The Environment and Childhood Cancer: What We Know and Don t Know Leslie L. Robison, Ph.D. Department of Epidemiology and Cancer Control St. Jude Children s Research Hospital Memphis, TN Overview of Presentation Descriptive Epidemiology of Cancer Epidemiologic Research Design Investigations of Etiology Future Challenges Excludes basal and squamous cell skin cancers. Source: American Cancer Society, 2007 1
Males and females combined. Source: NCI SEER Childhood Cancer Monograph 1.1 % of new cases annually Leading Causes of Death Among Children Ages 1-14 Years in the United States Septicemia/Other Infec 3% Pneumonia/Influenza 2% Suicide 2% Heart Disease 5% Homicide 6% Accidents 37% Congenital Anomalies 8% Cancer 12% Other 27% 2
Distribution of Cancer Types Among Children Ages 0-19 Years in the United States Other 9% Soft tissue 6% Bone 7% Leukemia 33% Liver 2% Kidney 3% NHL 6% Hodgkin's 2% Endocrine 8% CNS 24% 3
<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 4
<1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Temporal Patterns in Childhood Cancers SEER (1974): 1% per year increase Predominantly leukemia and central nervous system International increases Role of early detection in CNS tumors Leukemia patterns remain unclear 5
Secular Trend in Childhood Cancer Incidence Rates 250 200 15-19 Years Rate per 100,000 150 100 0-14 Years 50 0 1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 Year of diagnosis Strategies to Study Factors in Childhood Cancers Clusters Ecologic (GIS) Record Linkage Case-Control Studies PRE- CONCEPTION IN UTERO POST-NATAL Primary Individual [Parents] [Mother] [Child] OCCUPATIONAL MEDICAL GENERAL (e.g., household) LIFESTYLE (e.g., tobacco, diet) VIRAL/INFECTIONS 6
Hill s Criteria of Causation Applied to Epidemiologic Research Temporal Relationship Strength of Association Dose-Response Relationship Consistency Plausibility Consideration of Alternative Explanations Experiment Specificity Coherence Factors Investigated in Childhood Cancer Pesticides, Insecticides, Herbicides Solvents Heavy Metals Parental Occupation Radiation Diet Electric /Magnetic Fields Infectious Agents Tobacco Alcohol Medications 7
Factors Associated with Risk of Childhood Cancer EXPOSURE Radiation Atomic Bomb Nuclear Accident Medical Therapeutic Medical Diagnostic (in utero) CANCER TYPE Leukemia Thyroid CNS, Thyroid, Bone Acute Lymphoblastic Leukemia Medication Alkylating Agent Topoisomerase II Inhibitor Myelodysplastic Syndrome and Acute Myeloid Leukemia Acute Myeloid Leukemia Infection Immune Stimulation Hypotheses in Childhood Leukemia Rapid cell proliferation Low exposure to pathogens resulting in decreased proliferative stress Exposure to pathogens during period of increased lymphoid proliferation Fetal Development Birth Infancy - Early Childhood GREAVES HYPOTHESIS Random mutations Live in an environment with decreased exposure to common pathogens Delayed exposure to common pathogens KINLEN HYPOTHESIS Low or no exposure to the pathogens Exposure to the new pathogens as a result of increased population mixing Study Location Leukemia Other Cancers 1979 Denver OR=2.35* All cancer OR=2.22* 1980 Rhode Island OR=1.09 Not studied 1986 Sweden OR=0.30 CNS OR=3.70* 1988 Denver OR=1.54 All cancer OR=1.53* 1989 U.K. OR=1.50 Not studied 1989 Taiwan OR=1.31 All cancer OR=1.30 1990 U.K. OR=1.14 All cancer OR=0.98 1991 Los Angeles OR=2.15* Not studied 1991 Australia O/E=2.00 Not studied 1993 Sweden OR=3.80* All cancer OR=1.30 1993 Denmark OR=1.50 Not studied 1993 Greece OR=1.19 Not studied 1993 Finland SIR=1.60 All cancers SIR=1.50 1993 Mexico OR=2.63* Not studied * p < 0.05 8
The Electromagnetic Spectrum WAVE- FRE- LENGTH QUENCY (HZ) 10 8 1 10 4 10 4 1 10 8 10-4 10 12 10-8 10 16 10-12 10 20 10-16 10 24 ELECTRO- MAGNETIC FIELDS ELECTRIC POWER RADIO MICROWAVES INFRARED VISIBLE LIGHT ULTRAVIOLET X RAYS GAMMA RAYS NON- IONIZING IONIZING WHAT ARE ELECTROMAGNETIC FIELDS (EMF)? Power lines, electrical wiring, and appliances all produce electric and magnetic fields EMFs are invisible lines of force that surround any electrical device Electric and magnetic fields have difference properties and possibly different biological effects Electric and magnetic fields weaken with distance from the source 9
Measured Magnet Field (ut) Relative Risk Estimate 0 1 2 3 4 5 6 < 0.065 0.065-0.099 0.100-0.199 0.200-0.299 > 0.200 Magnetic-Field No. No. Odds 95% Confidence (microtesla) Cases Controls Ratio* Interval < 0.065 267 287 1.0 --- 0.065-0.099 123 117 1.10 (0.81-1.50) 0.100-0.199 151 143 1.10 (0.83-1.48) > 0.200 83 70 1.24 (0.86-1.79) 0.200-0.299 38 42 0.92 (0.57-1.48) 0.300-0.399 22 17 1.39 (0.72-2.72) 0.400-0.499 14 5 3.28 (1.15-9.39) > 0.500 9 6 1.41 (0.49-4.09) Promise of Molecular Epidemiology Exposure A Exposure C Exposure E Increase Risk For Genetic Lesion B Genetic Lesion D Genetic Lesion F Exposure X Genetic Lesion Y 10
Genetic Classification of Childhood ALL B - l i n e a g e H y p e r d i p l o i d y > 50 c h r o m o s o m e s 25 % C R L F 2 o v e r e x p r e s s i o n 6 % E R G d e l e t i o n 7 % i A M P 21 2 % E T V 6 - R U N X 1 t ( 12 ; 21 ) 25 % O t h e r s 7 % B C R - A B L 1 t ( 9 ; 22 ) 3 % M L L r e a r r a n g e m e n t s e. g., t ( 4 ; 11 ), t ( 11 ; 19 ), t ( 9 ; 11 ) 8 % L Y L 1 T A L 1 19 p 13 1 p 32 H O X 11 L 2 1. 5 % 7 % 5 q 35 2. 5 % T - l i n e a g e M Y C t ( 8 ; 14 ), t ( 2 ; 8 ), t ( 8 ; 22 ) 2 % E 2 A - P B X 1 t ( 1 ; 19 ) 5 % M L L - E N L 0. 3 % H O X 11 10 q 24 0. 3 % Promise of Molecular Epidemiology Exposure A Exposure B Exposure C Genetic Susceptibility in Gene A Genetic Susceptibility in Gene B Genetic Susceptibility in Gene C CANCER Exposure X Genetic Susceptibility in Gene X Genome-wide P values for Germline Allele Frequency Differences Between the ALL Cases and the non-all Control Groups 15 n=307,944 SNPs Observed distribution (-log 10 of p value) 10 5 0 1 2 3 4 5 6 7 8 9 10 11 12 13 22 Chromosome Trevino et al. Nature Genet 2009;41:1001-5 11
Future Considerations Regarding an Etiology in Childhood Cancers The scientific literature is replete with individual epidemiologic studies reporting selected environmental factors to be associated with an increased risk for childhood cancer. The only environmental factors that have been established to be associated with risk of childhood cancer are radiation and chemotherapy. Despite extensive investigation, no other environmental factor has been established to be a risk factor for childhood cancer. Future research into an environmental etiology of childhood cancer must adopt newer and more innovative approaches to understanding genetic mechanisms coupled with better exposure assessment. 12