Genetic Epidemiology and Function of Germline and Somatic Variants in Diffuse Large B-Cell Lymphoma
As the first comprehensive study of both germline and somatic genetic variants in diffuse large B-cell lymphoma, this research project in the University of Iowa/Mayo Clinic Lymphoma SPORE is likely to provide new insights into lymphomagenesis. These findings may help with risk assessment, prognostic stratification and identification of new treatment targets.
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma subtype. It is well-established that there are driver somatic mutations in DLBCL etiology and prognosis, as well as a role for germline genetic susceptibility.
Early results from candidate gene association studies have shown a promising role for common genetic variants in immune and apoptotic genes in non-Hodgkin lymphoma.
Re-sequencing of these genes in the tumors of 40 patients with diffuse large B-cell lymphoma identified novel genomic alterations. This project is characterizing the etiologic and therapeutic significance of these novel mutations and identifying additional risk variants.
The project team is leveraging the Lymphoma SPORE's involvement in the large International Lymphoma Epidemiology (InterLymph) Consortium genome-wide association study (GWAS) of DLBCL and the SPORE's whole-exome next-generation sequencing study of paired tumor and germline DLBCL cases.
This project has three aims.
Aim 1: Characterize the therapeutic significance of novel mutations in genes that regulate the intrinsic apoptosis pathway
This project hypothesizes that mutations in genes identified through re-sequencing work (CASP9, BCL2L11 and APAF1) will have functional impacts on the apoptosis pathway. The project team is assessing the functional significance of four novel mutations in CASP9, BCL2L11 and APAF1 by determining if there is an inherent defect in the intrinsic apoptosis pathway and apoptosome formation in cells that express mutant forms of these proteins.
Aim 2: Identify novel germline low-frequency variants associated with DLBCL risk
The project hypothesizes that germline variants of low frequency will be associated with a risk of developing diffuse large B-cell lymphoma. In stage 1, the project team is using whole-exome sequencing data from the 1000 Genomes Project to impute genotypes and then test for association. The team is conducting a technical validation on the top 1,536 significant imputed genotypes using the samples from stage 1. In stage 2, the team is conducting an in silico validation of all technically validated SNPs from stage 1 using InterLymph GWAS data. In stage 3, the team is re-sequencing the top 20 gene regions from stage 2 and testing for association. In secondary analyses, the team is testing whether these validated variants impact prognosis (event-free and overall survival).
Aim 3: Identify somatically acquired driver mutations in genes critical to diffuse large B-cell lymphoma pathogenesis
The project hypothesizes that somatically acquired mutations will be associated with a risk of developing DLBCL. Using exome data from 77 paired tumor-normal DLBCL samples, the project team is identifying novel and likely functional driver mutations by filtering against the paired germline DNA and bioinformatics analysis. The top 20 genes are being sequenced to validate regions of interest in 500 patients with DLBCL with paraffin tumor tissue in the SPORE. In secondary analyses, the project team is testing whether these mutations impact prognosis.
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