Elevated IgM and abnormal free light chain ratio are increased in relatives from high-risk chronic lymphocytic leukemia pedigrees

Abstract

Abnormal serum immunoglobulin (Ig) free light chains (FLC) are established biomarkers of early disease in multiple B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Heavy chains have also been shown to be biomarkers in plasma cell disorders. An unanswered question is whether these Ig biomarkers are heritable, i.e., influenced by germline factors. CLL is heritable but highly heterogeneous. Heritable biomarkers could elucidate steps of disease pathogenesis that are affected by germline factors, and may help partition heterogeneity and identify genetic pleiotropies across malignancies. Relatives in CLL pedigrees present an opportunity to identify heritable biomarkers. We compared FLCs and heavy chains between relatives in 23 high-risk CLL pedigrees and population controls. Elevated IgM (eIgM) and abnormal FLC (aFLC) ratio was significantly increased in relatives, suggesting that these Ig biomarkers are heritable and could offer risk stratification in pedigree relatives. Within high-risk CLL pedigrees, B-cell lymphoid malignancies were five times more prevalent in close relatives of individuals with eIgM, prostate cancer was three times more prevalent in relatives of individuals with aFLC, and monoclonal B-cell lymphocytosis increased surrounding individuals with normal Ig levels. These different clustering patterns suggest Ig biomarkers have the potential to partition genetic heterogeneity in CLL and provide insight into distinct heritable pleiotropies associated with CLL.

Chronic lymphocytic leukemia–like monoclonal B-cell lymphocytosis exhibits an increased inflammatory signature that is reduced in early-stage chronic lymphocytic leukemia

“…These results are in line with previous investigations suggesting a key role of self or foreign antigens in CLL development [2,20,34−36]. In this regard, the presence of immune stimulation was described several years before CLL diagnosis [37], and increased susceptibility to clonal expansions was associated with the development of the disease [38].…”

Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk

“…Cases and family members wishing to be part of the study were subsequently enrolled by the study team, including informed consent, questionnaires and biospecimens. Individuals in 23 high-risk CLL pedigrees were enrolled as previously described [ 16 ] . Only one six-generation pedigree with 24 CLL cases contained sufficient meioses (m ≥ 15) between sampled CLL cases for SGS analysis [ 17 ] .…”

“…A detailed explanation of the SGS method, including optimization over subsets and determination of the genome-wide significance threshold has been described elsewhere [15] . Briefly, a segment is defined as the stretch of consecutive SNPs shared IBS by a subset of cases.…”

“…Shared genomic segment (SGS) analysis is a recombinant-based family analysis ("linkage-like"), developed to identify regions that segregate to cases in an extended high-risk pedigree [15] . When available to study, a single large pedigree can increase homogeneity, garner equivalent power to many small pedigrees, and be sufficient alone to declare genome-wide significance.…”

Antibodies as biomarkers for cancer risk: a systematic review

“…Six studies were found looking into the association between IgM levels and the risk of cancer. One study reported an increased risk of chronic lymphocytic leukaemia in patients with increased levels of IgM [ 13 ]. No associations were found with other cancer types (i.e.…”