Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers

Juhi Ojha,Stuart C Finch,Kyle M Walsh,Jean L Nakamura ,Nataliya Gudzenko,Adam J De Smith,Robert F Reiss,Vadim Chumak ,Paige M Bracci,Nataliya Babkina,Iryna Dyagil,Amy L Sherborne,Dimitry Bazyka,Mi Zhou,Joseph L Wiemels,Maureen Hatch,Helen M Hansen,Semira Gonseth,Mark P Little,Lydia B Zablotska

doi:10.1186/s12940-018-0387-9

Abstract

BackgroundChronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population.MethodsA detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively).ResultsMutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival.ConclusionsNo significant enrichment in copy-number abnormalities at CLL-associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation.

Highlights

Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL)
Total numbers of nonsynonymous point mutations across the 538 cancerrelevant genes were comparable in Ukrainian Chornobyl cleanup workers exposed to IR (UR-CLL), UN-CLL, and W-CLL samples
The type of work performed in the 30-km Chornobyl zone, age at first exposure, age at diagnosis, calendar time and Rai stage of CLL were identified as significant predictors of genetic lesions, together explaining 20% of their variability

Summary

Introduction

Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Chronic lymphocytic leukemia (CLL) is the predominant type of leukemia among males in Western populations (30–40%) [1] and in Ukraine (> 50% in those 44 years and older) [2]. Evidence suggests that mortality-based studies could underestimate, possibly substantially, CLL occurrence due to its benign clinical course, incidence studies are needed to characterize risks of low-dose radiation exposures [6]. Recent incidence studies from our group [7, 8], other groups studying occupationally exposed radiation workers [9, 10], as well as the most recent update of the A-bomb incidence follow-up study [11], albeit based on a small number (12) of cases, reported significantly increased radiation risks of CLL

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Conclusion