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Risk Factors for Childhood Cancer: An Update

Martha Linet, M.D., MPH

Division of Cancer Epidemiology & GeneticsNational Cancer Institute

September 19, 2011U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

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OutlineI. Characteristics and descriptive features

II. Known and suspected causes

III. Recent findings (most studies report on risk factors for childhood leukemia)

IV. How can I4C contribute to understanding and validating recent findings?

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Characteristics and Descriptive Features

International Classification ofChildhood Cancer – 3rd Revision

I. LeukemiaII. Lymphomas and reticuloendothelial neoplasmsIII. CNS and other intracranial and intraspinal neoplasmsIV. Neuroblastoma and other peripheral nervous systemV. RetinoblastomaVI. Renal tumorsVII. Hepatic tumorsVIII. Malignant bone tumorsIX. Soft tissue & other extra-osseous sarcomasX. Germ cell, trophoblastic, & other gonadal neoplasmsXI. Carcinomas and other malignant epithelial neoplasmsXII. Other and unspecified malignant neoplasms

Childhood Cancer Statistics

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

SEER Cancer Statistics Review 1973-1998

Childhood Cancer SEER Incidence Rates1973-1998, by ICCC Group

Under 20 Years of Age, Both Sexes, All Races

Age-adjusted to 1970 Standard

National Cancer Institute

36.3

24.1

26

7.9

2.8

6.5

1.6

8.8

10.9

10.2

14.2

0.8

Leukemia - I

Lymphoma - II

Brain/CNS - III

Sympathetic Nerv. - IV

Retinoblastoma - V

Renal - VI

Hepatic - VII

Bone - VIII

Soft tissue - IX

Germ cell - X

Carcinomas - XI

Other - XII

ICCC group

0 10 20 30 40Rate per 1,000,000

Figure 3

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Pediatric Cancer Types Vary in Age,

Gender, and Race Patterns Characteristic Subgroup ↑ 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

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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

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Etiology by Major Category (A. Knudson)

Spontaneousmutation

20%

Mostlygenetic5-10%

Mostly environmental

5-10%

Gene-environmentinteraction

60-70%

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Known Risk Factors

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)

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)

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Known Risk Factors for Other Pediatric Cancers

Pediatric cancer• Burkitt’s lymphoma• Non-Hodgkin lymphoma

• Retinoblastoma (hereditary)• Hepatoblastoma• Wilms’ tumor

Risk Factor(s)• Epstein Barr Virus• HIV, immunodeficiency

syndromes, organ transplant• Mutation in RB gene• Low birth weight• Beckwith-Wiedemann

syndrome & idiopathic hemihypertrophy

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Recent Findings

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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.

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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.

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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).

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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)

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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.

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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. OccupEnviron Med 2009;66:598-606.

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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.

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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.

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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.

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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.

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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.

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How Can I4C Contribute to Understanding and Validating

Recent Findings?

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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