Plasma levels of leptin and soluble leptin receptor and polymorphisms of leptin gene -18G > A and leptin receptor genes K109R and Q223R, in survivors of childhood acute lymphoblastic leukemia

Abstract

BackgroundApproximately 20% of children and adolescents in Europe are overweight. Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk of overweight and obesity. The purpose of this study was to assess leptin and leptin soluble receptor levels, as well as polymorphisms of selected genes in survivors of pediatric ALL, and the influence of chemo- and radiotherapy on development of overweight in the context of leptin regulation.MethodsEighty two patients (55% males), of median age 13.2 years (m: 4.8 years; M: 26.2 years) were included in the study. The ALL therapy was conducted according to modified Berlin-Frankfurt-Munster (BFM; n = 69) regimen or New York (n = 13) regimen. In 38% of patients cranial radiotherapy (CRT) was used in median dose of 18.2Gy (m: 14Gy; M: 24Gy). Median age at diagnosis was 4.5 (m: 1 year; M: 16.9 years) and median time from completion of ALL treatment was 3.2 years (m: 0.5 year; M: 4.3 years). Patients with BMI ≥85 percentile were classified as overweight. Correlation of plasma levels of leptin and leptin soluble receptor, and polymorphisms of leptin gene -18G > A, leptin receptor genes K109R and Q223R, and the overweight status were analyzed in relation to gender, intensity of chemotherapy (high intensity vs. standard intensity regimens) and to the use of CRT.ResultsSignificant differences of leptin levels in patients treated with and without CRT, both in the entire study group (22.2+/- 3.13 ng/ml vs. 14.9+/-1.6 ng/ml; p < 0.03) and in female patients (29.9+/-4.86 ng/ml vs. 16.9+/-2.44 ng/ml; p = 0.014), were found. Significant increase of leptin levels was also found in overweight patients compared to the non-overweight patients in the entire study group (29.2+/-2.86 ng/ml vs. 12.6+/-1.51 ng/ml; p < 0.0001), female patients (35.4+/-6.48 ng/ml vs. 18.4+/-2.5 ng/ml; p = 0.005), and male patients (25.7+/-2.37 ng/ml vs. 6.9+/-0.95 ng/ml; p < 0.0001). Negative correlation was observed for plasma levels of soluble leptin receptor and overweight status, with significant differences in overweight and non-overweight patients, both in the entire study group (18.2+/-0.75 ng/ml vs. 20.98+/-0.67 ng/ml; p = 0.017) and in male patients (18.2+/-1.03 ng/ml vs. 21.8+/- 1.11 ng/ml; p = 0.038). Significant (p < 0.05) negative correlation was found between leptin and leptin receptor levels in the entire group (correlation coefficient: 0.393) and in both gender subgroups (correlation coefficient in female patients: -0.427; in male patients: -0.396).ConclusionsThe prevalence of overweight in our cohort was higher than in general European population (31% vs 20%) and increased regardless of the use of CRT. Leptin and leptin receptor levels may be used as useful markers of high risk of becoming overweight in ALL survivors, particularly in females treated with CRT. Polymorphisms of leptin gene -18G > A and leptin receptor genes K109R and Q223R were not associated with overweight status in ALL survivors.

Overweight in childhood cancer survivors: the Swiss Childhood Cancer Survivor Study

“…However, previous studies of overweight in CCSs and CRT have shown mixed results that vary from weak to strong associations (4). Older studies usually showed a clear association between overweight and CRT (9,10,12,14), whereas those with children treated more recently with no or lower-dose CRT have shown a smaller effect (15)(16)(17)43). We found an association only between ≥20 Gy CRT and overweight.…”

Obesity in Pediatric ALL Survivors: A Meta-Analysis

“…Genetic variations in leptin receptors have also been associated with obesity in female survivors. 56 This systematic review suggests that female survivors may have a slightly higher BMI z score than male survivors, but the difference was small, and the overall evidence does not support a clear gender effect. The potential impact of cancer treatment on energy balance, although occurring primarily during active treatment, may last beyond the completion of treatment and become permanent.…”

“…The prevalence of overweight/obesity ranged between 29% to 69% in 14 studies that Age at study and year since Dx are the mean or median as reported or estimated based on the reported age at diagnosis and duration of follow-up (the mean duration of treatment was estimated to be 2.5 y if not indicated by the study). evaluated pediatric ALL survivors off treatment 5 to 9 years (mean/median age = 13.2-19.4 years) [8][9][10]24,33,[51][52][53][54][55][56][57][58] except for 1 early study published in 1986 59 that reported a prevalence of obesity of 8% ( Table 2). The prevalence of overweight/obesity was fairly consistent in 5 studies that evaluated pediatric ALL survivors off treatment $10 years (mean/median age = 20.5-24.1 years), ranging from 34% to 46% 7,14,40,60,61 (Table 3).…”

Post-Therapy Profile of BMI-for-Age of Indian Survivors of Pediatric Acute Lymphoblastic Leukemia and Non-Hodgkin’s Lymphoma

“…CRT received at a young age may blunt hypothalamic leptin sensitivity and thereby alter the body's response to leptin and the regulation of body weight, metabolism, and reproductive function [3]. Two recent studies have reported about significantly higher leptin levels in survivors of ALL treated by CRT [4,5]. Hence, there may be a possibility of radiation-induced hypothalamic resistance to leptin.…”

“…It is reported that a negative correlation was found between leptin and soluble leptin receptor levels suggesting negative feedback between the two peptides. Impaired receptor function (in the context of macrophage/inflammatory reactions) caused by radio/chemotherapy may be the reason of leptin resistance [5].…”