AS301 - Expanded genome-wide association study of lymphoid malignancies and related disorders

Investigator Names and Contact Information

Sonja Berndt (berndts@mail.nih.gov)

Introduction/Intent

The genetic basis of non-Hodgkin lymphoma (NHL) has been a focus of lymphoma research for many years through both family and case-control studies. The candidate gene and candidate single nucleotide polymorphism (SNP) approach has been successful in studies of NHL in the US, Canada, Europe, and Australia, and particularly through pooled analyses of the InterLymph consortium. Further, taking advantage of new genomic technology, several genome-wide association studies (GWAS) for subtypes of NHL have been carried out by InterLymph case-control studies (e.g., UC Berkeley/UC San Francisco; SCALE; Mayo Clinic study; International CLL linkage consortium). We propose to conduct a comprehensive GWAS project in the context of this established consortium to identify the genetic variants that contribute to the etiology of NHL and in particular, the major histologic subtypes and their influence on survival, building on the success of InterLymph, a consortium of almost all active case-control studies of NHL worldwide, and the technical and scientific expertise of several of its members in GWAS.

The goal of this study is to conduct a genome-wide scan of NHL focusing on specific NHL subtypes with qualifying DNA samples from a subgroup of non-Hispanic Caucasian cases and controls from case-control studies in the InterLymph consortium and a subgroup of cases from cohorts in the Cohort Consortium. To optimize the genotype calling and complex quality control issues for a study drawing samples from many different sources, we plan to genotype cases and controls at a central facility, the NCI Core Genotyping Facility, using the Illumina® OmniExpress. We will scan the four most common NHL subtypes: 1) diffuse large B-cell lymphoma; 2) follicular lymphoma; 3) chronic lymphocytic leukemia/small lymphocytic lymphoma; and 4) marginal zone lymphoma from both case-control and cohort studies. Approximately 40-50% of controls from case-control studies will be frequency-matched to cases and scanned and combined with historical scanned data from controls in the cohort studies. Cases and all controls from case-control studies and cases from cohort studies that are not scanned will be genotyped by TaqMan or a similar technology for the most noteworthy findings that emerge from the genome-wide scans to increase statistical power to detect main effects and for eventual analysis of gene-gene and gene-environment interactions. A subgroup of controls from cohort studies may be genotyped by TaqMan for quality control purposes. In addition, controls from cohort studies that have already been matched to NHL cases for related biomarker studies will be genotyped by TaqMan for noteworthy findings.

We plan to conduct case-control comparisons for each SNP to identify etiologic susceptibility alleles for each NHL subtype and all NHL. Later, survival analyses for studies that have data on key outcome variables (e.g., death) will be analyzed. The new data will be combined when appropriate with results from GWAS that have been previously reported or are currently in progress (which have scanned in total about 1,800 cases and 2,000 controls from InterLymph case-control studies). We will also explore including case-series and clinical trials to increase our statistical power to detect effects for specific subtypes and on survival.

We anticipate a series of common subtype-specific publications followed by an analysis of the top findings to emerge from subtype-specific scans in all remaining NHL cases. The initial analyses of single SNP main effects and limited survival endpoints based on the merged genotype data set (scanned at NCI and elsewhere) will be conducted at the NCI. Upon completion of this first phase, the full genotype data set from the Interlymph case-control studies and, if agreed to, participating cohort studies, will be transferred to the InterLymph Data Coordinating Center at the Mayo Clinic to coordinate additional etiologic analyses including pathway-based, gene-gene and gene-environment interaction, and additional survival analyses. All components of the study, including selection of studies and samples for scanning and replication analysis, statistical analysis, and publication policy, will take place under the direction of the NHL GWAS Coordinating Committee, which will include representatives from all participating studies.

Aims

1. To conduct a genome-wide association study of LM, to identify new genetic loci for specific LM, NHL subtypes, and NHL overall, and to conduct in depth subtype analyses and comparisons.
2. To identify loci associated with survival and other related outcomes.
3. To conduct further pathway, gene-gene, gene-environment, and heritability analyses as directed by the NHL/LM GWAS Coordinating Committee or proposed by study investigators