A Genome-Wide Association Study of Non-Hodgkin Lymphoma

Summary

Principal Investigator: Christine F Skibola
Abstract: Incidence rates of non-Hodgkin lymphoma (NHL) have increased dramatically in the U.S. and other industrialized countries over the past 40 years, though reasons for this rise in rates are largely unexplained. In 2005, it has been estimated that NHL will account for 56,390 newly diagnosed cases and 19,200 associated deaths. Family and population-based studies provide evidence that genetic susceptibility plays a role in lymphomagenesis. However, the contribution of common genetic alleles and gene-environment interactions needs further investigation. Using Perlegen high-density oligonucleotide arrays, genome-wide genotyping on pooled DNA will be conducted to screen for NHL susceptibility markers. 267,000 haplotype tagging single nucleotide polymorphisms (SNPs) will be evaluated that span the genome on DNA pools from 1,000 NHL cases and 1,000 controls in a large population-based case-control study in the San Francisco Bay Area (recruitment of 2,000 cases and 2,000 controls to be completed in Spring 2006). Over 1,400 cases and 1,400 controls already have been ascertained with extensive epidemiological information collected from all study participants. Once target genes are identified by pooled genotyping, the association of these loci with NHL risk will be verified and further investigated by individual genotyping. An additional 7,000 SNPs will be individually genotyped in the human leukocyte antigen (HLA) region to investigate the involvement of HLA loci in the pathogenesis of NHL. Positive findings will be replicated in a second set of 1,000 NHL cases and 1,000 controls. Fine mapping genotyping will be performed on confirmed genes of interest. To add an additional replication step, another approximately 400 NHL cases and 800 controls from a previous NHL study (based in the San Francisco Bay Area) will be genotyped. This study, which constitutes one of the largest case-control NHL genetic epidemiology studies conducted to date, will broaden our current understanding of important mechanistic pathways involved in lymphomagenesis. Furthermore, these results may be translated to NHL screening, prevention or treatment regimens. The data generated from this study will provide a framework for further investigation within the NHL consortium, InterLymph. Results will later be combined with that from other InterLymph case-control studies in pooled analyses.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc A functional TNFRSF5 gene variant is associated with risk of lymphoma
    Christine F Skibola
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720 7360, USA
    Blood 111:4348-54. 2008
  2. pmc Non-Hodgkin lymphoma risk and variants in genes controlling lymphocyte development
    Johanna M Schuetz
    Canada s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
    PLoS ONE 8:e75170. 2013
  3. pmc Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk
    Jia Nee Foo
    Human Genetics, Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore 138672, Singapore
    Am J Hum Genet 93:167-72. 2013
  4. pmc Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
    Sonja I Berndt
    Division of Cancer Epidemiology and Genetics, National Cancer Institute NCI, Bethesda, Maryland, USA
    Nat Genet 45:868-76. 2013
  5. pmc Integrating GWAS and expression data for functional characterization of disease-associated SNPs: an application to follicular lymphoma
    Lucia Conde
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA 94720 7360, USA
    Am J Hum Genet 92:126-30. 2013
  6. pmc PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium
    Alexandra Nieters
    Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Strasse4, Freiburg, Germany
    Blood 120:4645-8. 2012
  7. pmc A meta-analysis of genome-wide association studies of follicular lymphoma
    Christine F Skibola
    School of Public Health, Division of Environmental Health Sciences, University of California, Berkeley, 94720, USA
    BMC Genomics 13:516. 2012
  8. pmc Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and, potentially, other non-Hodgkin lymphoma subtypes
    Susan L Slager
    Mayo Clinic College of Medicine, Rochester, MN, USA
    Br J Haematol 159:572-6. 2012
  9. pmc Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia
    Susan L Slager
    Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    Blood 120:843-6. 2012
  10. pmc Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma
    Christine F Skibola
    School of Public Health, Division of Environmental Health Sciences, University of California Berkeley, Berkeley, California, USA
    PLoS ONE 3:e2816. 2008

Scientific Experts

  • Paige M Bracci
  • David Wrench
  • Lucia Conde
  • Christine F Skibola
  • Susan L Slager
  • James R Cerhan
  • Tait D Shanafelt
  • Martyn T Smith
  • Nicholas K Akers
  • Celine M Vachon
  • Julie M Cunningham
  • Alice H Wang
  • Timothy G Call
  • Neil E Kay
  • Jacques Riby
  • Anne J Novak
  • Mark C Lanasa
  • Nicola J Camp
  • J Brice Weinberg
  • Alexandra Nieters
  • Jose F Leis
  • Angela R Brooks-Wilson
  • Jia Nee Foo
  • Karin E Smedby
  • Johanna M Schuetz
  • Henrik Hjalgrim
  • John J Spinelli
  • Mads Melbye
  • Sonja I Berndt
  • Hans Olov Adami
  • Bengt Glimelius
  • Claire M Vajdic
  • Anneclaire J De Roos
  • Tongzhang Zheng
  • Sara J Achenbach
  • Anthony Staines
  • Sara S Strom
  • Neil E Caporaso
  • Logan G Spector
  • Kari G Rabe
  • Sophia S Wang
  • Qing Lan
  • Lenka Foretova
  • Patricia Hartge
  • Martha Glenn
  • Wendy Cozen
  • Paolo Boffetta
  • Anne Kricker
  • Vicki A Morrison
  • Paul Brennan
  • Yawei Zhang
  • Nikolaus Becker
  • Marc Maynadie
  • Yolanda Benavente
  • Silvia de Sanjose
  • Lynn R Goldin
  • Stephen J Chanock
  • Pierluigi Cocco
  • Richard K Severson
  • Nathaniel Rothman
  • A Carvalho
  • Shannon K McDonnell
  • Fenna C M Sillé
  • Daniel J Serie
  • Eran Halperin
  • N K Akers
  • Kenneth Offit
  • Mark P Purdue
  • Brandt Jones
  • Elizabeth A Holly
  • Brian R Berry
  • Jarmo Virtamo
  • Xiaoming Jia
  • John A Snowden
  • Kimberly A Bertrand
  • Jacqueline Clavel
  • Ellen T Chang
  • Liming Liang
  • Paolo Vineis
  • Gunilla Enblad
  • W Ryan Diver
  • Jianjun Liu
  • James McKay
  • Rebecca D Jackson
  • Silvia Bea
  • Richard P Gallagher
  • Hatef Darabi
  • Brian K Link
  • Jeffrey Yuenger
  • Kevin B Jacobs

Detail Information

Publications22

  1. pmc A functional TNFRSF5 gene variant is associated with risk of lymphoma
    Christine F Skibola
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720 7360, USA
    Blood 111:4348-54. 2008
    ..These results suggest that the TNFRSF5 -1C>T polymorphism may increase FL susceptibility through mechanisms that hinder cellular immune responses. Further studies are needed to explore these findings...
  2. pmc Non-Hodgkin lymphoma risk and variants in genes controlling lymphocyte development
    Johanna M Schuetz
    Canada s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
    PLoS ONE 8:e75170. 2013
    ..It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings. ..
  3. pmc Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk
    Jia Nee Foo
    Human Genetics, Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore 138672, Singapore
    Am J Hum Genet 93:167-72. 2013
    ..01 × 10⁻¹⁴). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis...
  4. pmc Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
    Sonja I Berndt
    Division of Cancer Epidemiology and Genetics, National Cancer Institute NCI, Bethesda, Maryland, USA
    Nat Genet 45:868-76. 2013
    ..3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism...
  5. pmc Integrating GWAS and expression data for functional characterization of disease-associated SNPs: an application to follicular lymphoma
    Lucia Conde
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA 94720 7360, USA
    Am J Hum Genet 92:126-30. 2013
    ..The application of integrative methods, such as those presented here, to other post-GWAS investigations will help identify causal disease variants and enhance our understanding of biological disease mechanisms...
  6. pmc PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium
    Alexandra Nieters
    Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Strasse4, Freiburg, Germany
    Blood 120:4645-8. 2012
    ..These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes...
  7. pmc A meta-analysis of genome-wide association studies of follicular lymphoma
    Christine F Skibola
    School of Public Health, Division of Environmental Health Sciences, University of California, Berkeley, 94720, USA
    BMC Genomics 13:516. 2012
    ....
  8. pmc Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and, potentially, other non-Hodgkin lymphoma subtypes
    Susan L Slager
    Mayo Clinic College of Medicine, Rochester, MN, USA
    Br J Haematol 159:572-6. 2012
    ..These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes...
  9. pmc Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemia
    Susan L Slager
    Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
    Blood 120:843-6. 2012
    ..This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development...
  10. pmc Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma
    Christine F Skibola
    School of Public Health, Division of Environmental Health Sciences, University of California Berkeley, Berkeley, California, USA
    PLoS ONE 3:e2816. 2008
    ..Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms...
  11. pmc Obesity, diet and risk of non-Hodgkin lymphoma
    Christine F Skibola
    Division of Environmental Health Sciences, School of Public Health, 140 Earl Warren Hall, University of California, Berkeley, CA 94720 7360, USA
    Cancer Epidemiol Biomarkers Prev 16:392-5. 2007
    ..The accumulated scientific evidence concerning the associations between obesity, diet, and NHL suggests several identified modifiable risk factors that might be recommended to decrease lymphoma risk...
  12. pmc A search for overlapping genetic susceptibility loci between non-Hodgkin lymphoma and autoimmune diseases
    Lucia Conde
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, USA
    Genomics 98:9-14. 2011
    ..These results support continued investigation to further elucidate the relationship between lymphoma and autoimmune diseases...
  13. pmc Multiplexed, ligation-dependent probe amplification for rapid and inexpensive HLA-DQB1 allelotyping
    N K Akers
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
    Tissue Antigens 78:275-80. 2011
    ..This assay provides more specific allele data than genome-wide analysis and is more affordable than sequencing, making it a useful intermediate for researchers seeking to accurately allelotype human DNA samples...
  14. pmc The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphoma
    A Carvalho
    Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
    Genes Immun 13:197-201. 2012
    ..Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner...
  15. pmc Post-GWAS functional characterization of susceptibility variants for chronic lymphocytic leukemia
    Fenna C M Sillé
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California, United States of America
    PLoS ONE 7:e29632. 2012
    ....
  16. pmc Multi-locus HLA class I and II allele and haplotype associations with follicular lymphoma
    C F Skibola
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720 7356, USA
    Tissue Antigens 79:279-86. 2012
    ..These results provide further insight into the critical roles of HLA alleles and SNPs in FL pathogenesis that involve multi-locus effects across the HLA region...
  17. pmc SNP rs6457327 in the HLA region on chromosome 6p is predictive of the transformation of follicular lymphoma
    David Wrench
    Centre for Haemato Oncology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    Blood 117:3147-50. 2011
    ..008) with risk of FL and demonstrate that rs6457327 predicts both time to (P = .02) and risk of (P < .01) FL transformation independently of clinical variables, including the Follicular Lymphoma International Prognostic Index...
  18. pmc Association of HLA-DQB1 alleles with risk of follicular lymphoma
    Nicholas K Akers
    School of Public Health, University of California, Berkeley, CA, USA
    Leuk Lymphoma 52:53-8. 2011
    ..51, 95% CI 0.38-0.69; adjusted p-value = 4.46 × 10(-5)). Although these findings require verification, the role of HLA class II proteins in B-cell survival and proliferation makes this a biologically plausible association...
  19. pmc Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32
    Lucia Conde
    School of Public Health, University of California, Berkeley, Berkeley, California, USA
    Nat Genet 42:661-4. 2010
    ..We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9))...
  20. pmc Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) polymorphisms and risk of non-Hodgkin lymphoma in the InterLymph Consortium
    Christine F Skibola
    237A Hildebrand Hall, School of Public Health, University of California, Berkeley, Berkeley, CA 94720 7360, USA
    Am J Epidemiol 171:267-76. 2010
    ..04). These findings strengthen previous results for DLBCL and the LTA 252A>G/TNF -308A locus and provide robust evidence that these TNF/LTA gene variants, or others in linkage disequilibrium, are involved in NHL etiology...
  21. pmc Chemokine polymorphisms and lymphoma: a pooled analysis
    Paige M Bracci
    Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94118 1944, USA
    Leuk Lymphoma 51:497-506. 2010
    ..The CCL5 -403A allele conferred reduced risks of FL and chronic lymphocytic leukemia/small lymphocytic lymphoma. Results should be interpreted conservatively. Continued investigation is warranted to confirm these findings...
  22. pmc Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma
    Christine F Skibola
    Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California, USA
    Nat Genet 41:873-5. 2009
    ..7 x 10(-11)). The region of strongest association overlapped C6orf15 (STG), located near psoriasis susceptibility region 1 (PSORS1)...