Problems of Radiation Medicine and Radiobiology

N. I. Bilous¹, I. V. Abramenko¹, A. A. Chumak¹, I. S. Dyagil¹, Z. V. Martina¹,
V. Saenko², D. A. Bazyka¹

¹State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», 53 Melnykova str., Kyiv, 04050, Ukraine
²Department of Radiation Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan

THE SPECTRUM OF TP53, SF3B1, AND NOTCH1 MUTATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS EXPOSED TO IONIZING RADIATION DUE TO THE CHORNOBYL NPP ACCIDENT

Objective. to analyze TP53, NOTCH1 and SF3B1 mutations in chronic lymphocytic leukemia (CLL) patients, sufferers of Chornobyl NPP accident to clarify the possible relationship between ionizing radiation (IR) and CLL.
Methods. Mutations of TP53, NOTCH1, and SF3B1 genes were studied by direct sequencing in the main group of 106 CLL patients exposed to IR due to Chornobyl NPP accident and in the control group of 130 IR non-exposed CLL patients.
Results. We found TP53 and SF3B1 mutations with similar incidence in both groups – 11.3 % and 10.0 % in the main group, and 12.7 % and 11.5 % in the control group, respectively. In contrast, the frequency of NOTCH1 mutations was lower in IR-exposed patients (6.7 % vs 17.7 %; p = 0.012). TP53 mutations were seen with equal frequency among mutated (11.1 %) and unmutated (11.8 %) immunoglobulin heavy-chain variable gene (IGHV) cases in IR-exposed CLL patients, while the tendency to prevalence of TP53 mutations in unmutated compared with mutated IGHV cases was found in the control group (14.1 % and 5.6 %, correspondingly; p = 0.178). In IR-exposed group SF3B1 mutations were combined with mutations in TP53 almost in half of detected cases. In opposite, in the control group there was mutual exclusivity between SF3B1 and TP53 lesions (p = 0.001). Among IR-exposed CLL patients we found two different cases with identical rare mutation of TP53 gene – c.665C>T substitution (Pro222Leu). This substitution is very likely to represent inherited TP53 mutation, which may influence CLL development under IR exposure.
Conclusion. Our preliminary data suggest that TP53 abnormalities are involved in CLL development in subjects exposed at the Chornobyl accident and also a possible connection between inherited sensitivity to ionizing radiation caused by mutation in TP53, radiation and CLL development.
Key words: chronic lymphocytic leukemia, TP53, SF3B1, NOTCH1 mutations, ionizing radiation, Chornobyl NPP accident.

Problems of radiation medicine and radiobiology.
2018;23:283_301. doi: 10.33145/2304-8336-2018-23-283-301.

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