Germline Genes Specific to Chronic Lymphocytic Leukemia (CLL) and Genes Common to CLL, Lymphoplasmacytic Lymphoma/Waldenström’s Macroglobulinemia, and Other Non-Hodgkin Lymphomas Are Important in Susceptibility

Background. Evidence from multiply affected families, case-control and population-based registry studies implicate a role for genetic factors in chronic lymphocytic leukemia (CLL). Population-based studies have found CLL and non-Hodgkin lymphomas (NHLs) to aggregate in families. The aim of this study was to expand our understanding on the role of susceptibility genes in CLL and other lymphoproliferative malignancies.

Methods. Using the population-based Swedish Population-, Cancer-, and Multigenerational registries, we identified all CLL patients (n=9,717) diagnosed from 1958–2004 with linkable first-degree relatives (N=26,947). We also obtained information on 38,159 matched controls and their 107,223 first-degree relatives. Cancer risks in relatives of CLL patients were compared with those in relatives of controls using marginal survival models. In parallel, we conducted a candidate gene association study in unrelated familial lymphoma cases (44 CLL, 71 Waldenström’s macroglobulinemia (WM)) from our clinical studies of high risk families (which were selected for having multiple cases of either CLL or WM) compared to 107 spouses from the same families. We tested 1536 single nucleotide polymorphisms (SNPs) in 152 candidate genes in several pathways including apoptosis, DNA repair, immune response, and oxidative stress using a custom Illumina genotyping platform.

Results. In our population-based study, we found relatives of CLL patients to have an increased risk for CLL (relative risk [RR]=8.5, 95%CI=6.1–11.7), lymphoplasmacytic lymphoma (LPL)/WM (RR=4.0, 95%CI=2.0–8.2) and other NHLs (RR=1.7, 95%CI=1.4–2.2), but not for Hodgkin lymphoma, multiple myeloma, or other hematologic tumors. In our SNP-based study, we found several genes (e.g., IL-10, BCL-2, TRAIL, and TRAILR1) to be significantly associated with both familial CLL and WM. In particular, a SNP in the promoter region of IL-10 (rs1800890, −3575T>A), which has been previously detected in other NHL case-control studies, was associated with both CLL and WM.

Conclusions. We conclude that germline genes specific to CLL and genes common to CLL, LPL/WM and other NHLs are important in susceptibility. We found consistent patterns in both our population-based study and our clinical high-risk families. Our findings for BCL-2, TRAIL, and TRAILR1 highlight the important role of apoptosis pathways in the etiology of these lymphomas. Better characterization of early genetic lesions will ultimately provide clues to pathogenesis and allow identification of novel molecular targets.