|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|
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.