Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23.

Haplotype analysis and targeted next-generation resequencing allowed us to identify a mutation in the KIF23 gene and to show its association with an autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III). The region at 15q23 where CDA III was mapped in a large Swedish family was targeted by array-based sequence capture in a female diagnosed with CDA III and her healthy sister. Prioritization of all detected sequence changes revealed 10 variants unique for the CDA III patient. Among those variants, a novel mutation c.2747C>G (p.P916R) was found in KIF23, which encodes mitotic kinesin-like protein 1 (MKLP1). This variant segregates with CDA III in the Swedish and American families but was not found in 356 control individuals. RNA expression of the 2 known splice isoforms of KIF23 as well as a novel one lacking the exons 17 and 18 was detected in a broad range of human tissues. RNA interference-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23/MKLP1, a conserved mitotic kinesin crucial for cytokinesis.

Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics.

Recent genome-wide studies conducted in European Whites have identified novel susceptibility genes for childhood acute lymphoblastic leukemia (ALL). We sought to examine whether these loci are susceptibility genes among Hispanics, whose reported incidence of childhood ALL is the highest of all ethnic groups in California, and whether their effects differ between Hispanics and non-Hispanic Whites (NHWs). We genotyped 13 variants in these genes among 706 Hispanic (300 cases, 406 controls) and 594 NHW (225 cases, 369 controls) participants in a matched population-based case-control study in California. We found significant associations for the five studied ARID5B variants in both Hispanics (p values of 1.0 × 10(-9) to 0.004) and NHWs (p values of 2.2 × 10(-6) to 0.018). Risk estimates were in the same direction in both groups (ORs of 1.53-1.99 and 1.37-1.84, respectively) and strengthened when restricted to B-cell precursor high-hyperdiploid ALL (>50 chromosomes; ORs of 2.21-3.22 and 1.67-2.71, respectively). Similar results were observed for the single CEBPE variant. Hispanics and NHWs exhibited different susceptibility loci at CDKN2A. Although IKZF1 loci showed significant susceptibility effects among NHWs (p < 1 × 10(-5)), their effects among Hispanics were in the same direction but nonsignificant, despite similar minor allele frequencies. Future studies should examine whether the observed effects vary by environmental, immunological, or lifestyle factors.

Haplotypes of DNA repair and cell cycle control genes, X-ray exposure, and risk of childhood acute lymphoblastic leukemia.

BACKGROUND: Acute leukemias of childhood are a heterogeneous group of malignancies characterized by cytogenetic abnormalities, such as translocations and changes in ploidy. These abnormalities may be influenced by altered DNA repair and cell cycle control processes. METHODS: We examined the association between childhood acute lymphoblastic leukemia (ALL) and 32 genes in DNA repair and cell cycle pathways using a haplotype-based approach, among 377 childhood ALL cases and 448 controls enrolled during 1995-2002. RESULTS: We found that haplotypes in APEX1, BRCA2, ERCC2, and RAD51 were significantly associated with total ALL, while haplotypes in NBN and XRCC4, and CDKN2A were associated with structural and numerical change subtypes, respectively. In addition, we observed statistically significant interaction between exposure to 3 or more diagnostic X-rays and haplotypes of XRCC4 on risk of structural abnormality-positive childhood ALL. CONCLUSIONS: These results support a role of altered DNA repair and cell cycle processes in the risk of childhood ALL, and show that this genetic susceptibility can differ by cytogenetic subtype and may be modified by exposure to ionizing radiation. To our knowledge, our study is the first to broadly examine the DNA repair and cell cycle pathways using a haplotype approach in conjunction with X-ray exposures in childhood ALL risk. If confirmed, future studies are needed to identify specific functional SNPs in the regions of interest identified in this analysis.

Household exposure to paint and petroleum solvents, chromosomal translocations, and the risk of childhood leukemia.

BACKGROUND: Few studies have examined the association between home use of solvents and paint and the risk of childhood leukemia. OBJECTIVES: In this case-control study, we examined whether the use of paint and petroleum solvents at home before birth and in early childhood influenced the risk of leukemia in children. METHODS: We based our analyses on 550 cases of acute lymphoblastic leukemia (ALL), 100 cases of acute myeloid leukemia (AML), and one or two controls per case individually matched for sex, age, Hispanic status, and race. We conducted further analyses by cytogenetic subtype. We used conditional logistic regression techniques to adjust for income. RESULTS: ALL risk was significantly associated with paint exposure [odds ratio (OR) = 1.65; 95% confidence interval (CI), 1.26-2.15], with a higher risk observed when paint was used postnatally, by a person other than the mother, or frequently. The association was restricted to leukemia with translocations between chromosomes 12 and 21 (OR = 4.16; 95% CI, 1.66-10.4). We found no significant association between solvent use and ALL risk overall (OR = 1.15; 95% CI, 0.87-1.51) or for various cytogenetic subtypes, but we observed a significant association in the 2.0- to 5.9-year age group (OR = 1.55; 95% CI, 1.07-2.25). In contrast, a significant increased risk for AML was associated with solvent (OR = 2.54; 95% CI, 1.19-5.42) but not with paint exposure (OR = 0.64; 95% CI, 0.32-1.25). CONCLUSIONS: The association of ALL risk with paint exposure was strong, consistent with a causal relationship, but further studies are needed to confirm the association of ALL and AML risk with solvent exposure.

Potential Role of Community-Based Healthcare System Data in Research on Survivors of Adolescent and Young Adult Cancer.

PURPOSE: We sought to examine issues of generalizability in research on adolescent and young adult (AYA) cancer survivorship that relies on using community-based healthcare delivery system data. METHODS: Individuals aged 15 to 39 diagnosed with cancer between 1992 and 2006 were identified using data from community-based healthcare systems in California and Seattle. Loss to follow-up was defined as the first disenrollment (the end) of membership in the healthcare systems after cancer. Censoring occurred at death or study end (2009). We used Kaplan-Meier analysis to quantify follow-up, and multiple Cox regression to examine the association of follow-up loss with demographic and cancer characteristics. RESULTS: Of 6828 eligible AYAs, most (93%) were aged between 20 and 39 years at diagnosis; 62% were female and 39% were non-White. Solid tumors accounted for 81% of diagnoses. The majority (89%) of patients continued to be members of the healthcare systems and available for follow-up 1 year after diagnosis. Approximately 60% remained enrolled 5 years after diagnosis. Loss to follow-up was associated with younger age at diagnosis, male gender, and African American or Hispanic race/ethnicity. CONCLUSION: Data from community-based healthcare delivery systems offer an efficient way to identify large and diverse samples of AYA-onset cancer survivors. Differential loss to follow-up can threaten the generalizability of results from these studies and should be assessed quantitatively. Healthcare system data offer an alternative to studies requiring direct contact with participants.

Blood levels of folate at birth and risk of childhood leukemia.

BACKGROUND: A role for folate in cancer etiology has long been suspected because of folate's function as a cofactor in DNA methylation and maintenance of DNA synthesis. Previous case-control studies examining the association between risk of childhood acute lymphoblastic leukemia (ALL) and mothers' self-reported folate intake and supplementation have been inconclusive. MATERIALS AND METHODS: We used a quantitative microbiologic assay to measure newborn folate concentrations in archived dried bloodspots collected at birth from 313 incident ALL cases, 44 incident acute myeloid leukemia (AML) cases, and 405 matched population-based controls. RESULTS: Overall, we found no difference in hemoglobin-normalized newborn folate concentrations (HbFol, nmol/g) between ALL cases and controls (2.76 vs. 2.77, P = 0.97) or between AML cases and controls (2.93 vs. 2.76, P = 0.32). Null results persisted after stratification by both birth period (1982-94, 1995-98, and 1999-2002) to account for the start of folate fortification of grain products in the United States, and by self-reported maternal prepregnancy supplement use. Similarly, no association was observed for major ALL subgroups. CONCLUSIONS: Our results do not support an association between birth folate concentrations and risk of childhood AML or major ALL subgroups. IMPACT: However, they do not rule out a role for folate through exposures after birth or in early stages of fetal development.

Food consumption by children and the risk of childhood acute leukemia.

The possible relation between child's early diet and risk of childhood leukemia has remained largely unexplored. The authors' objective was to determine what particular foods consumed early in life (first 2 years) are associated with risk of childhood leukemia in a 1995-2002 case-control study of a diverse California population. Dietary data were obtained from a questionnaire administered to the child's caregiver. Conditional logistic regression was used to analyze 328 case-control sets matched on age, sex, Hispanic status, and maternal race. Regular consumption of oranges/bananas (odds ratio = 0.49, 95% confidence interval: 0.26, 0.94) and orange juice (odds ratio = 0.54, 95% confidence interval: 0.31, 0.94) during the first 2 years of life was associated with a reduction in risk of childhood leukemia diagnosed between the ages of 2 and 14 years. Restricting the analysis to leukemia diagnosed between the ages of 2 and 5 years reflected a similar pattern of reduced risk. No association between eating hot dogs/lunch meats and risk of leukemia was found. These results suggest that fruits or fruit juices that contain vitamin C and/or potassium may reduce the risk of childhood leukemia, especially if they are consumed on a regular basis during the first 2 years of life.

Maternal dietary risk factors in childhood acute lymphoblastic leukemia (United States).

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and the second most common cause of mortality in children aged 1-14 years. Recent research has established that the disease can originate in utero, and thus maternal diet may be an important risk factor for ALL. METHODS: The Northern California Childhood Leukemia Study is a population-based case-control study of risk factors for childhood leukemia, including maternal diet. Cases (n = 138) and controls (n = 138) were matched on sex, date of birth, mother's race, Hispanicity, and county of residence at birth. Maternal dietary intake in the 12 months prior to pregnancy was obtained by a 76-item food frequency questionnaire. RESULTS: Consumption of the vegetables (OR = 0.53; 95% CI, 0.33-0.85; p = 0.008), protein sources (OR = 0.40; 95% CI, 0.18-0.90, p = 0.03), and fruits (OR = 0.71; 95% CI, 0.49-1.04; p = 0.08) food groups were inversely associated with ALL. Among nutrients, consumption of provitamin A carotenoids (OR = 0.65, 95% CI, 0.42-1.01; p = 0.05), and the antioxidant glutathione (OR = 0.42; 95% CI, 0.16-1.10; p = 0.08) were inversely associated with ALL. CONCLUSION: Maternal dietary factors, specifically the consumption of vegetables, fruits, protein sources and related nutrients, may play a role in the etiology of ALL. Dietary carotenoids and glutathione appear to be important contributors to this effect.