INTRODUCTION

Improved treatments for childhood cancer during the last 30 years have dramatically increased long-term survival; 5-year relative survival rates of all childhood cancers combined increased from 56% during 1974 to 1976, to 77% during 1992 to 1998.¹ As a result of these advances in treatment, there is a large and growing number of childhood cancer survivors. Associated with this increased survival are long-term health-related consequences of therapy, including second malignancies, cardiovascular abnormalities, pulmonary complications, and obesity.² Because some of these adverse health effects may be modifiable, the identification of treatment and patient factors that contribute to them is important.

The Childhood Cancer Survivor Study (CCSS) is a cohort of more than 14,000 5-year survivors of childhood cancer from the United States and Canada who are being observed longitudinally to study late effects of cancer treatment.³ Oeffinger et al⁴ recently examined whether adult survivors of acute lymphoblastic leukemia (ALL) in the CCSS were at an increased risk for obesity and whether patient or treatment characteristics modified risk. A total of 1,765 survivors of childhood ALL were compared with 2,565 adult siblings of childhood cancer survivors. Using body mass index (BMI), the authors found that the age- and race-adjusted odds ratio (OR) for obesity (BMI ≥ 30) in survivors treated with cranial radiation therapy (CRT) ≥ 20 Gy in comparison with siblings was 2.59 (95% CI, 1.88 to 3.55) and 1.86 (95% CI, 1.33 to 2.57) for females and males, respectively. Female survivors were also more likely to be overweight (BMI = 25 to 29) in comparison with siblings. Furthermore, overweight or obesity was not associated with treatment consisting of chemotherapy only or radiation doses of less than 20 Gy.

One proposed mechanism to explain the association between CRT and obesity in survivors of childhood ALL is leptin insensitivity. Leptin is an adipocyte-derived hormone that binds to the biologically active long form of its receptor (LEPR) in the hypothalamus.⁵ It has been speculated that radiation-induced damage to the pituitary-hypothalamus axis may result in a disruption of leptin signal, which eventually results in obesity.⁶ Because the majority of patients treated for ALL do not develop this complication, it is possible that individual susceptibility through population polymorphism could contribute to adult survivors of childhood ALL becoming overweight or obese.

Polymorphisms in the LEPR gene have been studied with respect to obesity in healthy populations. Of these, Gln223Arg appears most consequential. Quinton et al⁷ found that postmenopausal women with the Arg allele had significantly lower leptin-binding affinity than women who were Gln homozygous, suggesting that this polymorphism affects ligand binding. Others have shown that carriers of the Arg allele have higher serum levels of leptin, and/or higher BMIs,^8-10 although the reports are not entirely consistent.^11,12 Given the diversity of populations studied and the polygenic nature of obesity, these contradictory results are not surprising. We hypothesized that the LEPR Gln223Arg polymorphism might influence susceptibility to obesity in childhood ALL survivors and that there may be an interaction with CRT.

PATIENTS AND METHODS

This study includes a subset of participants from the CCSS (a list of investigators appears in the Appendix). The current report is restricted to those individuals who met the following eligibility criteria: diagnosis and initial treatment for ALL at one of 25 collaborating CCSS institutions; diagnosis date between January 1, 1970, and December 31, 1986; age younger than 21 years at diagnosis; survived 5 years from diagnosis; participated in the Oeffinger et al⁴ analysis; and provided a buccal cell sample before the initiation of this study. The CCSS protocol and contact documents were reviewed and approved by the human subjects committee at each participating institution. Baseline data, including current weight and height without shoes, were collected for members of the study cohort in 1996 using a 24-page questionnaire.

RESULTS

A total of 711 individuals included in the recent analysis by Oeffinger et al⁴ returned a buccal cell sample before the initiation of this laboratory study. Of these, 38 had missing race information and 54 were nonwhite or of Hispanic ethnicity. Because the frequency of the LEPR Gln223Arg polymorphism varies by race and ethnicity,¹³ we restricted our analyses to 619 non-Hispanic white ALL survivors with an available buccal cell sample. Six hundred (97%) samples were successfully amplified for the Gln223Arg genotype. The demographics and characteristics of these 600 ALL survivors who returned a buccal cell sample compared with the 891 non-Hispanic white ALL survivors who did not return a buccal cell sample are listed in Table 1. Although the mean age at baseline and the mean age at diagnosis were significantly different between the two groups, there were no statistically significant differences with respect to weight at baseline or treatment groups. The distribution of the Gln223Arg genotype among the ALL survivors was Gln/Gln (32%), Gln/Arg (48%), and Arg/Arg (20%), which was in Hardy-Weinberg equilibrium. This distribution is similar to literature reports,¹⁴ suggesting that the genotype is not associated with ALL.

Table 2 lists genotype distribution by sex and BMI. A higher frequency of the Arg/Arg genotype (there was no significant difference between Gln/Gln or Gln/Arg, so these genotypes were grouped together) was found in females who had BMI ≥ 25 kg/m² (24% v 12%; P = .007). In contrast, no statistically significant difference was observed in males.

The adjusted estimates for the overall effect of the polymorphism on BMI in females and males are listed in Table 3. Among females who had CRT ≥ 20 Gy, those who were Arg homozygous had 6.1 times (95% CI, 2.2 to 22.0) higher odds of having a BMI ≥ 25 kg/m² compared with females who possessed at least one Gln allele (P = .002). In contrast, among females who had chemotherapy only or CRT less than 20 Gy, the risk of ≥ 25 BMI kg/m² did not differ appreciably by genotype (OR, 1.4; 95% CI, 0.6 to 3.3). This difference in LEPR effect by CRT was statistically significant for females (P = 0.04 for interaction). Although the LEPR effect on BMI ≥ 25 kg/m² was slightly higher for males, it was not statistically significant (P = 0.44 for interaction) for those treated with ≥ 20 Gy (OR, 1.8; 95% CI, 0.8 to 4.0) compared with those who had chemotherapy only or less than 20 Gy radiation (OR, 0.9; 95% CI, 0.4 to 2.0).

Three-way interaction of LEPR effects with age at diagnosis and CRT dosage was also explored, recognizing that small numbers reduce interpretability. A suggestion of an interaction was observed between older age (5 to 21 years) at diagnosis and radiation dose ≥ 20 Gy for both females and males homozygous for the Arg genotype.

DISCUSSION

Our study showed that the LEPR GlnQ223Arg polymorphism influenced susceptibility to obesity in female ALL survivors. Males had a similar distribution of the genotype regardless of weight. Studies of healthy children and adolescents show that serum leptin levels increase with age in girls but decrease in boys. Importantly, females have higher circulating levels of leptin compared with males, despite lower BMI, suggesting that females may be more resistant to the effects of leptin.¹⁵ In a study of 32 childhood ALL survivors and 35 age- and BMI-matched controls, leptin levels were highest in female survivors.⁶ Collectively, these data support a sex difference with respect to leptin regulation. Our data support the hypothesis that female ALL survivors who are homozygous for the Arg genotype have lower leptin binding affinity, as suggested by Quinton et al,⁷ although additional studies are needed.

The observation of an interaction between the homozygous Arg genotype and CRT is notable. It is possible that the Arg genotype in the presence of CRT may further decrease leptin receptor binding affinity in susceptible females. Although these results are preliminary, they may help explain why females seem most prone to obesity after CRT.

Several limitations of this study needed to be discussed. This study focused only on the leptin pathway for which CRT may influence obesity. Other pathways, including growth hormone deficiency,⁶ may also play a role. Height and weight were self-reported at one time point, which can lead to imprecision in calculating BMI. Measurement of self-reported height and weight, however, are generally accurate and do not contribute significantly to errors in assessing BMI.¹⁶ Moreover, BMI is the standard measure of obesity in most population-based studies. Our study was restricted to ALL survivors who were non-Hispanic white, thus the results might not be generalizable to other populations. Finally, because only 40% percent of ALL survivors in the recent analysis by Oeffinger et al⁴ had sent in a buccal cell sample before this analysis, it is possible that there are differences between the groups that may influence the results. However, we were able to compare the major variables of interest between the group of ALL survivors who returned a buccal cell sample with those who did not and found no statistically significant differences with BMI or radiation exposure.

Obesity in children and young adults is associated with an increased risk of developing cardiovascular disease, cancer, and diabetes in later life.^17,18 Importantly, recent modifications in treatment for children with ALL will likely reduce this late effect for future survivors. Nevertheless, many children with cancer still necessarily receive significant doses of CRT, which can influence future weight and height.^19,20 Additional study of LEPR polymorphisms is needed to confirm whether there is a sex effect and whether the Arg allele results in lower leptin receptor binding affinity. Identification of children at high risk of obesity after therapy might allow early targeted interventions to reduce subsequent obesity-related morbidity and mortality.

Appendix

The following CCSS institutions and investigators participated in this study: University of California-San Francisco, CA (Arthur Ablin, MD*); University of Alabama, Birmingham, AL (Roger Berkow, MD*); International Epidemiology Institute, Rockville, MD (John Boice, Sc.D.^‡); University of Washington, Seattle, WA (Norman Breslow, PhD^‡); UT-Southwestern Medical Center at Dallas, TX (George R. Buchanan, MD*); Dana-Farber Cancer Institute, Boston, MA (Lisa Diller, MD,* Holcombe Grier, M.D,^† Frederick Li, MD^‡); Texas Children's Center, Houston, TX (Zoann Dreyer, MD*); Children's Hospital and Medical Center, Seattle, WA (Debra Friedman, MD, MPH,* Thomas Pendergrass, MD^†); Roswell Park Cancer Institute, Buffalo, NY (Daniel M. Green, MD*^‡); Hospital for Sick Children, Toronto, ON (Mark Greenberg, MB, ChB*); St Louis Children's Hospital, MO (Robert Hayashi, MD,* Teresa Vietti, MD^†); St Jude Children's Research Hospital, Memphis, TN (Melissa Hudson, MD*^‡); University of Michigan, Ann Arbor, MI (Raymond Hutchinson, MD*); Stanford University School of Medicine, Stanford, CA (Michael P. Link, MD,* Sarah S. Donaldson, MD^‡); Children's Hospital of Philadelphia, PA (Anna Meadows, MD,*^‡ Bobbie Bayton^‡); Children's Hospital, Oklahoma City, OK (John Mulvihill, MD^‡); Children's Hospital, Denver, CO (Brian Greffe,* Lorrie Odom, MD^†); Children's Health Care-Minneapolis, MN (Maura O'Leary, MD*); Columbus Children's Hospital, OH (Amanda Termuhlen, MD,* Frederick Ruymann, MD,^† Stephen Qualman, MD^‡); Children's National Medical Center, Washington, DC (Gregory Reaman, MD,* Roger Packer, MD^‡); Children's Hospital of Pittsburgh, PA (A. Kim Ritchey, MD,* Julie Blatt, MD^†); University of Minnesota, Minneapolis, MN (Leslie L. Robison, PhD,*^‡ Ann Mertens, PhD,^‡ Joseph Neglia, MD, MPH,^‡ Mark Nesbit, MD,^‡ Stella Davies, MD, PhD^‡); Children's Hospital Los Angeles, CA (Kathy Ruccione, RN, MPH*); Memorial Sloan-Kettering Cancer Center New York (Charles Sklar, MD*^‡); National Cancer Institute, Bethesda, MD (Malcolm Smith, MD,^‡ Martha Linet, MD^‡); Mayo Clinic, Rochester, MN (W. Anthony Smithson, MD,* Gerald Gilchrist, MD^†); University of Texas M. D. Anderson Cancer Center, Houston, TX (Louise Strong, MD,*^‡ Marilyn Stovall, PhD^‡); Riley Hospital for Children, Indianapolis, IN (Terry A. Vik, MD,* Robert Weetman, MD^†); Fred Hutchinson Cancer Center, Seattle, WA (Yutaka Yasui, PhD,* John Potter, MD, PhD^†‡); and University of California-Los Angeles, CA (Lonnie Zeltzer, MD*^‡).

*Institutional principal investigator.

^†Former Institutional Principal Investigator.

^‡Member CCSS Steering Committee.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.