Elevated Rates of Monoclonal Gammopathy in High-Risk Chronic Lymphocytic Leukemia Pedigrees

High-risk pedigrees can be a powerful design for disease gene discovery. Understanding tumor spectrum in high-risk pedigrees optimizes power for discovery, allows meaningful assessment of segregation and determination of familial risk. Many studies have observed that different hematological malignancies co-aggregate in families. In particular, we previously performed genealogical cluster analysis in the Utah Population Database and identified significant co-aggregation between chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We have also determined that the frequency of the pre-clinical state, monoclonal B-cell lymphocytosis (MBL), is elevated in high-risk CLL pedigrees. Here, we explore evidence for monoclonal gammopathies in high-risk CLL pedigrees using serum immunoglobulin (Ig) biomarkers.

Monoclonal gammopathies are characterized by a clonal expansion of plasma cells that secrete a monoclonal Ig. We used two serum biomarker tests to indicate the existence of clonal Ig proteins: Freelite™ and Hevylite™ immunoassays. These were performed on 498 frozen serum samples: 163 population controls; 97 MM/MGUS cases; 114 CLL cases (91 sporadic CLL and 23 from high-risk pedigrees); and 124 relatives in CLL pedigrees. Freelite detects and quantitates free light chains (κ and λ). Hevylite detects and quantitates specific immunoglobulins (IgA, IgG or IgM) bound to specific light chains. We determined monoclonality if either assay indicated an abnormal κ/λ ratio (specifically in conjunction with increased total Ig-type for Hevylite).The majority of monoclonality identified (92%) included restricted free lights chains. Those involving monoclonal Ig heavy chains only were all positively confirmed by standard serum protein and/or immunofixation electrophoresis.

We observed a background of monoclonal gammopathy in our control samples (5/163, frequency =0.031), consistent with the advanced age of this comparison set (average 67y). As expected, monoclonal gammopathy was evident in the MM/MGUS cases (38/97, frequency=0.392, p=3.5×10^-14), which increased to frequency=0.732, for abnormal κ/λ ratio considered without requiring increase of the specific Ig-type for Hevylite. The absence of complete identification is likely due to our samples being from prevalent cases at different treatment stages, in addition to non-secretory disease. The CLL cases (sporadic or pedigree) exhibited very similar rates of suggested monoclonal gammopathy (together 43/114, frequency=0.377, p=6.5×10^-14). Pedigree relatives also exhibited evidence of clonal Ig proteins (9/124, frequency=0.073). The frequency across all relatives was not statistically different than the control set; however, the relatives were substantially younger than controls (minimum age 20y). When relatives were restricted to those over 49y (with average 67y), the frequency increased to 0.095 and became statistically increased compared to controls (p=0.028). The 9 relatives with monoclonality were: 1 non-Hodgkin lymphoma NOS, 1 MBL case, 2 solid cancer cases, and 5 relatives with no known cancer diagnoses.

In conclusion, using sensitive Ig biomarkers we find that individuals in high-risk CLL pedigrees are at a greater risk of monoclonal gammopathy than the general population. This observation is consistent with previous clustering results indicating co-aggregation and a possible genetic etiologic overlap between CLL and MM. Furthermore, these Ig quantitative measures offer detailed phenotypes for all pedigree members, creating more informative pedigrees, increasing the power for gene identification. These measures offer an avenue for exploiting similarities across B-cell malignancies and have the potential to improve our ability to identify at-risk individuals.