Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

Geffen Kleinstern; Huihuang Yan; Michelle A T Hildebrandt; Joseph Vijai; Sonja I Berndt; Hervé Ghesquières; James McKay; Sophia S Wang; Alexandra Nieters; Yuanqing Ye; Alain Monnereau; Angela R Brooks-Wilson; Qing Lan; Mads Melbye; Rebecca D Jackson; Lauren R Teras; Mark P Purdue; Claire M Vajdic; Roel C H Vermeulen; Graham G Giles; Pier Luigi Cocco; Brenda M Birmann; Peter Kraft; Demetrius Albanes; Anne Zeleniuch-Jacquotte; Simon Crouch; Yawei Zhang; Vivekananda Sarangi; Yan Asmann; Kenneth Offit; Gilles Salles; Xifeng Wu; Karin E Smedby; Christine F Skibola; Susan L Slager; Nathaniel Rothman; Stephen J Chanock; James R Cerhan

doi:10.1093/hmg/ddz228

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Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

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Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

Geffen Kleinstern, Huihuang Yan, Michelle A T Hildebrandt, Joseph Vijai, Sonja I Berndt, Hervé Ghesquières, James McKay, Sophia S Wang, Alexandra Nieters, Yuanqing Ye, …

Human molecular genetics, Vol.29(1), pp.70-79

01/01/2020

DOI: 10.1093/hmg/ddz228

PMCID: PMC7001601

PMID: 31600786

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Abstract

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

B7-2 Antigen - genetics

Chromosomes, Human, Pair 3 - genetics

Gene Frequency - genetics

Genetic Predisposition to Disease - genetics

Genome-Wide Association Study - methods

Genotype

Humans

Linkage Disequilibrium - genetics

Lymphoma, B-Cell - metabolism

Odds Ratio

Polymorphism, Single Nucleotide - genetics

Promoter Regions, Genetic - genetics

Receptors, Cell Surface - genetics

Details

Title: Subtitle: Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways
Creators: Geffen Kleinstern - Mayo Clinic
Huihuang Yan - Mayo Clinic
Michelle A T Hildebrandt - The University of Texas MD Anderson Cancer Center
Joseph Vijai - Memorial Sloan Kettering Cancer Center
Sonja I Berndt - National Cancer Institute
Hervé Ghesquières - Centre Léon Bérard
James McKay - Centre international de recherche sur le cancer
Sophia S Wang - City Of Hope National Medical Center
Alexandra Nieters - University of Freiburg
Yuanqing Ye - The University of Texas MD Anderson Cancer Center
Alain Monnereau - Centre de recherche en Epidémiologie et Santé des Populations
Angela R Brooks-Wilson - BC Cancer Agency
Qing Lan - National Cancer Institute
Mads Melbye - Statens Serum Institut
Rebecca D Jackson - The Ohio State University
Lauren R Teras - American Cancer Society
Mark P Purdue - National Cancer Institute
Claire M Vajdic - UNSW Sydney
Roel C H Vermeulen - University Medical Center Utrecht
Graham G Giles - Cancer Council Victoria
Pier Luigi Cocco - University of Cagliari
Brenda M Birmann - Brigham and Women's Hospital
Peter Kraft - Harvard University
Demetrius Albanes - National Cancer Institute
Anne Zeleniuch-Jacquotte - New York University
Simon Crouch - University of York
Yawei Zhang - Yale University
Vivekananda Sarangi - Mayo Clinic in Florida
Yan Asmann - Mayo Clinic in Florida
Kenneth Offit - Memorial Sloan Kettering Cancer Center
Gilles Salles - Hospices Civils de Lyon
Xifeng Wu - The University of Texas MD Anderson Cancer Center
Karin E Smedby - Karolinska Institutet
Christine F Skibola - Emory University
Susan L Slager - Mayo CLinic, Rochester, MN, USA,
Nathaniel Rothman - National Cancer Institute
Stephen J Chanock - National Cancer Institute
James R Cerhan - Mayo Clinic
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.29(1), pp.70-79
DOI: 10.1093/hmg/ddz228
PMID: 31600786
PMCID: PMC7001601
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: UM1 CA182934 / NCI NIH HHS UL1 TR001863 / NCATS NIH HHS R01 CA200703 / NCI NIH HHS P30 CA008748 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
Language: English
Date published: 01/01/2020
Academic Unit: Epidemiology
Record Identifier: 9984368211902771

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