Genetic variation in the leptin receptor gene and obesity in survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

PURPOSE: Overweight (body mass index [BMI] 25 to 29 kg/m2) and obesity (BMI > or = 30 kg/m2) frequently follow treatment for childhood acute lymphoblastic leukemia (ALL). Recent studies suggest that risk is most apparent in females treated with cranial radiation at a younger age. Because radiation at a young age may affect the hypothalamus causing leptin receptor insensitivity, we hypothesized that a polymorphism in the leptin receptor (LEPR) gene, Gln223Arg, might influence susceptibility to obesity in survivors of childhood ALL. PATIENTS AND METHODS: We genotyped 600 non-Hispanic white adult ALL survivors enrolled onto the Childhood Cancer Survivor Study. BMI was compared between those with two copies of the Arg allele to those who had at least one copy of the Gln allele. RESULTS: Female survivors with BMI > or = 25 kg/m2 were more likely Arg homozygous than those with BMI less than 25 kg/m2 (24% v 12%; P =.007). This difference was not observed in males. Moreover, among females treated with > or = 20 Gy cranial radiation, Arg/Arg individuals had six times higher odds of having BMI > or = 25 kg/m2 (95% CI, 2.1 to 22.0) than those with a Gln allele (P =.04 for interaction). CONCLUSION LEPR polymorphism may influence obesity in female survivors of childhood ALL, particularly those exposed to cranial radiation. Because obesity is associated with increased morbidity and mortality in later life, identification of children at high risk might allow for early targeted interventions.

High-producer interleukin-2 genotype increases risk for acute graft-versus-host disease after unrelated donor bone marrow transplantation.

BACKGROUND: Cytokine polymorphisms may modulate immunologic reactivity, including graft-versus-host disease (GVHD). A single nucleotide polymorphism resulting in a thymine-to-guanine transition in the interleukin (IL)-2 gene promoter region occurs at position -330. In vitro studies have shown that the G allele is associated with early and sustained enhancement of IL-2 production, a so-called high-producer genotype. Because IL-2 is a proinflammatory cytokine, we hypothesized that recipients with high-producer genotypes would have increased frequency of GVHD after allogeneic bone marrow transplantation (BMT). METHODS: We studied 95 consecutive donor and recipient pairs who received an unrelated donor BMT at the University of Minnesota. The median age at time of BMT was 14.1 years (range 0.9-54.8 years). Stem cells were human leukocyte antigen-A, B, and DRB1 matched in 70 cases (74%) and single-antigen mismatched in 25 cases (26%). GVHD prophylaxis consisted of cyclosporine-containing regimens (53%), T-cell depletion by elutriation (42%), and others (2%). RESULTS: The probability of grade II-IV acute GVHD at day 100 was 36% (95% confidence interval 26%-46%) and was significantly affected by the presence of recipient IL-2 G allele. The probability of acute GVHD was 49% in 49 patients (52%) with at least one G allele compared with 24% in 42 patients (44%) with no G allele (P<0.01). In the Cox regression analysis, the presence of at least one IL-2 G allele was associated with a twofold increased risk of acute GVHD. CONCLUSIONS: If confirmed by others, our results indicate that more intensive GVHD prophylaxis is needed for patients with at least one IL-2 G allele, possibly directed toward blunting early host cell production of IL-2.

Cancer in the Minnesota Hmong population.

BACKGROUND: The Hmong are an isolated, agrarian people who settled in the mountainous regions of what today are Vietnam, Cambodia, and Laos. After the Vietnam War, many Hmong were relocated to the U.S. Minnesota has the second largest population (after California) of Hmong individuals. The objective of this study was to examine cancer incidence in this population, because it may indicate areas for targeted surveillance and intervention. METHODS: The Minnesota Cancer Surveillance System database was screened for Hmong surnames, and proportional incidence ratios (PIRs) were calculated for the period 1988-1999. RESULTS: Compared with all Minnesotans, the Hmong population had increased PIRs for nasopharyngeal cancer (PIR, 39.39; 95% confidence interval [95% CI], 21.01-66.86), gastric cancer (PIR, 8.70; 95% CI, 5.39-13.25), hepatic cancer (PIR, 8.08; 95% CI, 3.88-14.71), and cervical cancer (PIR, 3.72; 95% CI, 2.04-6.20) and had decreased PIRs for prostate cancer, breast cancer, Hodgkin disease, and melanoma. CONCLUSIONS: The current observations have implications for cancer control interventions. In particular, an increased incidence of cervical cancer might be addressed in part by targeting culturally sensitive screening programs in the Hmong population.

Genetic polymorphisms in the Hmong population: implications for cancer etiology and survival.

BACKGROUND: The Hmong, an isolated, agrarian people from southern China, migrated to the mountainous regions of what are today Vietnam, Cambodia, and Laos. Minnesota has the second largest Hmong population in the United States. The authors compared frequencies of common genetic polymorphisms believed to influence risk of malignancy to determine whether frequencies in the Hmong are different from those in other Asian populations and in white Minnesotans. METHODS: Genotyping for glutathione S-transferase micro1 (GSTM1), glutathione S-transferase theta1 (GSTT1), myeloperoxidase (MPO) (C(-)463T), nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase (NQO1) (C609T), 5,10-methylenetetrahydrofolate reductase (MTHFR) (C677T), MTHFR (A1298C), methionine synthase reductase (MTRR) (A66G), X-ray repair cross complementing 1 (XRCC1) 194 (Arg194Trp), XRCC1 280 (Arg280His), and XRCC1 399 (Arg399Gln) alleles was performed by TaqMan analysis using DNA isolated from newborn heel-stick spots provided by the Minnesota Department of Health. RESULTS: The Hmong had significantly higher frequencies of the NQO1 T allele and the XRCC1 Trp polymorphism (Arg194Trp) and had significantly lower frequencies of the G allele in MTRR (A66G) and the T allele in MTHFR (C677T) compared with white Minnesotans. The Hmong also were significantly more likely to lack the GSTM1 and GSTT1 genes compared with whites (82% vs. 54% and 61% vs. 18%, respectively). Genotype frequencies were similar for MTHFR (A1298C), MPO (C(-)463T), and XRCC1 (Arg280His, Arg399Gln). Genotype frequencies at these loci also were compared with those reported for other Asian populations and showed notable differences between the Hmong and Chinese/Taiwanese, Korean, and Japanese populations. CONCLUSIONS: The genetic differences identified have implications for both cancer etiology and prognosis in this unique population.

Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia.

The glutathione S-transferase (GST) genes are involved in the metabolism of environmental carcinogens and of some classes of chemotherapy drugs. GSTM1 and GSTT1 genotypes are polymorphic in humans, and the phenotypic absence of enzyme activity is caused by a homozygous inherited deletion of the gene. Previous, smaller studies of childhood acute lymphoblastic leukemia (ALL) provided contrasting data on the role of the GST genotype in susceptibility and treatment outcomes. We analyzed GST genotypes in 710 children with ALL treated by the Children's Cancer Group. Frequencies were compared with those of normal controls, and outcomes were analyzed according to genotype. Comparisons of gene frequencies in ALL case and control patients showed similar frequencies (54% vs 53% GSTM1 null in whites, P =.9; 40% versus 32% in blacks, P =.45; 16% versus 15% GSTT1 null in whites, P =.8; 17% versus 28% in blacks, P =.3). ALL was not associated with the GSTM1-null genotype or the double-null genotype in blacks or whites, in contrast to previous reports. Stratification of cases by age at diagnosis, sex, white blood cell count at diagnosis, B or T lineage, or cytogenetics revealed no differences in genotype frequencies. Analysis of treatment outcomes showed no differences in outcome according to GST genotype; in particular, there were no differences in frequencies of relapse at any site. These data, representing a larger series than any reported previously, suggest that GST genotype does not affect etiology or outcome of childhood ALL.

XRCC1 and glutathione-S-transferase gene polymorphisms and susceptibility to radiotherapy-related malignancies in survivors of Hodgkin disease.

BACKGROUND: One of the most serious late effects of treatment for childhood cancer is the occurrence of subsequent malignancy. Survivors of Hodgkin disease (HD), in particular, have been shown to be at high risk of subsequent malignancy, the occurrence of which has been associated strongly with exposure to radiotherapy. METHODS: In the current study, the authors investigated the association between polymorphisms in 3 genes--glutathione-S-transferase M1 (GSTM1), glutathione-S-transferase T1 (GSTT1), and XRCC1, with roles in protection from a variety of DNA-damaging agents-and the risk of subsequent malignancy in 650 survivors of HD enrolled in the Childhood Cancer Survivor Study who had received radiotherapy. RESULTS: Individuals lacking GSTM1 but not GSTT1 were at increased risk of any subsequent malignancy (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.0-2.3), and for subsequent cancer within the radiation field (OR, 1.4; 95% CI, 0.9-2.1). A nonsignificant increased risk of thyroid carcinoma was observed in individuals lacking either GSTM1 (OR, 2.9; 95% CI, 0.8-10.9) or GSTT1 (OR, 3.7; 95% CI, 0.6-23.5). Individuals having the genotype of the arginine/glutamine polymorphism at codon 399 in the XRCC1 gene (R399) showed a nonsignificant increased risk of breast carcinoma compared with those without (OR, 1.4; 95% CI, 0.7-2.7), and a nonsignificant decreased risk against a subsequent thyroid carcinoma (OR, 0.6; 95% CI, 0.2-1.6). No differences in genotype frequencies were observed between survivors with basal cell carcinoma when compared with survivors without a subsequent cancer. CONCLUSIONS: These data illustrated the potential value of incorporating the collection of genomic DNA in longitudinal cohort studies of populations with well defined, potentially carcinogenic exposures. Evaluation of additional genetic polymorphisms in this cohort may help define genes that influence individual sensitivity to radiotherapy.