Logan G. Spector

Maternal diet and infant leukemia: the DNA topoisomerase II inhibitor hypothesis: a report from the children's oncology group.

Background: The MLL 11q23 translocation arises in utero and is present in 75% of infant leukemias. That MLL+ acute myeloid leukemia (AML) can arise following chemotherapy with DNA topoisomerase II (DNAt2) inhibitors suggests that these substances, which also occur naturally in foods, may contribute toward infant leukemia. We hypothesized that maternal consumption of dietary DNAt2 inhibitors during pregnancy would increase the risk of infant leukemia, particularly AML(MLL+). Methods: This Childrens Oncology Group case-control study consisted of 240 incident cases of infant acute leukemia [AML and acute lymphoblastic leukemia (ALL)] diagnosed during 1996 to 2002 and 255 random digit dialed controls. Maternal diet during pregnancy was determined through a food frequency questionnaire. An index of specific foods identified a priori to contain DNAt2 inhibitors as well as vegetables and fruits were created and analyzed using unconditional logistic regression. Results: There was little evidence of an association between the specific DNAt2 index and leukemia overall and by subtype. An exception was AML(MLL+); odds ratios (95% confidence intervals) comparing the second to fourth quartiles to the first were 1.9 (0.5-7.0), 2.1 (0.6-7.7), and 3.2 (0.9-11.9), respectively (P for trend = 0.10). For the vegetable and fruit index, there were significant or near-significant inverse linear trends for all leukemias combined, ALL(MLL+), and AML(MLL−). Conclusion: Overall, maternal consumption of fresh vegetables and fruits during pregnancy was associated with a decreased risk of infant leukemia, particularly MLL+. However, for AML(MLL+) cases, maternal consumption of specific DNAt2 inhibitors seemed to increase risk. Although based on small numbers, these data provide some support for distinct etiologic pathways in infant leukemia.

The Epidemiology of Sarcoma

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.

Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32

To identify susceptibility loci for non-Hodgkin lymphoma subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma at 6p21.32 (rs10484561, combined P = 1.12 × 10−29 and rs7755224, combined P = 2.00 × 10−19; r2 = 1.0), supporting the idea that major histocompatibility complex genetic variation influences follicular lymphoma susceptibility. We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 × 10−9).

Genome-wide association study identifies two susceptibility loci for osteosarcoma

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.

Parental age and risk of childhood cancer: a pooled analysis.

Background: Few risk factors for childhood cancer are well-established. We investigated whether advancing parental age increases childhood cancer risk. Methods: We assessed the relationship between parental age and childhood cancer in a case-control study using pooled population-based data. Our pooling was based on linked cancer and birth registry records from New York, Washington, Minnesota, Texas, and California. Subjects included 17,672 cancer cases diagnosed at ages 0–14 years during 1980–2004 and 57,966 controls born during 1970–2004. Individuals with Down syndrome were excluded. Odds ratios and 95% confidence intervals were calculated by logistic regression for the association between parental age and childhood cancer after adjustment for sex, birth weight, gestational age, birth order, plurality, maternal race, birth year, and state. Results: Positive linear trends per 5-year maternal age increase were observed for childhood cancers overall (odds ratio = 1.08 [95% confidence interval = 1.06–1.10]) and 7 of the 10 most frequent diagnostic groups: leukemia (1.08 [1.05–1.11]), lymphoma (1.06 [1.01–1.12]), central nervous system tumors (1.07 [1.03–1.10]), neuroblastoma (1.09 [1.04–1.15]), Wilms’ tumor (1.16 [1.09–1.22]), bone tumors (1.10 [1.00–1.20]), and soft tissue sarcomas (1.10 [1.04–1.17]). No maternal age effect was noted for retinoblastoma, germ cell tumors, or hepatoblastoma. Paternal age was not independently associated with most childhood cancers after adjustment for maternal age. Conclusions: Our results suggest that older maternal age increases risk for most common childhood cancers. Investigation into possible mechanisms for this association is warranted.

Epidemiology of leukemia in children with Down syndrome

Studies suggest nearly a 20‐fold increased risk of leukemia in individuals with Down syndrome. Most of this increased risk appears in the first few decades of life, with the highest incidence in children less than 5 years of age. It is unknown why children with Down syndrome are at such an increased risk of leukemia. With respect to environmental exposures, it will be important to investigate risk factors associated with childhood leukemia in general (including diagnostic x‐rays, pesticides, and other occupational exposures) as well as experiences common to children with Down syndrome (including routine medical screening tests, increased susceptibility to infections, and increased vitamin deficiencies).

The epidemiology of hepatoblastoma

Few causes of hepatoblastoma have been conclusively identified, mainly due to the extreme rarity of the disease. Inherited conditions including Familial Adenomatous Polyposis and Beckwith–Wiedemann Syndrome dramatically raise risk of hepatoblastoma but account for few cases overall. A small number of case–control studies investigating risk factors for sporadic hepatoblastoma have been conducted to date. Although most of these studies feature fewer than 200 cases, several clues have emerged. Most notably there is a roughly 20‐fold increased risk of hepatoblastoma among children with very low birth weight (<1,500 g) and a doubling of risk among those with moderately low birth weight (1,500–2,500 g). A modicum of evidence points to a possible role of parental tobacco use prior to or during pregnancy in the causation of hepatoblastoma as well. Pediatr Blood Cancer 2012; 59: 776–779.

Genome-wide association study identifies a novel susceptibility locus at 6p21.3 among familial CLL.

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.

Cancer risk among children with very low birth weights.

OBJECTIVE: The risk of hepatoblastoma is strongly increased among children with very low birth weight (<1500 g). Because data on very low birth weight and other childhood cancers are sparse, we examined the risk of malignancy with very low birth weight in a large data set. METHODS: We combined case-control data sets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which included 17672 children diagnosed as having cancer at 0 to 14 years of age and 57966 randomly selected control subjects. Unconditional logistic regression analysis was used to examine the association of cancer with very low birth weight and moderately low birth weight (1500–1999 g and 2000–2499 g, respectively), compared with moderate/high birth weight (≥2500 g), with adjustment for gender, gestational age, birth order, plurality, maternal age, maternal race, state, and year of birth. RESULTS: Most childhood cancers were not associated with low birth weights. However, retinoblastomas and gliomas other than astrocytomas and ependymomas were possibly associated with very low birth weight. The risk of other gliomas was also increased among children weighing 1500 to 1999 g at birth. CONCLUSIONS: These data suggested no association between most cancers and very low birth weight, with the exception of the known association of hepatoblastoma and possibly moderately increased risks of other gliomas and retinoblastoma, which may warrant confirmation.

The Epidemiology of Childhood Leukemia with a Focus on Birth Weight and Diet

Leukemia is the most common childhood cancer and a major source of morbidity and mortality. The etiology of childhood leukemia remains largely unknown. Cytogenetic abnormalities determine disease subtypes, prognosis, clinical presentation, and course and may help in discovering etiological factors. Epidemiologic investigations of leukemia are complicated by many factors, including the rarity of the disease, necessitating careful study design. Two emerging areas of interest in leukemia etiology are birth weight and diet. High birth weight has been associated with increased risk of childhood leukemia. The biological mechanism behind this association may involve insulin-like growth factor I (IGF-I), which is associated with high birth weight. IGF-I may act by increasing the absolute number of stem cells available for transformation, stimulating the growth of cells that are already transformed, or a combination of effects. Diet has been linked with leukemia. Maternal dietary DNA topoisomerase II (DNAt2) inhibitor intake is associated with infant acute myeloid leukemia (AML) with the MLL gene translocation. Increased intake of fruits and vegetables has been associated with decreased leukemia risk and, relatedly, lack of maternal folate supplementation has been associated with increased childhood leukemia risk, possibly by causing DNA hypomethylation and increased DNA strand breaks. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms modify this risk.