Catherine Metayer

Second Cancers Among Long-Term Survivors of Hodgkin’s Disease Diagnosed in Childhood and Adolescence

PURPOSE To quantify the risk of second cancers among long-term survivors of Hodgkins disease (HD) diagnosed before 21 years of age and to explore sex-, age-, and site-related differences. PATIENTS AND METHODS We analyzed data from 5,925 pediatric HD patients, including 2,646 10-year and 755 20-year survivors, who were reported to 16 population-based cancer registries in North America and Europe between 1935 and 1994. RESULTS A total of 157 solid tumors (observed/expected ratio [O/E] = 7.0; 95% confidence interval [CI], 5.9 to 8.2.) and 26 acute leukemias (O/E = 27.4; 95% CI, 17.9 to 40. 2) were reported. Risk of solid tumors remained significantly increased among 20-year survivors (O/E = 6.6, observed [O] = 40, cumulative risk = 6.5%) and persisted for 25 years (O/E = 4.6, O = 15, cumulative risk = 11.7%). Temporal trends for cancers of thyroid, female breast, bone/connective tissue, stomach, and esophagus were consistent with the late effects of radiotherapy. Greater than 50-fold increased risks were observed for tumors of the thyroid and respiratory tract (one lung and one pleura) among children treated before age 10. At older ages (10 to 16 years), the largest number of second cancers occurred in the digestive tract (O/E = 19.3) and breast (O/E = 22.9). Risk of solid tumors increased with decreasing age at HD on a relative but not absolute scale. CONCLUSION Children and adolescents treated for HD experience significantly increased risks of second cancers at various sites for 2 to 3 decades. Although our results reflect the late effects of past therapeutic modalities, they underscore the importance of lifelong follow-up of pediatric HD patients given early, more aggressive treatments.

Cooking oil fumes and risk of lung cancer in women in rural Gansu, China.

Cooking oil fumes have been suggested to increase the risk of lung cancer in Chinese women by exposing them to mutagenic substances. We investigated the association between lung cancer and locally made rapeseed and linseed oils in a population-based case-control study in Gansu Province, China. Two hundred and thirty-three incident, female lung cancer cases diagnosed from 1994-98 were identified. A control group of 459 women was selected from census lists and were frequency matched on age and prefecture. Interviewers obtained information on cooking practices and cooking oil use. The odds ratio (OR) for lung cancer associated with ever-use of rapeseed oil, alone or in combination with linseed oil, was 1.67 (95% CI 1.0-2.5), compared to use of linseed oil alone. ORs for stir-frying with either linseed or rapeseed oil 15-29, 30 and > or =31 times per month were 1.96,1.73, and 2.24, respectively (trend, P=0.03), relative to a lower frequency of stir-frying. Lung cancer risks also increased with total number of years cooking (trend, P<0.09). Women exposed to cooking fumes from rapeseed oil appeared to be at increased risk of lung cancer, and there was some evidence that fumes from linseed oil may have also contributed to the risk.

Residential exposure to polychlorinated biphenyls and organochlorine pesticides and risk of childhood leukemia.

Background Incidence of childhood leukemia in industrialized countries rose significantly during 1975–2004, and the reasons for the increase are not understood. Objectives We used carpet dust as an exposure indicator to examine the risk of childhood leukemia in relation to residential exposure to persistent organochlorine chemicals: six polychlorinated biphenyl (PCB) congeners and the pesticides α- and γ-chlordane, p,p′-DDT (dichlorodiphenyltrichloroethane), p,p′-DDE (dichlorodiphenyldichloroethylene), methoxychlor, and pentachlorophenol. Methods We conducted a population-based case–control study in 35 counties in northern and central California in 2001–2006. The study included 184 acute lymphocytic leukemia (ALL) cases 0–7 years of age and 212 birth certificate controls matched to cases by birth date, sex, race, and Hispanic ethnicity. We collected carpet dust samples from the room where the child spent the most time before diagnosis (similar date for controls) using a specialized vacuum. Results Detection of any PCB congener in the dust conferred a 2-fold increased risk of ALL [odds ratio (OR) = 1.97; 95% confidence interval (CI), 1.22–3.17]. Compared with those in the lowest quartile of total PCBs, the highest quartile was associated with about a 3-fold risk (OR = 2.78; 95% CI, 1.41–5.48), and the positive trend was significant (p = 0.017). Significant positive trends in ALL risk were apparent with increasing concentrations of PCB congeners 118, 138, and 153. We observed no significant positive associations for chlordane, DDT, DDE, methoxychlor, or pentachlorophenol. The associations with PCBs were stronger among non-Hispanic whites than among Hispanics despite similar distributions of PCB levels among controls in each racial/ethnic group. Conclusions Our findings suggest that PCBs, which are considered probable human carcinogens and cause perturbations of the immune system, may represent a previously unrecognized risk factor for childhood leukemia.

Diagnostic X-rays and risk of childhood leukaemia

BACKGROUND The association between diagnostic X-ray exposures early in life and increased risk of childhood leukaemia remains unclear. METHODS This case-control study included children aged 0-14 years diagnosed with acute lymphoid leukaemia (ALL, n = 711) or acute myeloid leukaemia (AML, n = 116) from 1995 to 2008. Controls were randomly selected from the California birth registry and individually matched to cases with respect to date of birth, sex, Hispanic ethnicity and maternal race. Conditional logistic regression analyses were performed to assess whether ALL or AML was associated with self-reported childs X-rays after birth (post-natal), including number of X-rays, region of the body X-rayed and age at first X-ray, as well as maternal X-rays before and during pregnancy (preconception and prenatal). RESULTS After excluding X-rays in the year prior to diagnosis (reference date for matched controls), risk of ALL was elevated in children exposed to three or more post-natal X-rays [odds ratio (OR) = 1.85, 95% confidence interval (CI) 1.12-2.79]. For B-cell ALL specifically, any exposure (one or more X-rays) conferred increased risk (OR = 1.40, 95% CI 1.06-1.86). Region of the body exposed was not an independent risk factor in multivariable analyses. No associations were observed between number of post-natal X-rays and AML (OR = 1.05, 95% CI 0.90-1.22) or T-cell ALL (OR = 0.84, 95% CI 0.59-1.19). Prevalence of exposure to prenatal and preconception X-rays was low, and no associations with ALL or AML were observed. CONCLUSIONS The results suggest that exposure to post-natal diagnostic X-rays is associated with increased risk of childhood ALL, specifically B-cell ALL, but not AML or T-cell ALL. Given the imprecise measures of self-reported X-ray exposure, the results of this analysis should be interpreted with caution and warrant further investigation.

MDR1 gene variants, indoor insecticide exposure, and the risk of childhood acute lymphoblastic leukemia

Objective: The multidrug resistance (MDR) 1 gene encodes a membrane transporter called P-glycoprotein, which plays an important role in protecting cells against lipophilic xenobiotics by way of an ATP-dependent cellular efflux mechanism. Among children enrolled in the Northern California Childhood Leukemia Study, we examined the susceptibility conferred by MDR1 single nucleotide polymorphisms (SNP) and predicted haplotypes and whether they modify the association between indoor insecticide exposure and risk of childhood acute lymphoblastic leukemia (ALL). Methods: Buccal cell DNA from ALL cases (n = 294) and controls (n = 369) individually matched on gender, date of birth, Hispanic status, and maternal race were whole genome amplified and genotyped for four MDR1 SNPs, T−129C (rs3213619), C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642). Detailed and time-specific information on household pesticide use was obtained using in-home interviews with the mother. Results: Allele frequencies in non-Hispanic White and Hispanic controls were similar, and with the exception of T−129C, seemed to be in strong linkage disequilibrium. Overall, the SNPs considered individually or within haplotypes (C1236T-G2677T/A-C3435T) were not significantly associated with childhood ALL. However, we observed strong evidence of a differential effect of indoor insecticide exposure (interaction odds ratio, 0.31; 95% confidence interval, 0.15-0.64; P = 0.025) on risk of ALL between carriers and noncarriers of haplotype CGC. Conclusion: These preliminary data suggest that children carrying the haplotype CGC may be less susceptible to the leukemogenic effects of indoor insecticide exposures. Future studies are needed to confirm these findings. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1172–7)

Determinants of Agricultural Pesticide Concentrations in Carpet Dust

Background: Residential proximity to agricultural pesticide applications has been used as a surrogate for exposure in epidemiologic studies, although little is known about the relationship with levels of pesticides in homes. Objective: We identified determinants of concentrations of agricultural pesticides in dust. Methods: We collected samples of carpet dust and mapped crops within 1,250 m of 89 residences in California. We measured concentrations of seven pesticides used extensively in agriculture (carbaryl, chlorpyrifos, chlorthal-dimethyl, diazinon, iprodione, phosmet, and simazine). We estimated use of agricultural pesticides near residences from a statewide database alone and by linking the database with crop maps. We calculated the density of pesticide use within 500 and 1,250 m of residences for 180, 365, and 730 days before collection of dust and evaluated relationships between agricultural pesticide use estimates and pesticide concentrations in carpet dust. Results: For five of the seven pesticides evaluated, residences with use of agricultural pesticides within 1,250 m during the previous 365 days had significantly higher concentrations of pesticides than did residences with no nearby use. The highest correlation with concentrations of pesticides was generally for use reported within 1,250 m of the residence and 730 days before sample collection. Regression models that also accounted for occupational and home use of pesticides explained only a modest amount of the variability in pesticide concentrations (4–28%). Conclusions: Agricultural pesticide use near residences was a significant determinant of concentrations of pesticides in carpet dust for five of seven pesticides evaluated.

Cytogenetics of Hispanic and White Children with Acute Lymphoblastic Leukemia in California

Epidemiologic studies of childhood leukemia have made limited use of tumor genetic characteristics, which may be related to disease etiology. We characterized the cytogenetics of 543 childhood leukemia patients (0-14 years of age) enrolled in the Northern California Childhood Leukemia Study, an approximately population-based study comprised primarily of Hispanics (42%) and non-Hispanic Whites (41%), and compared the cytogenetic profiles between these two ethnic groups. Subjects were classified by immunophenotype, conventional cytogenetic characteristics, and fluorescence in situ hybridization findings. The ploidy levels most frequently observed among acute lymphoblastic leukemia patients were high hyperdiploidy (51-67 chromosomes) and pseudodiploidy (34% and 27%, respectively). No ethnic differences in the frequency of 11q23/MLL rearrangements were observed between Hispanics and non-Hispanic Whites. Among B-lineage acute lymphoblastic leukemia patients, the percentage of TEL-AML1 translocations was significantly lower in Hispanics (13%) than in non-Hispanic Whites (24%; P = 0.01). This is the first time that this ethnic variation has been observed in a large number of patients in a defined geographic region, which is consistent with findings from smaller international studies. The mechanistic basis for this 2-fold variation in frequency of TEL-AML1 may be due to ethnic-specific risk factors or genetics and should be explored further. (Cancer Epidemiol Biomarkers Prev 2006;(15)3:578–81)

Lung cancer and indoor exposure to coal and biomass in rural China.

Incomplete combustion of coal in homes has been linked with lung cancer in China. We report on a lung cancer case-control study in a rural area of China, where many residents live in underground dwellings and burn coal and unprocessed biomass (crop residues, wood, sticks, and twigs) for heating and cooking. We interviewed 846 patients with lung cancer (626 men, 220 women; aged 30 to 75 years) diagnosed between 1994 and 1998, and 1740 population-based controls. The odds ratio for lung cancer associated with coal use compared with that for biomass in the house of longest residence was 1.29 (95% confidence interval, 1.03 to 1.61), adjusted for smoking and socioeconomic status. The risk for lung cancer increased relative to the percentage of time that coal was used over the past 30 years (P = 0.02). Our findings suggest that coal may contribute to the risk of lung cancer in this rural area of China.

Ethnic Difference in Daycare Attendance, Early Infections, and Risk of Childhood Acute Lymphoblastic Leukemia

A role for infectious agents has been proposed in the etiology of childhood acute lymphoblastic leukemia (ALL), particularly for common ALL (c-ALL; ALL diagnosed in children ages 2-5 years and expressing CD10 and CD19 surface antigens). We evaluated the possible etiologic role of daycare attendance (a proxy measure for exposure to infectious agents) and infections during infancy in the Northern California Childhood Leukemia Study. A total of 294 incident ALL cases (ages 1-14 years) and 376 individually matched controls were included in this analysis. In non-Hispanic White children, daycare attendance measured by child-hours was associated with a significantly reduced risk of ALL. Compared with children who did not attend any daycare, the odds ratio (OR) for those who had >5,000 child-hours during infancy was 0.42 [95% confidence interval (95% CI), 0.18-0.99] for ALL and 0.33 (95% CI, 0.11-1.01) for c-ALL. Test for trend is also significant, which supports a dose-response relationship. The magnitude of effect associated with the same number of child-hours was stronger for daycare attendance during infancy than for daycare attendance before diagnosis. In addition, self-reported ear infection during infancy was associated with a significantly reduced risk of c-ALL (OR, 0.32; 95% CI, 0.14-0.74) in non-Hispanic White children. In Hispanic children, no association was observed among daycare attendance, early infections, and risk of childhood ALL or c-ALL. These results offer indirect yet strong support for the infectious disease hypothesis in the etiology of ALL in non-Hispanic White children and highlight an important ethnic difference.

The Childhood Leukemia International Consortium

BACKGROUND Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case-control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene-environment interactions. OBJECTIVES The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene-environment interactions and subtype-specific associations through the pooling of data from independent studies. METHODS By September 2012, CLIC included 22 studies (recruitment period: 1962-present) from 12 countries, totaling approximately 31000 cases and 50000 controls. Of these, 19 case-control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child-parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. CONCLUSIONS CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene-environment interactions and associations among specific leukemia subtypes in different ethnic groups.