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Risk Factors for Childhood Cancer: An Update

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health. Risk Factors for Childhood Cancer: An Update. National Cancer Institute. Martha Linet, M.D., MPH Division of Cancer Epidemiology & Genetics National Cancer Institute September 19, 2011. Outline.

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Risk Factors for Childhood Cancer: An Update

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  1. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Risk Factors for Childhood Cancer: An Update National Cancer Institute Martha Linet, M.D., MPH Division of Cancer Epidemiology & Genetics National Cancer Institute September 19, 2011

  2. Outline • Characteristics and descriptive features • Known and suspected causes • Recent findings (most studies report on risk factors for childhood leukemia) IV.How can I4C contribute to understanding and validating recent findings?

  3. Characteristics and Descriptive Features

  4. International Classification ofChildhood Cancer – 3rd Revision • Leukemia II. Lymphomas and reticuloendothelial neoplasms III. CNS and other intracranial and intraspinal neoplasms IV.Neuroblastoma and other peripheral nervous system V. Retinoblastoma VI. Renal tumors VII. Hepatic tumors VIII. Malignant bone tumors IX. Soft tissue & other extra-osseous sarcomas X. Germ cell, trophoblastic, & other gonadal neoplasms XI. Carcinomas and other malignant epithelial neoplasms XII. Other and unspecified malignant neoplasms

  5. Childhood Cancer Statistics • Total childhood cancer <15 yrs estimated 2007 -10,400 incident -1,545 deaths -5-yr survival: currently 80%

  6. Pediatric Cancer Types Vary in Age, Gender, and Race Patterns CharacteristicSubgroup↑ Risk by Cancer Types -Age infancy neuroblastoma, CNS, leukemia, retinoblastoma adolescence Hodgkin lymphoma, germ cell cancers, CNS, leukemia - Gender male lymphoma - Race Caucasian Ewing’s sarcoma, acute lymphoblastic leukemia African-American Wilms’ tumor, retinoblastoma African endemic Burkitt’s lymphoma

  7. Trends in Total U.S. Childhood Cancer Incidence Children ≤ 20 Years Old, 1975-2004 • Incidence rose for total • childhood cancer • 1975-1991: 1.1% per year • 1992-2008: 0.4% per year • Mortality rates for total • childhood cancer • 1975-1996: - 2.7% per year • 1996-2007: - 1.2% per year

  8. Etiology by Major Category (A. Knudson)

  9. Known Risk Factors

  10. Known Risk Factors for Childhood Leukemia • High-dose single exposure to ionizing radiation (atomic bomb survivors) • Pre-natal diagnostic x-ray exposures • Chemotherapy (alkylating agents, epipodophyllotoxins) • Genetic & constitutional disorders (e.g., Down syndrome, Bloom syndrome, ataxia telangiectasia, neurofibromatosis type I)

  11. Known Risk Factors for Childhood Brain Tumors • High-dose single exposure to ionizing radiation (atomic bomb survivors) • Fractionated radiotherapy • Genetic & constitutional disorders (e.g., neurofibromatosis, nevoid basal cell carcinoma syndrome, tuberous sclerosis, familial Li-Fraumeni syndrome)

  12. Known Risk Factors for Other Pediatric Cancers Pediatric cancer Risk Factor(s) Epstein Barr Virus HIV, immunodeficiency syndromes, organ transplant Mutation in RB gene Low birth weight Beckwith-Wiedemann syndrome & idiopathic hemihypertrophy • Burkitt’s lymphoma • Non-Hodgkin lymphoma • Retinoblastoma (hereditary) • Hepatoblastoma • Wilms’ tumor

  13. Recent Findings

  14. Birth weight and Childhood ALL • Moderate association of fetal growth (proportion of optimal birth weight) and childhood ALL • Association in children without ↑ birth weight • Conclusion: accelerated growth, not high birth weight per se, involved in causal pathway Milne E et al. AJE 2009;170:221-8.

  15. Folic Acid, MTHFR Variants, Diet, and Childhood ALL • Multivitamin use in pregnancy(5 studies, OR=0.83 [95%CI=0.73-0.94] • Protective effects found in 6/12 studies evaluating MTHFR C677T variant, 3/10 for A1298C variant • Maternal fruit & vegetable consumption ↓ risk De Klerk N and Milne E. Radiat Prot Dosim 2008;132:255-8. Milne E. Int J Cancer 2010;126:2690-9.

  16. Maternal Diagnostic X-rays & Childhood Leukemia • Meta-analysis: 38% increased risk of leukemia in children of women x-rayed in pregnancy • Report linking paternal preconception IVP & barium enema with pediatric leukemia • Concerns about pediatric CT scans and cancer risks • Maternal CT ↑ in pregnancy Wakeford R. Radiat Prot Dosim 2008;132:166-74. Bailey HD et al. CEBP 2010;19:2897-2909).

  17. Pesticides and Risk of Childhood Leukemia • Large literature implicating pesticides • Higher incidence in rural areas than in urban regions • Questionnaire data shows associations • before pregnancy (1 study) • during pregnancy (8 studies) • postnatal (6 studies) • parental occupational exposures • use of professional pest controllers pre- & postnatal • 7 countries (U.S., Canada, Germany, Sweden, France, China, and Australia)

  18. Chemicals in House Dust & Childhood Leukemia • Environmental measurements provide alternative to questionnaires and are more specific • Hypothesis: persistent organochlorine pesticides (DDT, DDE, chlordane, methoxychlor, pentachlorophenol) are linked with childhood leukemia • Measurements in house dust in high-exposure region in California showed: -no association with POPs -unexpected association with PCBs Ward MH et al. Environ Health Perspect 2009;117:1007-13.

  19. Residential Proximity to Chemical Sources • 5/6 studies assessing indicators of heavy traffic or air pollution showed association with childhood leukemia • Two independent case-control studies by same investigators found positive associations between pediatric leukemia and living next to automotive repair garage or petrol station Steffen C et al. Occup Environ Med 2004;61:773-8. Brosselin P et al. Occup Environ Med 2009;66:598-606.

  20. House Painting & Childhood Leukemia • 6 studies • 3 found modest excesses for postnatal exposures • No associations with prenatal or preconception exposures • Some evidence for higher risks for oil-based paints, more than 3 rooms painted, for painter other than parents, and for periods with higher VOCs Bailey HD et al. Int J Cancer 2011;128: 2405-2414.

  21. Allergies & Childhood Acute Lymphoblastic Leukemia • 10 studies have evaluated association • Most found inverse relationship based on recall; few assessed type of allergy • Large UK study found: - eczema ↓30% - hay fever ↓40 - 50% - asthma no association • Primary care records vs. parental recall: moderate agreement Hughes AM et al. Int J Cancer 2007;121: 819-824.

  22. Timing of Mutations in Childhood Leukemia • Chromosome 12p deletions in TEL-AML1 (ETV6-RUNX1) occur postnatally • IGH rearrangements were back-tracked in 3 RAS-positive childhood ALL patients and found before birth • FLT3 mutations are uncommon and are most likely acquired after birth Wiemels JL et al. Cancer Res 2008;68:9935-44. Wiemels JL et al. Blood Cells, Molecules & Diseases 2010;45:186-91. Chang P et al. BMC Cancer 2010;10:513.

  23. Inherited Susceptibility for B-Precursor ALL • GWA studies found modest but significant risks: • IKZF1 (7p12.2) • ARID5B (10q21.2) • CEBPE (14q11.2) • Performed replication of 34 SNPs: - 33 no association -CDKN2A (rs3731217 maps to 9p21.3) OR=0.71, p=3.01 x 10-11 • Major histocompatibility complex-defined variation in immune-mediated response is not a major risk factor Papaemmanuil E, Hosking FJ et al. Nature Genetics 2009;41:1006-10. Sherborne AK, Hosking FJ et al. Nature Genetics 2010;42:492-4. Hosking FJ et al. Blood 2011;117:1633-40.

  24. Biologic Plausibility of Variation in CDKN2A • CDKN2A encodes both p16, negative regulator of cyclin-dependent kinases, and p14, an activator of p53 • CDKN2A and CDKN2B are frequently inactivated in multiple hematologic malignancies • Mono- or bi-allelic deletion of CDKN2A is frequent genetic event in childhood B- and T-lineage ALL • CDKN2A deletions arise as secondary genetic events in cases of ALL initiated by ETV6-RUNX1 gene fusions and increase in frequency in cases of ALL relapse Sherborne AI, Hosking FJ et al. Nature Genetics 2010;42:492-4.

  25. How Can I4C Contribute to Understanding and Validating Recent Findings?

  26. Methodological Considerations:Cohort Vs. Case-Control Design • Study design: due to rarity → case-control approach; cohort approach has yielded insights& can identify mechanisms • Selection of cases and controls: ↓ selection bias • Retrospective exposure assessment: minimize recall bias, validate exposure • Observational study limitations: difficult to identify small risks, requires confirmation & different designs for validation

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