Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility

Abstract

Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10−8) and for nodular sclerosis Hodgkin lymphoma at 3q28 (rs4459895, P = 9.43 × 10−17), 6q23.3 (rs6928977, P = 4.62 × 10−11), 10p14 (rs3781093, P = 9.49 × 10−13), 13q34 (rs112998813, P = 4.58 × 10−8) and 16p13.13 (rs34972832, P = 2.12 × 10−8). Additionally, independent loci within the HLA region are observed for nodular sclerosis Hodgkin lymphoma (rs9269081, HLA-DPB1*03:01, Val86 in HLA-DRB1) and mixed cellularity Hodgkin lymphoma (rs1633096, rs13196329, Val86 in HLA-DRB1). The new and established risk loci localise to areas of active chromatin and show an over-representation of transcription factor binding for determinants of B-cell development and immune response.

The role of HLA variation in lymphoma aetiology and survival

“…A second independent signal was identified as a variant in DQA1*02:01 , but this was nearly perfectly correlated with the previously identified DRB1*07:01 and thus is not likely to be a novel variant. A third GWAS from the same group identified additional potential associated HLA variants that were histology subtype‐specific: for NSHL, rs9269081 mapping close to the 3′ end of HLA class II DRA, and for MCHL, rs1633096 mapping to the 3′ end of HLA‐F . Finally, rs6457715, near HLA‐DPB1, was identified by a European GWAS to reduce EBV‐positive HL risk, independent of histological subtype .…”

Precision Medicine in Lymphoma by Innovative Instrumental Platforms

“…For example, the meta-analysis of 7 GWAS studies, for a total of 5,325 HL patients and 22,423 controls (31), demonstrated that 5 new loci were significantly associated with inherited susceptibility to HL and dysfunction of the immune system, independently from patients' age or histological subtype. A similar study based on three GWAS trials identified a set of loci (with a special representation of transcription factors) significantly correlated with the risk of developing classical HL (30). In other cases, GWASs investigate possible predictive markers of drug sensitivity or tolerability to optimize pharmacological treatments in the clinical routine.…”

Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma

“…We used GWAS data generated on 3 nonoverlapping casecontrol series of Northern European ancestry, which have been the subject of previous analyses (supplemental Tables 1 and 2, available on the Blood Web site). 11 The UK-GWAS was based on 622 cases ascertained through the Royal Marsden Hospital National Health Service Trust Family History study during 2004 to 2008, 14 and 5677 control patients from the UK Wellcome Trust Case Control Consortium 2. 15 The German-GWAS comprised 1001 cases ascertained by the German Hodgkin Study Group during 1998 to 2007, and 2092 control patients from the Heinz Nixdorf Recall study.…”

“…16 The UK-NSHLG-GWAS used 1717 cases ascertained through the National Study of Hodgkin Lymphoma Genetics (https://www.ukctg.nihr.ac.uk) from 2010 to 2013. 11 Control patients comprised 2976 cancer-free men recruited by the PRACTICAL Consortium, the UK Genetic Prostate Cancer Study (UKGPCS; age ,65 years), a study conducted through the Royal Marsden NHS Foundation Trust and Study of Epidemiology & Risk Factors in Cancer, recruited via general practitioner practices in East Anglia (2003)(2004)(2005)(2006)(2007)(2008)(2009); and 4446 cancer-free women from across the United Kingdom via the Breast Cancer Association Consortium. Details of the genotyping platform and quality control measures applied to each of the 3 GWAS have been described previously and are detailed in supplemental Tables 3 and 4.…”

“…9,10 More recently, genome-wide association studies (GWAS) have confirmed an HLA association for HL and have identified single nucleotide polymorphisms (SNPs) at 13 non-HLA loci influencing risk. 11,12 To gain further insight into HL susceptibility, we have conducted a meta-analysis of data from 7 independent GWAS and report 5 new HL risk loci. [11][12][13] Integration of gene expression, histone modification, and in situ promoter capture Hi-C data (PCHi-C) at the 5 new and the 13 known risk loci provides evidence for cell-type specificity in B and T cells and implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-kB activation as mechanisms by which loci influence HL risk.…”