Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Osteosarcoma (OS) is the most common form of bone cancer in children and displays a peak incidence that coincides with the pubertal growth spurt. Consequently a number of studies have investigated whether cases are taller at diagnosis than the general pediatric population; a recent analysis which pooled seven such studies found that cases were disproportionately in the 51st-89th and especially the >90th percentiles of height-for-age (HFA). However, no study to our knowledge has examined whether OS patients exhibit greater HFA at earlier ages. During 2008-2010 we enrolled 290 OS cases <20 years of age diagnosed at Children's Oncology Group institutions in the United States and Canada in a genetic epidemiologic study. In addition to collecting buccal cell samples for genetic analysis we requested permission to obtain length/height data from medical records from birth to diagnosis. Records were obtained for 153 male and 111 female participants. Anthropometrics and date of measurement were doubly entered into a custom database, and inconsistencies were resolved by a third abstraction. Between 1 and 46 measurements (median = 11) were recorded up to the earlier of diagnosis or 12 years of age. Mixed effects cubic spline models were applied to length/height to produce individual growth curves using Stata. Sex was included as a main effect and as interactions with the model slope terms to account for gender differences in growth. Individual estimates of length/height at every three months of age between birth and age two years, and at each year of age thereafter, were computed and transformed to Z-scores according to the CDC 2000 reference. OS cases of both sexes were consistently longer or taller than reference data at all ages, as at no age did the 95% confidence interval around mean Z-score include 0 (i.e. the population mean and median). Under 2 years of age length was examined; mean Z-score at birth was 0.56 (71st %ile), rose to 0.72 (76th %ile) at 0.5 years, and fell to 0.31 (62nd %ile) at 2 years. Over 2 years of age height was examined; mean Z-score was 0.48 (68th %ile) at 4 years, dipped to 0.33 (63rd %ile) at 8-9 years, and rose to 0.49 (69th %ile) at 12 years. No differences in mean Z-score at each age were observed by age at diagnosis (sex specific inter-quartile range of age at diagnosis vs. other), location of tumor (long bone of the lower limb vs. other), or race (White non-Hispanic vs. other). Our data clearly indicate that pediatric OS patients are substantially longer/taller than the United States national norm at all ages before puberty. Citation Format: Logan G. Spector, Kathryn Ritter, Ellen W. Demerath, Charles Sklar, Julie A. Ross, Mark Krailo, Rajaram Nagarajan, David Malkin, Tracy L. Bergemann, Sharon A. Savage, William Johnson. Pediatric osteosarcoma patients are taller than average from birth to age twelve: a report from the Children's Oncology Group. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2532. doi:10.1158/1538-7445.AM2013-2532

Investigators worldwide have for over 40 years conducted case-control studies aimed at determining the causes of childhood cancer. The central challenge to conducting such research is the rarity of childhood cancer, thus many studies aggregate cases through clinical trials organizations such as COG. Rarity also precludes the use of prospective study designs, which are less prone to recall and selection biases. Despite these challenges a substantial literature on childhood cancer etiology has emerged but few strong environmental risk factors have been identified. Genetic studies are thus now coming to the fore with some success. The ultimate aim of epidemiologic studies is to reduce the population burden of childhood cancer by suggesting preventive measures or possibly by enabling early detection. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 × 10(-9)) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 × 10(-8) and 2.9 × 10(-7), respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma.

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case–control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth—weight-for-gestational-age and proportion of optimal birth weight (POBW)—were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one-standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin-like growth factors. © 2013 UICC

BACKGROUND: While a possible link between assisted reproductive technology (ART) and rare imprinting disorders has been found, it is not clear if this is indicative of subtler disruptions of epigenetic mechanisms. Results from previous studies have been mixed, but some methylation differences have been observed.\n\nMETHODS: Children conceived through ART and children conceived spontaneously were recruited for this cross-sectional study. Information about reproductive history, demographic factors, birth characteristics, and infertility treatment was obtained from maternal interview and medical records. Peripheral blood lymphocytes and buccal cell samples were collected from participating children. Methylation analysis was performed on five loci using pyrosequencing. Statistical analysis of methylation differences was performed using linear regression with generalized estimating equations. Results are reported as differences with 95% confidence intervals (CI).\n\nRESULTS: A total of 67 ART children and 31 spontaneously conceived (SC) children participated. No significant difference in methylation in lymphocyte samples was observed between groups for any loci. Possible differences were found in buccal cell samples for IGF2 DMR0 (Difference: 2.07; 95% confidence interval (CI): -0.28, 4.42; p = 0.08) and IGF2R (Difference: -2.79; 95% CI: -5.74, 0.16; p = 0.06). Subgroup analysis indicated potential lower methylation in those whose parents used ART for unexplained infertility.\n\nCONCLUSIONS: Observed differences in methylation between the ART and SC groups were small for all loci in the two sample types examined and no statistical differences were observed. It is still unclear whether or not small differences observed in several studies represent a real difference between groups and if this difference is biologically meaningful. Larger studies with long term follow-up are needed to fully answer these questions.

Sarcomas account for over 20% of all pediatric solid malignant cancers and less than 1% of all adult solid malignant cancers. The vast majority of diagnosed sarcomas will be soft tissue sarcomas, while malignant bone tumors make up just over 10% of sarcomas. The risks for sarcoma are not well-understood. We evaluated the existing literature on the epidemiology and etiology of sarcoma. Risks for sarcoma development can be divided into environmental exposures, genetic susceptibility, and an interaction between the two. HIV-positive individuals are at an increased risk for Kaposi's sarcoma, even though HHV8 is the causative virus. Radiation exposure from radiotherapy has been strongly associated with secondary sarcoma development in certain cancer patients. In fact, the risk of malignant bone tumors increases as the cumulative dose of radiation to the bone increases (p for trend <0.001). A recent meta-analysis reported that children with a history of hernias have a greater risk of developing Ewing's sarcoma (adjusted OR 3.2, 95% CI 1.9, 5.7). Bone development during pubertal growth spurts has been associated with osteosarcoma development. Occupational factors such as job type, industry, and exposures to chemicals such as herbicides and chlorophenols have been suggested as risk factors for sarcomas. A case-control study found a significant increase in soft tissue sarcoma risk among gardeners (adjusted OR 4.1, 95% CI 1.00, 14.00), but not among those strictly involved in farming. A European-based study reported an increased risk in bone tumors among blacksmiths, toolmakers, or machine-tool operators (adjusted OR 2.14, 95% CI 1.08, 4.26). Maternal and paternal characteristics such as occupation, age, smoking status, and health conditions experienced during pregnancy also have been suggested as sarcoma risk factors and would be important to assess in future studies. The limited studies we identified demonstrate significant relationships with sarcoma risk, but many of these results now require further validation on larger populations. Furthermore, little is known about the biologic mechanisms behind each epidemiologic association assessed in the literature. Future molecular epidemiology studies may increase our understanding of the genetic versus environmental contributions to tumorigenesis in this often deadly cancer in children and adults.

Osteosarcoma (OS) is a rare malignant bone tumor with an overall incidence rate of 4.6 cases per million children aged 0-19 years in the United States. While the etiology of OS is largely unknown, its distinctive age-incidence pattern suggests that growth and development is crucial in genesis. Prior studies have suggested that variants in genes in the estrogen metabolism (ESTR) and insulin-like growth factor/growth hormone (IGF/GH) pathways are associated with OS. We examined 798 single nucleotide polymorphisms (SNPs) in 42 genes from these pathways in a case-parent study (229 complete triads and 56 dyads) using buccal cell samples. Relative risks (RR) and 95% confidence intervals (CI) associated with transmitting one or two copies of the variant were estimated using log-linear models. After Bonferroni correction, 1 SNP within the ESTR pathway (rs1415270: RR = 0.50 and 8.37 for 1 and 2 vs. 0 copies, respectively; p = 0.010), and two SNPs in the IGF/GH pathway (rs1003737: RR = 0.91 and 0.0001 for 1 and 2 vs. 0 copies, respectively; p <0.0001 and rs2575352: RR = 2.62 and 0.22 for 1 and 2 vs. 0 copies; p < 0.0001) were significantly associated with OS incidence. These results confirm previous findings that variation in the estrogen metabolism and bone growth pathways influence OS risk and further support a biologically and epidemiologically plausible role in OS development.

Previous epidemiologic studies have shown an inverse association between a personal history of atopy/allergies, both overall and among asthma, eczema, and hay fever investigated separately, and childhood acute lymphoblastic leukemia (ALL) with some consistency; however, in most of these studies, exposure data were collected by maternal interview. Now, in a population-based and records-based study in this issue of the Journal (Am J Epidemiol. 2012;176(11):970978), Chang et al. report an increased risk for allergic conditions across different etiologic time periods, calling the former paradigm into doubt. A review of the basic biology literature shows that proposed mechanisms support either a positive or an inverse association. In light of this ambiguity, it is epidemiologys turn to determine the direction of association.

Osteosarcoma (OS) is the most common primary bone malignancy affecting children and young adolescents. Downregulation of microRNAs at 14q32 locus is implicated in the pathogenesis of OS. However, array comparative genome hybridization did not show any DNA copy number loss at this locus. We hypothesized that epigenetic alterations may regulate genes and microRNAs present in this locus and contribute to the development and progression of OS. Here, we show that OS is characterized by a selective loss of imprinting (LOI) at 14q32 locus. LOI at the 14q32 locus was unique to OS, compared with 10 other cancer cell lines representing 6 tissue types. Furthermore, the average demethylation at 14q32 locus was 24%, but the global demethylation as determined by LINE-1 retrotransposons was only 7%. We also found LOI in H19, MEST, and PEG3 loci in OS samples, albeit less frequently. LOI at the 14q32 locus is highly prevalent (82.6%, 19 out of 23) only in OS patients with early-onset (12-30 years of age) of the disease. Imprinted genes at 14q32 locus were downregulated in OS due to histone modifications and the locus was controlled by bivalent domain enriched with both K4-3m and K27-3m. We determined the tumor suppressor function of this locus by overexpression of 3 imprinting genes, DLK1, RTL1 or DIO3 in SaoS2 cells. We found that all 3 genes inhibited cell proliferation and enhanced apoptosis. We also tested methylation patterns using matched buccal DNA samples obtained from OS patients and their parents. Interestingly, loss of imprinting at 14q32 locus was found in most of the OS patients and their parents, suggesting that children might be predisposed to developing OS by inheriting the instability of imprinting at this genomic site. To determine if loss of imprinting at 14q32 locus is the driving mechanism, or a secondary genetic event, we evaluated tumor tissues obtained from p53LSLR270H/;Osx-Cre mice OS models. These mice developed OS at 8-12 months (potentially representing the late-onset (> 30yrs) of human OS). LOI was found only in 33% of mice OS samples, which is in agreement with the low rate of LOI detected in late-onset human OS. In conclusion, our findings suggest that LOI at the 14q32 genomic locus is likely a contributing event in the pathogenesis of OS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4042. doi:1538-7445.AM2012-4042

PURPOSE: To test intensive alkylator-based therapy in desmoplastic small round-cell tumor (DSRCT). PATIENTS AND METHODS: Patients received the P6 protocol, which has seven courses of chemotherapy. Courses 1, 2, 3, and 6 included cyclophosphamide 4,200 mg/m2, doxorubicin 75 mg/m2, and vincristine (HD-CAV). Courses 4, 5, and 7 consisted of ifosfamide 9 g/m2 and etoposide 500 mg/m2 for previously untreated patients, or ifosfamide 12 g/m2 and etoposide 1,000 mg/m2 for previously treated patients. Courses started after neutrophil counts reached 500/microL and platelet counts reached 100,000/microL. Tumor resection was attempted. Post-P6 treatment options included radiotherapy and a myeloablative regimen of thiotepa (900 mg/m2) plus carboplatin (1,500 mg/m2), with stem-cell rescue. RESULTS: Ten previously untreated and two previously treated patients have completed therapy. The male-to-female ratio was 11:1. Ages were 7 to 22 years (median, 14). The largest masses were infradiaphragmatic (n = 11) or intrathoracic (n = 1). Other findings included serosal implants (n = 11), regional lymph node invasion (n = 8), ascites or pleural effusion (n = 7), and metastases to liver (n = 5), lungs (n = 4), distant lymph nodes (n = 3), spleen (n = 2), and skeleton (n = 2). Tumors uniformly responded to HD-CAV, but there were no complete pathologic responses. One patient died at 1 month from tumor-related Budd-Chiari syndrome. Of seven patients who achieved a complete remission (CR), five remain in CR 9, 12, 13, 33, and 38 months from the start of P6, one patient died of infection at 12 months (autopsy-confirmed CR), and one patient relapsed 4 months off therapy. Of four patients who achieved a partial remission (PR), one remains progression-free at 34 months and three developed progressive disease. Five patients received local radiotherapy: three were not assessable for response, but in two patients, antitumor effect was evident. Four patients received thiotepa/carboplatin: two were in CR and remain so, and two patients had measurable disease that did not respond. CONCLUSION: For control of DSRCT, our experience supports intensive use of HD-CAV, aggressive surgery to resect visible disease, radiotherapy to high-risk sites, and myeloablative chemotherapy with stem-cell rescue in selected cases.

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Osteosarcoma (OS) is a rare malignant bone tumor with an overall incidence rate of 4.6 cases per million children aged 0-19 years in the United States. OS incidence peaks sharply in adolescence coinciding with the pubertal growth spurt. While the etiology of OS is largely unknown, its distinctive age-incidence pattern suggests that growth and development is crucial in the genesis of OS. Prior studies have suggested that variants in genes in the insulin-like growth factor 1 (IGF1)/growth hormone (GH) axis pathway are associated with OS. We assessed this hypothesis by examining 307 single nucleotide polymorphisms (SNPs) in 12 genes from this pathway (GHRH, GH1, GHR, GHRHR, IGF1, IGF1R, IGF2, IGF2R, IGFBP1, IGFBP3, IGFBP6, AND IGFALS) in a case-parent-triad study of cases and their biological parents. The sample included 229 complete triads and 56 dyads diagnosed during 2008-2011 at Children's Oncology Group institutions. Buccal cell samples were collected via the Oragene kit (DNA Genotek, Ottawa, Ontario) and returned by mail; genotyping was conducted by Sequenom iPLEX Gold method. We used log-linear models to estimate relative risks (RR) and 95% confidence intervals (CI) associated with transmitting one or two copies of the variant compared to no copies. After Bonferroni correction, 2 SNPs in IGFBP1 (rs10231774: RR = 1.44 and 0.07 for 1 and 2 vs. 0 copies, respectively; p < 0.001) and IGFALS (rs2575352: RR = 2.82 and 0.22 for 1 and 2 vs. 0 copies, respectively; p < 0.001), both in the upstream coding regions of IGF pathway genes, were significantly associated with OS incidence. These results confirm previous findings that variation in the IGF1/GH axis influence OS risk and further support the axis’ biologically and epidemiologically plausible role in OS development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-333. doi:1538-7445.AM2012-LB-333

Objective: To examine the relationship between maternal physical activity during the first half of pregnancy and infant birth size. Methods: Selfreported physical activity data collected between 2008 and 2010 and newborn anthropometrics from offspring birth records were obtained from 308 mothers in Minneapolis, Minnesota. Physical activity was categorized into light, moderate, or vigorous intensity based on metabolic equivalent (MET) score. Continuous MET-hours per week were calculated overall and by activity category. Z-scores standardized for gestational age and sex were calculated for birthweight, length, and head circumference using national birth data charts. We used linear regression to estimate associations between maternal physical activity and standardized newborn birth size, adjusting for potential confounders. Results: Total, light, and moderate physical activity were not associated with any of the birth outcomes. However, vigorous physical activity was positively associated with birthweight, length, and head circumference (all P < 0.05), but not ponderal index (P = 0.8). An increase of three MET-hours per week of vigorous activity was estimated to result in a ~50 gram increase in birthweight, a ~1/3 centimeter increase in length, and a ~1/6 centimeter increase in head circumference. Conclusion: Women who engaged in greater amounts of vigorous physical activity during the first half of pregnancy tended to give birth to larger infants. Future studies are warranted to confirm these results and explore potential biological mechanisms of enhanced fetal growth associated with vigorous physical activity.

IntroductionThe acute leukemias of childhood are a heterogeneous group of diseases. In this review of the descriptive and analytic epidemiology of these malignancies, specific subgroups are emphasized, as defined by morphology, cytogenetic features, or molecular markers. There is evidence that specific leukemic subgroups may have distinct etiologies, and that molecular abnormalities associated with particular subgroups may be linked with specific causal mechanisms. Moreover, the mutations produced at the successive stages of leukemogenesis, from initiation through induction to promotion, may all involve separate etiologic processes.It is also important to note that changes over time in diagnostic practice and precision may account in part for some reported epidemiologic trends. Moreover, changes in terminology and classification schemes for leukemia make it difficult to make direct comparisons between studies, particularly if risk factors differ for different subgroups. However, in assessing risk factors, studies of the childhood leukemias present several methodologic advantages. The interval between exposure to putative risk factors and onset of leukemia may be shorter, recall of exposures is likely to be better, and intervening factors may be fewer than those associated with adult leukemias. These characteristics of childhood leukemia may facilitate identification of the most likely risk factors for the various leukemic subgroups. Furthermore, they lend themselves to an approach that includes both population studies and molecular epidemiologic techniques, permitting the design of research to assess genetic–environmental causal interactions. As studies of potential environmental causes of childhood leukemia have now accumulated to a degree that allows data synthesis, and in order to succinctly summarize the literature, recent meta-analyses rather than individual studies are cited preferentially below.

BACKGROUND: A recent study suggested a markedly increased risk of hepatoblastoma (HB) among children conceived with treatment for infertility. However, it is not clear whether this finding is confounded by the association between HB and low birthweight (LBW).\n\nMETHODS: Associations between parental infertility and its treatment and HB were examined using data from a case-control study conducted through the Children's Oncology Group (COG). Telephone interviews were completed for 383 mothers of cases diagnosed with HB at US COG institutions between January 2000 and December 2008 and for 387 mothers of controls recruited through state birth registries. Logistic regression was used to examine possible associations.\n\nRESULTS: After adjusting for birthweight and other potential confounders, no significant association was found for any of the measures of parental infertility or its treatment. In HB cases conceived through assisted reproductive technology (ART), 4 of 16 also had Beckwith-Wiedemann syndrome (BWS) compared with 9 of 365 in HB cases without ART.\n\nCONCLUSIONS: Little evidence of an association between parental infertility or its treatment and HB was found. The relationship found in a previous study could be due to LBW and BWS which are risk factors for HB and also associated with parental infertility and its treatment.

Background: Studies of family history of cancer and non-malignant diseases in childhood acute lymphoblastic leukemia (ALL) show inconsistent findings. Most studies show no increased risk with family history of cancer. Non-malignant diseases such as allergic diseases, autoimmune diseases, birth defects and thyroid diseases have been reported to be associated with ALL. Methods: We conducted a case-control study of family history of cancer and selected non-malignant conditions (allergic diseases, autoimmune diseases, birth defects, and thyroid diseases). ALL cases were obtained from Children's Cancer Group institutions from January 1989 to June 1993. Controls were recruited via random digit dialing. Family history for first degree relatives and grandparents of ALL cases and controls was collected by structured telephone questionnaires. Conditional logistical regression was used to calculate odds ratios adjusting for potential confounders. Results: We found a borderline association of ALL and having a family member with a history of cancer in cases (n= 1842) compared to controls (n= 1986) (OR = 0.98, 95%CI = 0.93, 1.00) and an inverse association for esophageal cancer based on small numbers. Family history of food and drug allergies demonstrated a modestly reduced risk (OR = 0.83, 95%CI = 0.73, 0.95) as did family history of rheumatoid arthritis (OR = 0.79, 95%CI = 0.65, 0.96). There were no associations with family history of any autoimmune diseases, immunodeficiencies, birth defects, thyroid diseases and risk of childhood ALL. Conclusions: These results show no association of overall family history of cancer with childhood ALL, while providing additional evidence for an inverse association with family history of allergic disease. Two potentially new associations of ALL with family history of esophageal cancer and rheumatoid arthritis require confirmation in other studies and validation with medical records. © 2011.

BACKGROUND: High birth weight increases the risk of childhood acute lymphoid leukemia (ALL) through unknown mechanisms. Whether this risk is specific to ALL subtypes is unknown, and low case numbers have prevented investigation of the rarer leukemias. Here we address these associations using a large population-based dataset. PROCEDURE: Using the National Registry of Childhood Tumors, birth weights of 7,826 leukemia cases, defined by immunophenotype and cytogenetic subgroup, were compared with those of 10,785 controls born in England and Wales between 1980 and 2007. RESULTS: The risk for overall leukemia increases 7% with each 0.5 kg increase in birth weight (OR 1.07, 95%CI 1.04-1.10). This risk is limited to the lymphoid leukemias (OR 1.08, 95%CI 1.05-1.12) diagnosed between 1 and 9 years of age. Analysis by cytogenetic feature reveals that there appears to be association with specific chromosomal abnormality: the risk of tumors with high hyperdiploid karyotypes increases 12% per 0.5 kg increase in birth weight (OR 1.12, 95%CI 1.05-1.20), and t(1;19) tumors show an increased risk of 41% per 0.5 kg increase (OR 1.41, 95%CI 1.09-1.84). The risk of acute myeloid leukemia is elevated in high and low birth weight babies. There is no significant risk relationship to other leukemias or myeloproliferative diseases. CONCLUSIONS: Birth weight is a risk factor for ALL and AML. Other subtypes of the disease are not significantly affected. There appears to be association with specific chromosomal abnormality, which may aid our understanding of the development of childhood leukemia in utero.

BACKGROUND: Infant leukaemia is likely initiated in utero.\n\nMETHODS: We examined whether analgesic use during pregnancy was associated with risk by completing telephone interviews of the mothers of 441 infant leukaemia cases and 323 frequency-matched controls, using unconditional logistic regression.\n\nRESULTS: With the exception of a reduced risk for infant acute myeloid leukaemias with non-aspirin non-steroidal anti-inflammatory drugs (NSAID) use early in pregnancy (odds ratios=0.60; confidence intervals: 0.37-0.97), no statistically significant associations were observed for aspirin, non-aspirin NSAIDs, or acetaminophen use in early pregnancy or after knowledge of pregnancy.\n\nCONCLUSION: Overall, analgesic use during pregnancy was not significantly associated with the risk of infant leukaemia.

Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10(-8)), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10(-9)). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.

BACKGROUND: There is increasing interest in the possible association between cancer incidence and vitamin D through its role as a regulator of cell growth and differentiation. Epidemiological studies in adults and one paediatric study suggest an inverse association between sunlight exposure and cancer incidence.$\$n$\$nMETHODS: We carried out an ecological study using childhood cancer registry data and two population-level surrogates of sunlight exposure, (1) latitude of the registry city or population centroid of the registry nation and (2) annual solar radiation. All models were adjusted for nation-level socioeconomic status using socioeconomic indicators.$\$n$\$nRESULTS: Latitude and radiation were significantly associated with cancer incidence, and the direction of association was consistent between the surrogates. Findings were not consistent across tumour types.$\$n$\$nCONCLUSION: Our ecological study offers some evidence to support an association between sunlight exposure and risk of childhood cancer.

Several case-control studies have evaluated associations between maternal smoking, alcohol consumption and illicit drug use during pregnancy and risk of childhood leukaemia. Few studies have specifically focused on infants (<1 year) with leukaemia, a group that is biologically and clinically distinct from older children. We present data from a Children's Oncology Group case-control study of 443 infants diagnosed with acute leukaemia [including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML)] between 1996 and 2006 and 324 population controls. Mothers were queried about their cigarette, alcohol and illicit drug use 1 year before and throughout pregnancy. Odds ratios (ORs) and 95% confidence intervals [CI] were calculated using adjusted unconditional logistic regression models. Maternal smoking (>1 cigarette/day) and illicit drug use (any amount) before and/or during pregnancy were not significantly associated with infant leukaemia. Alcohol use (>1 drink/week) during pregnancy was inversely associated with infant leukaemia overall [OR = 0.64; 95% CI 0.43, 0.94], AML [OR = 0.49; 95% CI 0.28, 0.87], and leukaemia with mixed lineage leukaemia gene rearrangements ('MLL+') [OR = 0.59; 95% CI 0.36, 0.97]. While our results agree with the fairly consistent evidence that maternal cigarette smoking is not associated with childhood leukaemia, the data regarding alcohol and illicit drug use are not consistent with prior reports and are difficult to interpret. It is possible that unhealthy maternal behaviours during pregnancy, some of which carry potential legal consequences, may not be adequately measured using only self-report. Future case-control studies of childhood leukaemia that pursue these exposures may benefit from incorporation of validated instruments and/or biomarkers when feasible.