S, Staines A, Spinelli JJ, Achenbach SJ, Call TG, Camp NJ, Glenn M, Caporaso NE, Cerhan JR, Cunningham JM, Goldin LR, Hanson CA, Kay NE, Lanasa MC, Leis JF, Marti GE, Rabe KG, Rassenti LZ, Spector LG, Strom SS, Vachon CM, Weinberg JB, Holly EA, Chanock S, Smith MT, Bracci PM, Skibola CF
Source: Nat Genet, 2010 Aug;42(8), p. 661-4.
EPub date: 2010 Jul 18.
PMID: 20639881
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A functional TNFRSF5 polymorphism and risk of non-Hodgkin lymphoma, a pooled analysis.
Authors: Nieters A, Bracci PM, de Sanjosé S, Becker N, Maynadié M, Benavente Y, Foretova L, Cocco P, Staines A, Holly EA, Boffetta P, Brennan P, Skibola CF
Source: Int J Cancer, 2011 Mar 15;128(6), p. 1481-5.
PMID: 20473910
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Acute lymphoblastic leukaemia in children - is there a role for MTHFR?
Authors: Lightfoot TJ, Roman E, Smith MT, Skibola CF
Source: Br J Haematol, 2010 Jun;149(5), p. 797-8; author reply 799-800.
EPub date: 2010 Feb 8.
PMID: 20148884
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