Abstract
A Meta-Analysis Of Hodgkin Lymphoma Reveals 19p13.3 (TCF3) As a Novel Susceptibility Loc
Blood, Vol.122(21), pp.626-626
11/15/2013
DOI: 10.1182/blood.V122.21.626.626
Abstract
Abstract
Background
Recent genome wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified several associations at both HLA and non-HLA loci. However, much of HL heritability remains unexplained.
Methods
To identify novel risk loci, we performed a meta-analysis of 3 HL GWAS including a total of 1,810 cases and 7,879 controls. Results were replicated in an independent set of 1,163 cases and 2,580 controls, for a total of 3,097 and 11,097 cases and controls combined, respectively. participants in discovery and replication stages were of European descent. quality control and imputation we conducted a meta-analysis addressing 1,004,829 variants (λ= 1.10, λ1000= 1.03).
Associations between SNP genotypes and HL risk were evaluated under a log-additive model of inheritance adjusting for sex, study center and significant principal components to control for population stratification. We performed an analysis with all HL cases and then conducted stratified analyses by histological subtype (classical, nodular sclerosis and mixed cellularity), age at diagnosis (nodular sclerosis among those diagnosed at 15- 35 years in all studies, and those diagnosed at 35 and older years in the European Study only) and EBV tumor status (negative and positive). We then used a bioinformatic approach (FunciSNP) to identify potential functional variants associated with HD risk correlated with risk loci of interest. We extracted publically available ENCODE data on biofeatures to identify potential functional motifs associated with the index SNP or correlated SNPs. Finally, we measured expression levels of the two alternative mRNA transcripts in lymphoblastoid cell lines (LCLs) from 49 post-therapy HL patients and 25 unaffected controls. RT-PCR was carried out in triplicate. Relative expression levels were calculated relative to TBP as housekeeping gene. Linear models were used to assess correlation between genotype and TCF3expression levels.
Results
The meta-analysis identified a novel susceptibility variant at chromosome 19p13.3 (rs1860661) associated with HL risk (Odds Ratio [OR]= 0.78, P=2.0*10-8, I2=0%). variant is located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment. was also significantly associated with HL (OR= 0.85, P=0.002) in the replication series of 1,281 cases and 3,218 controls. the combined analysis consisting of the discovery and replication sets, rs1860661was strongly associated with HL (OR=0.81,=3.5*10-10), with no evidence of heterogeneity between contributing studies (Phom=0.41, I2=0%).
The number of G alleles defined by rs1860661 was significantly associated with a reduced risk of each HL subtype except EBV positive HL. rs1860661 and two correlated SNPs, rs10413888 (r2=0.90) and rs8103453 (r2=0.89) identified by FunciSNP analysis map in or near marks of open chromatin and in DNAse hypersensitivity sites in TCF3 in CD20+ B cell lines., the protective minor alleles of these SNPs as defined by the G-G-G haplotype map to the binding sites for ZBTB7a (rs10413888 and rs1860661) and (rs8103453) transcription factors, likely improving the binding efficiency to the sites which may result in increased transcription rates of TCF3. TCF3 is encoded by two alternative transcripts (E12 and E47). Higher expression levels of TCF3-E47, whose transcription start site is located close to rs1860661, was associated with the rs1860661-G allele in controls (P=0.02), but not in HL patients (P=0.22).
Conclusion/Discussion
TCF3 is essential for the commitment of lymphoid progenitors to both B-cell and T-cell lineage development. A molecular and phenotypic hallmark of classical HL is the loss of the B-cell phenotype in HRS cells, including lack of demonstrable B-cell receptor and most B-cell specific markers such as CD19 or CD20. HRS cells have a low level of TCF3, particularly homodimers of the isoform E47, due to expression of the ABF-1 and ID2 inhibitors that bind to TCF3. Thus, higher TCF3 levels in HRS precursor cells may lead to enhanced retention of the B cell phenotype, thereby conferring a protective effect. These data suggest a link between the 19p13.3 locus including TCF3 and HL risk, indicating that TCF3 could be relevant to HL etiology and pathogenesis.
Disclosures:
Link: Genentech: Consultancy; Millenium: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy.
Details
- Title: Subtitle
- A Meta-Analysis Of Hodgkin Lymphoma Reveals 19p13.3 (TCF3) As a Novel Susceptibility Loc
- Creators
- Wendy Cozen - University of Southern CaliforniaDalin Li - Cedars-Sinai Medical CenterMaria Timofeeva - Centre international de recherche sur le cancerArjan Diepstra - University Medical Center GroningenDennis Hazelett - University of Southern CaliforniaManon Delahaye-Sourdeix - Centre international de recherche sur le cancerChristopher K. Edlund - University of Southern CaliforniaKlaus Rostgaard - Statens Serum InstitutDavid J. Van Den Berg - University of Southern CaliforniaLude Franke - University of GroningenKarin Eckstrom Smedby - Karolinska InstitutetSally L. Glaser - Cancer Prevention Institute of CaliforniaHarm-Jam Westra - University of GroningenLeslie L. Robison - St. Jude Children's Research HospitalThomas M. Mack - University of Southern CaliforniaHerve Ghesquieres - Centre National de la Recherche ScientifiqueAmie E. Hwang - USC Norris Comprehensive Cancer Center, Department of Preventive Medicine, Univ of Southern California, USC Keck School of Medicine and Norris Cancer Ctr, Los Angeles, CA, USAAlexandra Nieters - University Medical Center FreiburgSilvia de Sanjosé - Institut Català d'OncologiaVictoria K. Cortessis - University of Southern CaliforniaTracy Lightfoot - University of YorkNikolaus Becker - German Cancer Research CenterMarc Maynadie - Service d'Hématologie Biologique, Plateau Technique de Biologie, Dijon cedex, FranceLenka Foretova - Masaryk Memorial Cancer InstituteEve Roman - University of YorkYolanda Benavente - Institut Català d'OncologiaBharat N. Nathwani - City Of Hope National Medical CenterBengt Glimelius - Uppsala UniversityAnthony Staines - Dublin City UniversityPaolo Boffetta - Mount Sinai HospitalBrian K Link - University of IowaL. A. Kiemeney - Radboud University Medical CenterStephen M Ansell - Mayo ClinicSmita Bhatia - City Of Hope National Medical CenterLouise C Strong - The University of Texas at AustinPilar Galan - Université Paris CitéLars Vatten - Norwegian University of Science and TechnologyThomas M Habermann - Mayo ClinicEric J. Duell - Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, SpainAnnette Lake - University of GlasgowRianne Veenstra - University of GroningenLydia Visser - University Medical Center GroningenKevin Urayama - St. Luke's International HospitalDorothy Montgomery - University of GlasgowValerie Gaborieau - Centre international de recherche sur le cancerLawrence Weiss - Clarient Pathology Services, Aliso Viejo, CA, USAGraham Byrnes - Centre international de recherche sur le cancerMark Lathrop - McGill UniversityHans-Olov Adami - Karolinska InstitutetMads Melbye - Statens Serum InstitutJames R Cerhan - Mayo ClinicAlice Gallagher - University of GlasgowG. Malcolm Taylor - St Mary's Hospital, Manchester, United KingdomSusan L Slager - Mayo Clinic in FloridaPaul Brennan - Centre international de recherche sur le cancerDavid V. Conti - University of Southern CaliforniaGerhard Coetzee - University of Southern CaliforniaKenan Onel - University of ChicagoRuth F. Jarrett - University of GlasgowHenrik Hjalgrim - Statens Serum InstitutAnke Van Den Berg - University Medical Center GroningenJames D. McKay - Centre international de recherche sur le cancer
- Resource Type
- Abstract
- Publication Details
- Blood, Vol.122(21), pp.626-626
- DOI
- 10.1182/blood.V122.21.626.626
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Language
- English
- Date published
- 11/15/2013
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Internal Medicine
- Record Identifier
- 9984362683702771
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