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

Martha J Glenn,Brandt Jones,Michael H Tomasson,Nicola J Camp,Karen Curtin,Justin A Williams,Cassandra D Garner,Ethan Davis,Michael J Madsen

doi:10.1038/s41408-019-0186-8

Martha J Glenn, Brandt Jones + Show 7 more

Open Access

https://doi.org/10.1038/s41408-019-0186-8

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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.

Highlights

Chronic lymphocytic leukemia (CLL) is the most common leukemia affecting adults diagnosed in the UnitedStates (4.7/100,000 per year), with similar incidence in other western countries
High-risk pedigrees are defined as those containing a statistical excess of chronic lymphocytic leukemia (CLL) (p < 0.05), compared with sex, birth cohort, and birth place-matched rates from the full Utah Population Database (UPDB) dataset
A statistically significant difference in IgM levels was found between high-risk pedigree relatives and controls (p = 0.033, after adjusting for age and sex), indicating a 16.0 mg/dL increase in relatives

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is the most common leukemia affecting adults diagnosed in the UnitedStates (4.7/100,000 per year), with similar incidence in other western countries. There are very few known risk factors for CLL. Ethnicity (risk is greatest in non-Hispanic White men1), and exposure to certain chemicals[2]. Family history is the strongest risk factor, with large population-. University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. Full list of author information is available at the end of the article. Madsen based studies consistently suggesting CLL as among the most familial cancers studied[3,4] and suggesting a striking

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