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Grant Details

Grant Number: 5R01CA154643-02 Interpret this number
Primary Investigator: Skibola, Christine
Organization: University Of California Berkeley
Project Title: Resequencing and Functional Studies to Identify Causal Gene Variants of Lymphoma
Fiscal Year: 2012
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Abstract

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and the number one hematological malignancy worldwide. NHL has a major impact on morbidity and mortality; thus, studies that lead to the identification of causal gene variants will help to identify at-risk individuals through better screening; provide important clues to identify biological pathways/targets that may be amenable to therapeutic modulation; and provide new directions for studies that benefit lymphoma research. To accomplish this, resequencing targeted genomic regions known to be associated with NHL based on genome-wide association studies, followed by validation of potentially causal SNPs in large, well-phenotyped studies (such as in a consortium) is of utmost importance and will help to establish true causal genetic variants. Further characterization of causal gene variants is also crucial. Based on findings from two GWAS of NHL, SNPs and HLA alleles on chromosome band 6p21.32-33 in the major histocompatibility complex (MHC) region were associated with risk of follicular lymphoma (FL), one of the major subtypes of NHL. Our GWAS suggests an important genetic role exists for FL. MHC regions have been previously linked to some autoimmune disorders suggesting that they may share common risk alleles with FL. InterLymph member studies have identified additional susceptibility loci, some outside of the MHC, that have been validated within the consortium. Thus, there is a strong impetus to identify causal gene variants known to affect risk of FL and other NHL subtypes since no studies of this kind for lymphoma have been performed. To accomplish this, the following Aims will be undertaken: In Aim 1, targeted DNA capture and next generation sequencing will be implemented to identify all gene variants (rare and common SNPs and structural variants) in the MHC and in other regions associated with FL. The DNA has already been extracted from two large population-based case-control studies of NHL. Once novel and known SNPs are identified and tested for association with FL in the study populations, in silico functional analysis will be undertaken to predict causal SNPs. In Aim 2, putatively functional SNPs will be genotyped in independent case-control studies within the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). In Aim 3, HLA allelotypes and SNPs will be assessed in African-American FL cases to help address the issue of high LD in European populations within the MHC. In Aim 4, validated SNPs will be functionally characterized. Accumulating evidence supports the role of genetic variation in the MHC with risk of many autoimmune diseases. Thus, the identification of causal gene variants in this region for lymphoma may also prove helpful in understanding other diseases sharing common susceptibility loci.

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Publications

Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma.
Authors: Cerhan JR, Berndt SI, Vijai J, Ghesquières H, McKay J, Wang SS, Wang Z, Yeager M, Conde L, de Bakker PI, Nieters A, Cox D, Burdett L, Monnereau A, Flowers CR, De Roos AJ, Brooks-Wilson AR, Lan Q, Severi G, Melbye M, Gu J, Jackson RD, Kane E, Teras LR, Purdue MP, Vajdic CM, Spinelli JJ, Giles GG, Albanes D, Kelly RS, Zucca M, Bertrand KA, Zeleniuch-Jacquotte A, Lawrence C, Hutchinson A, Zhi D, Habermann TM, Link BK, Novak AJ, Dogan A, Asmann YW, Liebow M, Thompson CA, Ansell SM, Witzig TE, Weiner GJ, Veron AS, Zelenika D, Tilly H, Haioun C, Molina TJ, Hjalgrim H, Glimelius B, Adami HO, Bracci PM, Riby J, Smith MT, Holly EA, Cozen W, Hartge P, Morton LM, Severson RK, Tinker LF, North KE, Becker N, Benavente Y, Boffetta P, Brennan P, Foretova L, Maynadie M, Staines A, Lightfoot T, Crouch S, Smith A, Roman E, Diver WR, Offit K, Zelenetz A, Klein RJ, Villano DJ, Zheng T, Zhang Y, Holford TR, Kricker A, Turner J, Southey MC, Clavel J, Virtamo J, Weinstein S, Riboli E, Vineis P, Kaaks R, Trichopoulos D, Vermeulen RC, Boeing H, Tjonneland A, Angelucci E, Di Lollo S, Rais M, Birmann BM, Laden F, Giovannucci E, Kraft P, Huang J, Ma B, Ye Y, Chiu BC, Sampson J, Liang L, Park JH, Chung CC, Weisenburger DD, Chatterjee N, Fraumeni JF Jr, Slager SL, Wu X, de Sanjose S, Smedby KE, Salles G, Skibola CF, Rothman N, Chanock SJ
Source: Nat Genet, 2014 Nov;46(11), p. 1233-8.
EPub date: 2014 Sep 28.
PMID: 25261932
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Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Morton LM, Slager SL, Cerhan JR, Wang SS, Vajdic CM, Skibola CF, Bracci PM, de Sanjosé S, Smedby KE, Chiu BC, Zhang Y, Mbulaiteye SM, Monnereau A, Turner JJ, Clavel J, Adami HO, Chang ET, Glimelius B, Hjalgrim H, Melbye M, Crosignani P, di Lollo S, Miligi L, Nanni O, Ramazzotti V, Rodella S, Costantini AS, Stagnaro E, Tumino R, Vindigni C, Vineis P, Becker N, Benavente Y, Boffetta P, Brennan P, Cocco P, Foretova L, Maynadié M, Nieters A, Staines A, Colt JS, Cozen W, Davis S, de Roos AJ, Hartge P, Rothman N, Severson RK, Holly EA, Call TG, Feldman AL, Habermann TM, Liebow M, Blair A, Cantor KP, Kane EV, Lightfoot T, Roman E, Smith A, Brooks-Wilson A, Connors JM, Gascoyne RD, Spinelli JJ, Armstrong BK, Kricker A, Holford TR, Lan Q, Zheng T, Orsi L, Dal Maso L, Franceschi S, La Vecchia C, Negri E, Serraino D, Bernstein L, Levine A, Friedberg JW, Kelly JL, Berndt SI, Birmann BM, Clarke CA, Flowers CR, Foran JM, Kadin ME, Paltiel O, Weisenburger DD, Linet MS, Sampson JN
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 130-44.
PMID: 25174034
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Medical history, lifestyle, family history, and occupational risk factors for adult acute lymphocytic leukemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Skibola CF, Slager SL, Berndt SI, Lightfoot T, Sampson JN, Morton LM, Weisenburger DD
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 125-9.
PMID: 25174033
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Medical history, lifestyle, and occupational risk factors for hairy cell leukemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Monnereau A, Slager SL, Hughes AM, Smith A, Glimelius B, Habermann TM, Berndt SI, Staines A, Norman AD, Cerhan JR, Sampson JN, Morton LM, Clavel J
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 115-24.
PMID: 25174032
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Medical history, lifestyle, family history, and occupational risk factors for sporadic Burkitt lymphoma/leukemia: the Interlymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Mbulaiteye SM, Morton LM, Sampson JN, Chang ET, Costas L, de Sanjosé S, Lightfoot T, Kelly J, Friedberg JW, Cozen W, Marcos-Gragera R, Slager SL, Birmann BM, Weisenburger DD
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 106-14.
PMID: 25174031
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Medical history, lifestyle, family history, and occupational risk factors for mycosis fungoides and Sézary syndrome: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Aschebrook-Kilfoy B, Cocco P, La Vecchia C, Chang ET, Vajdic CM, Kadin ME, Spinelli JJ, Morton LM, Kane EV, Sampson JN, Kasten C, Feldman AL, Wang SS, Zhang Y
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 98-105.
PMID: 25174030
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Medical history, lifestyle, family history, and occupational risk factors for lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Vajdic CM, Landgren O, McMaster ML, Slager SL, Brooks-Wilson A, Smith A, Staines A, Dogan A, Ansell SM, Sampson JN, Morton LM, Linet MS
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 87-97.
PMID: 25174029
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Medical history, lifestyle, family history, and occupational risk factors for mantle cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Smedby KE, Sampson JN, Turner JJ, Slager SL, Maynadié M, Roman E, Habermann TM, Flowers CR, Berndt SI, Bracci PM, Hjalgrim H, Weisenburger DD, Morton LM
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 76-86.
PMID: 25174028
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Medical history, lifestyle, family history, and occupational risk factors for peripheral T-cell lymphomas: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Wang SS, Flowers CR, Kadin ME, Chang ET, Hughes AM, Ansell SM, Feldman AL, Lightfoot T, Boffetta P, Melbye M, Lan Q, Sampson JN, Morton LM, Zhang Y, Weisenburger DD
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 66-75.
PMID: 25174027
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Medical history, lifestyle, family history, and occupational risk factors for marginal zone lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Bracci PM, Benavente Y, Turner JJ, Paltiel O, Slager SL, Vajdic CM, Norman AD, Cerhan JR, Chiu BC, Becker N, Cocco P, Dogan A, Nieters A, Holly EA, Kane EV, Smedby KE, Maynadié M, Spinelli JJ, Roman E, Glimelius B, Wang SS, Sampson JN, Morton LM, de Sanjosé S
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 52-65.
PMID: 25174026
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Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Slager SL, Benavente Y, Blair A, Vermeulen R, Cerhan JR, Costantini AS, Monnereau A, Nieters A, Clavel J, Call TG, Maynadié M, Lan Q, Clarke CA, Lightfoot T, Norman AD, Sampson JN, Casabonne D, Cocco P, de Sanjosé S
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 41-51.
PMID: 25174025
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Medical history, lifestyle, family history, and occupational risk factors for follicular lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Linet MS, Vajdic CM, Morton LM, de Roos AJ, Skibola CF, Boffetta P, Cerhan JR, Flowers CR, de Sanjosé S, Monnereau A, Cocco P, Kelly JL, Smith AG, Weisenburger DD, Clarke CA, Blair A, Bernstein L, Zheng T, Miligi L, Clavel J, Benavente Y, Chiu BC
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 26-40.
PMID: 25174024
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Medical history, lifestyle, family history, and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.
Authors: Cerhan JR, Kricker A, Paltiel O, Flowers CR, Wang SS, Monnereau A, Blair A, Dal Maso L, Kane EV, Nieters A, Foran JM, Miligi L, Clavel J, Bernstein L, Rothman N, Slager SL, Sampson JN, Morton LM, Skibola CF
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 15-25.
PMID: 25174023
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Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project.
Authors: Morton LM, Sampson JN, Cerhan JR, Turner JJ, Vajdic CM, Wang SS, Smedby KE, de Sanjosé S, Monnereau A, Benavente Y, Bracci PM, Chiu BC, Skibola CF, Zhang Y, Mbulaiteye SM, Spriggs M, Robinson D, Norman AD, Kane EV, Spinelli JJ, Kelly JL, La Vecchia C, Dal Maso L, Maynadié M, Kadin ME, Cocco P, Costantini AS, Clarke CA, Roman E, Miligi L, Colt JS, Berndt SI, Mannetje A, de Roos AJ, Kricker A, Nieters A, Franceschi S, Melbye M, Boffetta P, Clavel J, Linet MS, Weisenburger DD, Slager SL
Source: J Natl Cancer Inst Monogr, 2014 Aug;2014(48), p. 1-14.
PMID: 25174022
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Copy number variation analysis on a non-Hodgkin lymphoma case-control study identifies an 11q25 duplication associated with diffuse large B-cell lymphoma.
Authors: Conde L, Riby J, Zhang J, Bracci PM, Skibola CF
Source: PLoS One, 2014;9(8), p. e105382.
EPub date: 2014 Aug 18.
PMID: 25133503
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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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eALPS: estimating abundance levels in pooled sequencing using available genotyping data.
Authors: Eskin I, Hormozdiari F, Conde L, Riby J, Skibola CF, Eskin E, Halperin E
Source: J Comput Biol, 2013 Nov;20(11), p. 861-77.
EPub date: 2013 Oct 21.
PMID: 24144111
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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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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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