NEW YORK (GenomeWeb) – A new genome-wide association study and GWAS meta-analysis suggested that genetic variants affecting immune system genes may also influence an individual's susceptibility for developing Hodgkin lymphoma.
For their GWAS and meta-analyses, researchers from the Institute of Cancer Research and elsewhere considered genotyping profiles for more than 5,000 individuals with the B cell cancer and nearly 17,000 individuals without. Along with genetic variants already implicated in Hodgkin lymphoma susceptibility, they uncovered half a dozen new lymphoma-linked loci, including five sites implicated in the development of B cells, the antibody-producing white blood cells that become cancerous in Hodgkin lymphoma.
"Hodgkin lymphoma is a cancer of immune cells called B cells, and our study links the risk of the disease to changes in the genes that control how B cells develop," ICR molecular and population genetics researcher Richard Houlston, senior author on the Nature Communications study published online today, said in a statement.
He and his colleagues discerned between risk variants involved in the nodular sclerosis and mixed cellularity subtypes of Hodgkin lymphoma. The team also uncovered apparent overlap between variants associated with Hodgkin lymphoma in general and those implicated in multiple sclerosis, rheumatoid arthritis, and other autoimmune conditions.
Houlston reassured individuals with autoimmune conditions that the current results do not suggest that they are at elevated lymphoma risk, but do "offer fascinating genetic clues to these diseases," adding, "The new information could point towards new ways of diagnosing, treating, or even helping to prevent Hodgkin lymphoma."
For the first stage of their study, the researchers used Illumina Oncoarrays to profile SNP patterns in 1,717 individuals with Hodgkin lymphoma and 7,422 cancer-free individuals enrolled through large prostate or breast cancer studies in the UK and Europe. They also tapped into genotyping information for another 1,623 cases and 6,903 controls from two previous case-control studies in the initial GWAS.
By comparing directly genotyped and imputed SNP patterns in the 3,077 cases and 13,680 controls that met quality-control criteria, they uncovered eight suspicious SNPs outside of human leukocyte antigen (HLA) immune regions. When the team attempted to replicate these associations in 2,237 additional individuals with Hodgkin lymphoma and 3,069 unaffected controls, they were able to highlight variants at six new loci on chromosomes 3, 6, 10, 13, and 16.
All but one of these associations was mainly due to associations with the nodular sclerosis Hodgkin lymphoma (NSHL) subtype, the team noted. A variant near the PTPRK gene appeared to coincide with both NSHL and mixed cellularity Hodgkin lymphoma (MCHL) subtype susceptibility.
The researchers noted that the new and known non-HLA variants associated with Hodgkin lymphoma often fell in non-coding sequences with potential roles in B cell signaling, based on an analysis that included available chromatin immunoprecipitation profiles for dozens of transcription factors.
Within HLA regions, meanwhile, variants in class II HLA sequences were over-represented in NSHL cases. MCHL susceptibility was strongly tied to a variant in the class I HLA region, though other MCHL-associated variants fell in the class II HLA region.
Consistent with some past epidemiological reports, the team noted that the common variants implicated in classical Hodgkin lymphoma susceptibility fall at three autoimmune disease-linked loci. And using a cross-trait analysis, the group saw overlap between its GWAS signals for classical Hodgkin lymphoma and loci implicated in MS, rheumatoid arthritis, systemic lupus erythematosus, primary biliary cirrhosis, ulcerative colitis, and celiac disease.
The Hodgkin lymphoma and MS associations had the same directionality, the authors explained, "raising the possibility of shared environmental factors." They speculated that a "potential biological basis for such a relationship may encompass aberrant immune activation and cell proliferation."