Michaela Richardson

Obesity over the life course and risk of acute myeloid leukemia and myelodysplastic syndromes

BACKGROUND Overweight and obesity are known risk factors for a number of cancers, with recent evidence suggesting that risk of hematologic cancer is also increased in obese individuals. We evaluated associations between body mass index (BMI) at differing time points during the life course in population-based case control studies of acute myeloid leukemia (AML) and myelodysplatic syndromes (MDS). METHODS Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State drivers license/identification card list. BMI was calculated using self-reported height and weight at ages 18, 35, and 50 years and two years prior to interview, and categorized as normal (18.5-25 kg/m(2)), overweight (25-29.9 kg/m(2)), obese class I (30-34.9 kg/m(2)), and obese class II/III (35+ kg/m(2)). All analyses were stratified by sex. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS We included 420 AML cases, 265 MDS cases and 1388 controls. Obesity two years prior to diagnosis was associated with AML in both males and females (OR=2.22, 95% CI 1.28, 3.85 and OR=1.85, 95% CI 1.08, 3.15 for BMI≥35 vs. BMI 18.5-24.9, respectively). In contrast, associations between obesity and MDS were observed only in females. Weight change in adulthood was not consistently associated with either outcome. CONCLUSION Our results extend the emerging literature suggesting that obesity is a risk factor for hematologic malignancy and provide evidence that that the association remains regardless of timing of obesity. Obesity in adulthood is a modifiable risk factor for both MDS and AML.

Chemical exposures and risk of acute myeloid leukemia and myelodysplastic syndromes in a population-based study

Benzene exposure is one of the few well‐established risk factors for myeloid malignancy. Exposure to other chemicals has been inconsistently associated with hematologic malignancies. We evaluated occupational and residential chemical exposures as risk factors for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) using population‐based data. AML and MDS cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota drivers license/identification card list. Chemical exposures were measured by self‐report. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI). We included 265 MDS cases, 420 AML cases and 1388 controls. We observed significant associations between both MDS and AML and benzene (OR = 1.77, 95% CI 1.19, 2.63 and OR = 2.10, 95% CI 1.35, 3.28, respectively) and vinyl chlorides (OR = 2.05, 95% CI 1.15, 3.63 and OR = 2.81, 95% CI 1.14, 6.92). Exposure to soot, creosote, inks, dyes and tanning solutions and coal dust were associated with AML (range ORs = 2.68–4.03), while no association was seen between these exposures and MDS (range ORs = 0.57–1.68). Pesticides and agricultural chemicals were not significantly associated with AML or MDS. Similar results were observed in analyses stratified by sex. In addition to providing risk estimates for benzene from a population‐based sample, we also identified a number of other occupational and residential chemicals that were significantly associated with AML; however, all exposures were reported by only a small percentage of cases (≤10%). While chemical exposures play a clear role in the etiology of myeloid malignancy, these exposures do not account for the majority of cases.

Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children's Oncology Group study

Family history of lymphoid neoplasm (LN) is a strong and consistently observed Hodgkin lymphoma (HL) risk factor, although it has been only marginally examined in pediatric/adolescent patients. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL cases diagnosed at 0–14 years at Childrens Oncology Group institutions in 1989–2003. Detailed histories were captured by structured telephone interviews with parents of 517 cases and 783 controls. Epstein–Barr virus (EBV) RNA detection was performed for 355 available case tumors. Two analytic strategies were applied to estimate associations between family cancer history and pediatric/adolescent HL. In a standard case–control approach, multivariate conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). In a reconstructed cohort approach, each relative was included as a separate observation, and multivariate proportional hazards regression was used to produce hazard ratios (HRs) and 95% CIs. Using the latter, pediatric/adolescent HL was associated with a positive family history (HR = 1.20, 95% CI: 1.06–1.36), particularly early‐onset cancers (HR = 1.30, 95% CI: 1.06–1.59) and those in the paternal lineage (HR = 1.38, 95% CI: 1.16–1.65), with a suggested association for LN in first‐degree relatives (HR = 3.61, 95% CI: 0.87–15.01). There were no discernable patterns for EBV+ versus EBV– HL. The clustering of LN within pedigrees may signal shared genetic susceptibility or common environmental exposures. Heritable genetic risk variants have only recently begun to be discovered, however. These results are consistent with other studies and provide a compelling rationale for family‐based studies to garner information about genetic susceptibility to HL.

Maternal and paternal occupational exposures and hepatoblastoma: results from the HOPE study through the Children’s Oncology Group

Little is known about the etiology of hepatoblastoma. We aimed to confirm the results of a previous study evaluating the association between parental occupational exposures and hepatoblastoma. In our case–control study, we identified cases (n=383) from the Children’s Oncology Group and controls from birth certificates (n=387), which were frequency matched to cases on year and region of birth, sex, and birth weight. Occupational exposure in the year before and during the index pregnancy was collected through maternal interview and analyzed using unconditional logistic regression. The odds of both paternal and maternal “Likely” exposure to paints was elevated among cases compared with controls (paternal odds ratio (OR): 1.71, 95% confidence interval (CI): 1.04, 2.81; maternal OR: 3.29, 95% CI: 0.32, 33.78) after adjustment for matching factors and the confounding factors of maternal race (maternal only) and household income. In addition, paternal exposure to other chemicals was also elevated when adjusting for matching factors only (OR: 1.53, 95% CI: 1.02, 2.30). The results of our study provide further evidence of an association between parental occupation and hepatoblastoma. These results warrant further investigation of the etiologically relevant timing of occupational exposure to fumes and chemicals related to hepatoblastoma.

Abstract A25: Prevalence of Klinefelter syndrome among males aged 0-19 years diagnosed with germ cell tumors: A report from the Children’s Oncology Group

Previous studies have suggested that males with Klinefelter syndrome (KS; 47, XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. Due to the rarity of pediatric GCTs, there are no reports characterizing the prevalence of KS among males diagnosed with GCTs. We used data from a Children’s Oncology Group epidemiology study (2008-2015) to evaluate the prevalence of KS in males (n=433) diagnosed with GCTs (aged 0-19 years). These 433 cases provided saliva samples and had one parent who was willing to participate in the study and complete a questionnaire including questions about health history, demographics, and environmental exposures. Tumor characteristics (location and histology) were abstracted from pathology reports provided by the treating institution. GCT cases were classified as having KS if they had evidence of an extra copy of the X chromosome based on evaluation of array data from Illumina HumanCoreExome-12 genotyping chips. Genvisis was used to identify samples with sex aneuploidy and to determine the parent-of-origin for the nondisjunction. Using chi-square tests, we examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and a number of birth characteristics between KS-GCT cases and GCT cases without chromosomal abnormalities (n=415). Using publically available data, we estimated the 1-year risk and corresponding Risk Ratio (RR) and 95% Confidence Interval (95% CI) of a male with KS developing a GCT. Based on analysis of array genotyping data, 3% (n=13) of male GCT cases had KS. Among these 13 cases, the extra X chromosome was of maternal origin in 7 cases and of paternal origin in 6 cases. Of the 13 KS cases with genotyping data, 5/9 (56%) KS-GCT cases with parental questionnaire data reported receiving a diagnosis of KS. The average age at GCT diagnosis for cases with genotyping-detected KS (n=13) was 13.8 years (standard deviation [SD], 4.4 years) compared with 12.5 years (SD, 6.2 years) for GCT cases without chromosomal abnormalities (n=415; p=0.45). We did not observe significant differences in patient or birth characteristics including race, birth weight and length, maternal age, paternal age, and the use of fertility drugs between the two groups. We confirmed that KS-GCT cases were significantly more likely to be diagnosed with extragonadal tumors (GCT [n=69/411; 17%]; KS-GCT [n=11/13; 85%]; p In our large case series of males diagnosed with GCTs, we observed that 3% of GCT cases (n=13/433) were also carriers of an extra X chromosome based on array genotyping data and were thus classified as having KS. Males aged 0-19 years with KS experience a large increase in risk of developing a GCT compared with males from the general population. Collectively, these findings suggest that young males with KS should be monitored for the development of a GCT. Similarly, the possibility of KS should be considered in males diagnosed with a mediastinal GCT during childhood or adolescence and these patients should be tested for the presence of KS. Citation Format: Lindsay A. Williams, Nathan Pankratz, John Lane, Michelle Roesler, Michaela Richardson, A. Lindsay Frazier, James Amatruda, Jenny N. Poynter. Prevalence of Klinefelter syndrome among males aged 0-19 years diagnosed with germ cell tumors: A report from the Children’s Oncology Group [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A25.

Cesarean Delivery and Risk of Infant Leukemia: A Report from the Children's Oncology Group

Background: Studies have reported increased risks of pediatric acute lymphoblastic leukemia (ALL) among children born by cesarean delivery (CD). However, no previous study has examined the impact of CD on risk of infant leukemia specifically. Methods: In this study, 443 infants diagnosed with acute leukemia, including both ALL and acute myelogenous leukemia (AML), were identified at Childrens Oncology Group institutions between January 1996 and December 2006; 324 controls frequency matched by year of birth were identified though random digit dialing and random selection from U.S. birth registries. Using interview data and, for a subset of participants, medical record data, we analyzed CD overall and by indications that likely resulted in pre-labor CD (PLCD) or emergency CD (ECD). Odds ratios (ORs) and 95% confidence intervals (CIs) for risk of ALL and AML were estimated using multivariable unconditional logistic regression models, adjusted for year of birth, birth weight, and maternal race. Results: We observed an increased point estimate for the association between CD and ALL (OR, 1.52 and 95% CI, 1.02–2.25). We did not observe an association between CD and AML (OR, 1.02 and 95% CI, 0.64–1.62). In analyses of indication for CD, we observed elevated effect estimates for the associations of both PLCD and ECD and infant ALL. Conclusions: Our analysis suggests an increased risk of infant ALL following CD, including both PLCD and ECD. Altered microbiota colonization may be involved in development of leukemia in infants, but clear biological mechanisms have yet to be determined. Impact: This study provides the first in-depth examination of CD and infant leukemia. Cancer Epidemiol Biomarkers Prev; 27(4); 473–8. ©2018 AACR.

The association between sex and most childhood cancers is not mediated by birthweight

BACKGROUND Male sex is associated with an increased risk of childhood cancer as is high birthweight. Given that sex determination precedes birthweight we conducted a mediation analysis to estimate the direct effect of sex in association with childhood cancer tumor type with birthweight as the mediator. METHODS Cases (n = 12,632) and controls (n = 64,439) (ages 0-14 years) were identified from population-based cancer and birth registries in Minnesota, New York, and Washington states (1970-2014). An inverse odds weighting (IOW) mediation analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) as the measure of association between sex and cancer. RESULTS A significant indirect effect was observed for sex and lymphoid leukemia, mediated by birthweight (indirectOR: 1.03; 95% CI: 1.02-1.04). We observed significant direct effects for male sex and lymphoid leukemia (directOR: 1.16; 95% CI: 1.08-1.25), Hodgkin lymphoma (directOR: 1.48; 95% CI: 1.22-1.81), Burkitt lymphoma (directOR: 5.02; 95% CI: 3.40-7.42), other non-Hodgkin lymphoma (directOR: 1.42; 95% CI: 1.18-1.70), intracranial embryonal tumors (directOR: 1.49; 95% CI: 1.26-1.76), hepatoblastoma (directOR: 1.90; 95% CI: 1.40-2.59), and rhabdomyosarcoma (directOR: 1.47; 95% CI: 1.19-1.81). There were also inverse associations for extracranial GCTs (directOR: 0.41; 95% CI: 0.26-0.63) and thyroid carcinoma (directOR: 0.35; 95% CI: 0.25-0.50). CONCLUSION Significant direct effects for sex and numerous childhood cancer types suggests sex-specific factors such as differences in gene expression from the autosomes or the X chromosome, rather than birthweight, may underlie sex differences in tumor risk.

Klinefelter syndrome in males with germ cell tumors: A report from the children’s oncology group: A report from the children\x92s oncology group

Males with Klinefelter syndrome (KS) (47,XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. To date, there are no reports characterizing the prevalence of KS among male GCT cases.

Family history of cancer in children and adolescents with germ cell tumours: a report from the Children’s Oncology Group

Background:Studies of family history of cancer in paediatric germ cell tumours (GCTs) are few, and none has had sufficient sample size to specifically evaluate family history of GCT.Methods:We utilised family history data from a paediatric GCT study to calculate standardised incidence ratios (SIR) for GCT and other cancers using age- and sex-specific incidence rates from the SEER Program.Results:This analysis included 7998 relatives of paediatric GCT probands. We observed a higher number of GCT cases than expected in male and female relatives of probands (SIR=2.38, 95% CI 1.25, 3.51 for males; SIR=14.3, 95% CI 0.29, 28.4 for females). Further, we observed a particularly strong SIR for relatives of probands with intracranial GCT (SIR=8.07, 95% CI 3.51, 12.6). The SIR for relatives of probands with ovarian GCT was also elevated but did not reach statistical significance (SIR 4.35, 95% CI 0-9.27). Other notable associations include elevated SIRs for melanoma in male relatives and reduced SIRs for lymphatic/haematologic malignancies in male and female relatives.Conclusions:These results support the hypothesis that familial aggregation of GCT occurs in males and females.

Association between mitochondrial DNA haplogroup and myelodysplastic syndromes

Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State drivers license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non‐Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS‐R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H + V), JT (J + T), IWX (I + W + X), UK (U + K), and Z for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population‐based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes.