Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Assessment of Environmental and Genetic Factors in the Etiology of Childhood
Cancers: The Childrens Cancer Group Epidemiology Program
Leslie L. Robison,1 Jonathan D. Buckley,2 and
Greta Bunin3
For the Childrens Cancer Group Epidemiology Committee
1Division of Pediatric Epidemiology/Clinical Research, University
of Minnesota, Minneapolis, Minnesota; 2Department of Preventive
Medicine, University of Southern California School of Medicine, Los Angeles,
California; 3Division of Oncology, Children's Hospital of Philadelphia,
Philadelphia, Pennsylvania
Abstract
The occurrence of cancer during childhood represents one of the leading
causes of death within the pediatric and adolescent age group. It is estimated
that approximately 8000 children will be diagnosed annually with cancer
in the United States. Epidemiologic research addressing the etiology of
childhood cancer has been limited because of the difficulties in identifying
a sufficiently large study population. Moreover, the use of retrospectively
ascertained childhood cancer cases in epidemiologic investigations has restricted
the incorporation of biological and clinical parameters. The Childrens Cancer
Group has developed an active program in epidemiologic research, with over
a decade of experience demonstrating the feasibility and strengths of conducting
analytic epidemiologic studies within a cooperative clinical trials network.
The availability of detailed clinical and biologic data on cases diagnosed
within the cooperative group facilitates the transfer of state-of-the-art
technology to epidemiologic research. -- Environ Health Perspect
103(Suppl 6):111-116 (1995)
Key words: pediatric cancers, etiology, biological markers, clinical/pathologic
features
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington DC.
Address correspondence to Dr. Leslie L. Robison, Department
of Pediatrics, Division of Epidemiology/ Clinical Research, Box 422 UMHC,
Minneapolis, MN 55455. Telephone (612) 626-2778. Fax (612) 626-2815. Address
reprint requests to Dr. L.L. Robison, Childrens Cancer Group, P.O. Box
60012, Arcadia, CA 91066-6012.
Introduction
Approximately 8000 children in the United States are diagnosed annually
with cancer (1). The incidence of cancer in children less than 15
years old is approximately 13 per 100,000 for whites and 11 per 100,000
for blacks. While the absolute number of childhood cancer cases is low,
when compared to the number of adult cancers, U.S. mortality data demonstrate
that cancer is the second leading cause of death in children, second only
to accidents (2). It can be estimated that approximately one in every
400 individuals living in the United States will develop cancer before age
15.
Data from the Surveillance Epidemiology and End Results Program indicate
a gradual but continuous increase in the incidence rates of childhood cancers
(3,4). These increases are most apparent for leukemia and brain tumors,
the two diagnoses that comprise approximately 50% of cases in the 0 to 14
age group. There has been considerable speculation on the cause(s) of the
observed increase. Possibilities include random variations in the pattern
of occurrence of cancer, improvements in access to medical care and/or medical
detection, more complete case ascertainment by registries, new or more extensive
environmental exposures, or iatrogenically induced secondary cancers. A
recent analysis has demonstrated that secondary cancers do not account for
the increase (5).
The types and distributions of the malignancies seen in the pediatric
and adolescent age groups differ substantially from that seen in adults.
Although childhood cancers represent less than 2% of all cancers that occur
in the United States, the unique clinical and biologic features of pediatric
malignancies have contributed substantially to our understanding of cancer.
Most of the contribution of pediatric cancers has been in providing insights
into the genetic events associated with malignant transformation. Tumor
suppressor genes, first identified in retinoblastoma (a tumor with an annual
incidence of less than 5 per million), have now been described in Wilms'
tumor, rhabdomyosarcoma, and some adult malignancies (6-8). Childhood
cancers have also provided important information on familial cancer associations
and syndromes (9-10). In contrast to these genetic and familial findings,
childhood cancers have contributed much less to the understanding of the
environmental aspects of cancer.
Recognizing the difficulties of conducting epidemiologic studies of childhood
cancer, the Childrens Cancer Group (CCG) established an Epidemiology Committee
to propose and develop a program for conducting studies within the structure
of the existing clinical trials cooperative group. Following is a summary
of the program that currently exists in CCG.
The Childrens Cancer Group Epidemiology Program
The Division of Cancer Therapy of the National Cancer Institute supports
a program of collaborative cooperative clinical trials groups. Presently
there are two pediatric groups, Childrens Cancer Group and Pediatric Oncology
Group. Collectively, the members of these two large multi-institutional
programs diagnose and treat greater than 90% of cases of childhood cancer
in the United States and essentially 100% of cases diagnosed before age
five (11). It is a requirement in CCG that all pediatric oncology
patients seen at a member institution be registered with the group Operations
Office, whether or not the patient is entered into a clinical trial.
Recognizing the limitations imposed by the relative rarity of childhood
cancers and the strengths of the cooperative group mechanism, the CCG initiated
development of a program to conduct epidemiologic research within the existing
clinical trials infrastructure. The CCG Epidemiology Committee functions
as the primary source of expertise in areas related to childhood cancer
etiology and the conduct of epidemiologic/etiologic investigations. The
overall objectives of the Epidemiology Committee are to investigate environmental
and genetic factors related to childhood cancer etiology. The committee
is responsible for establishing long-range strategies and priorities, initiating
new proposals, reviewing proposed study concepts, preparing and submitting
study-specific grant applications, protocol development, monitoring study
progress, and reporting and publishing study results. Close collaboration
with the clinical and other CCG committees (e.g., study committees, strategy
groups, and discipline and scientific committees) is required to carry out
these functions.
Previous and Current Activities
Since the Epidemiology Committee was established in 1982, CCG has initiated
17 epidemiologic protocols and has proposed three studies (Table 1). The
majority of CCG epidemiology studies have been case-control designs. A methodology
has been successfully established (Figure 1) using telephone interviews
with parents of cases and controls. Controls are selected using a method
of random digit dialing (12).
Figure 1. General
procedure for CCG case-control studies.
The 12-year history of the CCG Epidemiology Committee has clearly demonstrated
the feasibility and advantages of conducting epidemiologic research within
the CCG. These include a) identification of large numbers of cases,
b) extremely high participation rates, c) integration of clinical
and biologic data into study designs, and d) the ability to compete
successfully for NIH and private research funding.
Using the large case population available from CCG, studies of some of
the less common pediatric tumors [e.g., hepatoblastoma, retinoblastoma,
acute myeloid leukemia (AML), Ewing's sarcoma, osteosarcoma] have been conducted.
Moreover, for common childhood cancers, it has been possible to target studies
within distinct subsets of cases [e.g., immunophenotype in acute lymphoblastic
leukemia (ALL), young age in brain tumors, etc.]. By and large these studies
would not have been feasible outside of a cooperative group setting. Provided
in Table 2 are the average numbers of new patients registered each month
with the CCG Operations Office.
Experience in CCG has shown that using the methodologic approach adopted
case-control studies designed to test specific hypotheses and/or generate
hypotheses within selected childhood cancers can be successfully conducted.
Impressively high rates of participation (both physician and parent) have
been achieved. For example, in the current case-control study of childhood
ALL (E-15), where over 2300 cases have been identified, permission to contact
parents was received from physicians of 98.4% of eligible cases. Physician
refusal occurred in only 1.1% and parent refusal, via the physician, in
0.5%. Of the parents contacted, 97.5% participated in the study. Using the
method of random digit dialing for control selection, the participation
rate in CCG studies has averaged approximately 80%.
In addition to the availability of the large numbers of cases, one of
the major advantages of conducting epidemiologic studies in CCG is the clinical
and biologic data that can be incorporated into the design of the epidemiologic
investigation. Table 3 summarizes the CCG epidemiology studies incorporating
the use of clinical/biological data in the study design and/or analysis.
Funding of CCG epidemiologic studies has been successfully obtained through
NIH R01-supported grants as well as private foundations (i.e., American
Cancer Society, March of Dimes). All the 12 R01 grant applications that
have undergone the NIH peer-review process have received priority ratings
resulting in funding.
Completed CCG Epidemiology Studies
Listed below are some of the findings of completed epidemiology studies
conducted by CCG (13-29):
* Identified risk factors for retinoblastoma differed according to the
two nonfamilial forms studied (sporadic heritable and nonheritable). Paternal
occupational exposure to metals was associated with the sporadic heritable
form, while employment as a welder or machinist was associated with an increased
risk of nonheritable retinoblastoma. (CCG-E07)
* Gestational factors including exposure to X-rays and use of morning
sickness medications were significantly associated with an increased risk
of nonheritable retinoblastoma, while vitamin use during the first trimester
of pregnancy was associated with a decreased risk in both nonfamilial forms
of retinoblastoma. (CCG-E07)
* Risk of astrocytic glioma is associated with a history of seizures
and epilepsy in first or second degree relatives (OR=2.4). The association
is strongest when the relative experienced seizures in childhood. (CCG-E12)
* Maternal intake of dietary substances relevant to the nitrosamine hypothesis
in childhood brain tumors was not found to be associated with an increased
risk for astrocytic glioma or primitive neuroectodermal tumor (PNET) in
young children. However, for PNET a protective effect existed for vegetables,
fruits, folate, and vitamin C, and for use of multivitamins early in pregnancy.
(CCG-E12)
* For cases diagnosed before age 6, a striking difference exists in identified
risk factors for cases of PNET versus astrocytic glioma. (CCG-E12)
* A previously reported association between parental cigarette smoking
and risk of rhabdomyosarcoma in offspring was not confirmed. However, in
utero X-ray exposure is associated with a significant increase in risk
of rhabdomyosarcoma. (CCG-E10)
* Parents' use of cocaine and marijuana significantly increased the risk
of rhabdomyosarcoma in their children. (CCG-E10)
* A consistent statistically significant association was identified between
reported pesticide exposure and risk of childhood AML (paternal occupation:
OR=2.7, maternal occupation: 7 cases/0 controls; and household: OR=3.5).
Risks were substantially increased for AML cases diagnosed before age 6
and for those with M4 or M5 morphology. (CCG-E05)
* Paternal occupational exposure to solvents and petroleum products was
found to be associated with a statistically significant increased risk of
AML. (CCG-E05)
* An 11-fold increased risk of AML was found for reported maternal use
of mind-altering drugs (primarily marijuana) just prior to or during the
index pregnancy. Exposed cases were significantly younger at diagnosis and
were predominantly of myelomonocytic or monocytic morphology. (CCG-E05)
* Maternal alcohol consumption during the index pregnancy is associated
with an increased risk of AML, particularly within the subgroup of cases
with M4/M5 morphology. (CCG-E05)
* Maternal history of fetal loss was significantly associated with risk
of childhood ALL. Risk increased dramatically in cases diagnosed at younger
ages (i.e., cases diagnosed before 2 years of age: OR=5.3 for any previous
miscarriage; OR=24.8 for more than one previous miscarriage). (CCG-E04)
* When assessing the potential role of parental occupation as a risk
factor for Wilms' tumor, elevated odds ratios were found for paternal occupations
as auto mechanic and welder. The estimated risks were highest for employment
during the preconception and pregnancy periods. (CCG-E06)
* Wilms' tumor cases were significantly more likely to have fathers employed
in occupations associated with solvent exposure. (CCG-E04)
* Previously reported associations between Wilms' tumor risk and parental
occupational exposure to hydrocarbons and lead were not confirmed. Similarly,
contrary to other reports in the literature, no associations were identified
between Wilms' tumor and a) maternal tobacco, tea, and coffee consumption
during pregnancy, b) maternal hypertension, hair dye use, or vaginal
infection during pregnancy, c) in utero exposure to exogenous
hormones, or d) increased birth weight. (CCG-E06)
* The hypothesis that maternal exposure to potentially hepatotoxic agents
(including alcohol, chlorinated hydrocarbons, nitrosamines, viruses, or
exogenous estrogens) would be associated with increased risk of hepatoblastoma
was tested and rejected. (CCG- E02)
* Maternal occupational exposures to metals (OR=8.0), hydrocarbons (OR=3.7),
and paints/pigments (OR=3.7) and paternal occupational exposures to metals
(OR=3.0) and petroleum products (OR=1.9) were associated with risk of hepatoblastoma.
(CCG-E02)
* A multi-center/organization study designed to determine zygosity and
frequency of cancer concordance of cancer in twins confirmed the view that
inherited genetic factors play a minor role in most childhood cancers. In
malignancies other than retinoblastoma and leukemia, only 3 of 334 twins
were concordant for cancer. Three of 197 leukemia twins were concordant,
as were 5 of 19 retinoblastomas. (CCG-E11)
Current CCG Epidemiology Studies
Epidemiology of Hodgkin's Disease (CCG-E13). This is the
first interview case-control study of childhood Hodgkin's disease (HD).
The study is designed to fill several important gaps in knowledge by investigating
environmental exposures as risk factors for childhood HD. This is a collaborative
study of the Pediatric Oncology Group and CCG. The specific aims of the
CCG-E13 study are: a) to evaluate whether, on epidemiologic grounds,
childhood HD is distinct from the young adult and old adult diseases; b)
to evaluate the hypothesis that children with HD have different patterns
of infectious disease than do matched controls; c) to assess day
care of children (with its attendant increased risk of infectious diseases
acquired at early ages) as a risk factor for HD; d) to evaluate the
association between breastfeeding and risk of HD; e) to evaluate
the association between indicators of socioeconomic status and HD; f)
to evaluate parental occupational exposures as risk factors for HD in children;
g) to evaluate environmental exposures to wood and chemicals as possible
risk factors in children; h) to evaluate familial aggregation of
HD (and possibly increased risk of other malignancies or multiple sclerosis);
i) to evaluate risk factors of HDzzz separately for each histologic
subtype of the disease, and by disease stage and age at diagnosis.
Epidemiology of Acute Myeloid Leukemia (CCG-E14). This
study is a followup to CCG-E05, an analytic study designed to assess specific
environmental exposures as risk factors for childhood AML. Two of the strongest
associations from our previous study were with maternal marijuana use and
pesticide exposure (using multivariate analyses, they were found to be independently
associated with an increased risk). The primary objectives of the study
are: a) to confirm the association of pesticide exposure and AML
risk, and to identify the substance(s) or class of pesticide responsible
for the association; b) to confirm the association of solvents and
petroleum products and AML risk, and to determine the class of solvent responsible;
c) to confirm the association of maternal marijuana use and AML risk;
d) to identify subgroups, defined by age at diagnosis, FAB morphology,
cytogenetic abnormality, or clinical features of the leukemia, in which
associations with pesticide, solvent or marijuana exposures are strongest.
Secondary aims are e) to further investigate identified associations
of childhood AML and parental occupational exposures to paints/pigments,
sawdust, metal dusts and fumes, plastics, and lead; and f) to assess
a possible association of an extended duration of use of morning sickness
medications and an increased risk for childhood AML.
Epidemiology of Acute Lymphoblastic Leukemia (CCG-E15).
This study is designed to investigate the role of risk factors for acute
lymphoblastic leukemia within biologically defined subgroups. Because of
the availability of immunophenotypic characteristics and cytogenetics for
all newly diagnosed cases, it will be possible to identify biologically
distinct subgroups from all newly diagnosed children with ALL. This case-control
study will investigate whether or not there are distinct risk factors within
subgroups of childhood ALL. Risk factors to be investigated include those
relating to demographic characteristics, preconception exposures of parents,
reproductive factors including reproductive history, medical exposures during
pregnancy, illnesses, events surrounding the labor and delivery, diet during
pregnancy, and possible occupational exposures of mothers and fathers during
the index pregnancy, postnatal exposures relating to parental occupations
and general environment, as well as a family medical history. Additional
objectives of this study include assessment of exposure to very low level
electromagnetic fields with indirect and direct measurements, assessment
of exposure to radon and gamma radiation (direct measurements), and measurement
of exposure to household pesticide residues (direct measurement). Studies
relating to electromagnetic field radiation, radon, and gamma radiation
are being conducted in collaboration with investigators from the National
Cancer Institute.
Parental Occupation and Childhood Cancer (CCG-E16). This
study uses the unique data source that contains information from a self-administered
questionnaire on 3549 children with cancer and 839 healthy children (E04).
The cancers we will study are: acute lymphoblastic leukemia, neuroblastoma,
acute myeloid leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, Wilms'
tumor, osteosarcoma, astrocytoma, primitive neuroectodermal tumor (PNET)/medulloblastoma,
rhabdomyosarcoma, germ cell and gonadal tumor, hepatoblastoma, Ewing's sarcoma,
and histiocytosis X. The following specific hypotheses will be tested: a)
children with Wilms' tumor, brain tumor, and other cancers are more likely
than controls to have parents who worked in metal-related occupations or
industries; b) children with neuroblastoma, brain tumor, and other
cancers are more likely than controls to have parents employed in the electric
and electronic industry; c) children with brain tumor, acute myeloid
leukemia, and other cancers are more likely than controls to have parents
employed in agriculture or occupations with exposure to pesticides.
Epidemiology of Neuroblastoma (CCG-E18). The major purpose
of the CCG-E18 study is to examine the relationships between specific environmental
exposures and the occurrence of neuroblastoma. The specific aim of the study
is to evaluate hypothesized risk factors, including maternal use of drugs,
sex hormones, alcohol, and diuretics during pregnancy. The analysis of maternal
drug use during pregnancy will include a special evaluation of the potential
for these drugs to result in transplacental N-nitroso compound exposure.
In addition, paternal employment in the electronics industry and occupational
exposure to electromagnetic fields will be examined. Other risk factors
previously found to be associated with neuroblastoma such as maternal age,
length of gestation, birth weight, and family socioeconomic status will
be evaluated. In addition, this study will collect information on additional
potential risk factors that may be used to develop new etiologic hypotheses
(such as family medical history, neonatal, gestational, and delivery history,
and household environmental exposures); and evaluate the above potential
risk factors separately for subgroups of patients defined by clinical, biologic
and genetic markers such as cytogenetic abnormality and n-myc oncogene amplification.
Current and Future Research Objectives
Through continued reliance on externally-funded investigations (primarily
R01 grants), the CCG Epidemiology Committee plans to increase further the
focus and complexity of future epidemiologic studies conducted within CCG
by a) concentrating efforts on more detailed testing of specific
hypotheses, b) greater integration of biologic parameters, and c)
including more quantitative measures of exposure.
Part of the future strategy of the CCG Epidemiology Committee is to continue
to perform detailed assessments of associations identified in previous CCG
epidemiologic studies. Through the series of case-control studies that have
been successfully conducted within CCG, associations have been identified
that require confirmation and further elucidation. For example, the CCG-E05
study found pesticide exposures and maternal drug use to be significantly
associated with an increased risk of childhood AML, particularly M4 and
M5 morphologies. Since the E05 study represented the first large case-control
study of childhood AML, the interview included a wide range of topics, thus
limiting the degree of detail that could be obtained about factors of interest.
Based on the results, NIH funded a case-control study of 550 cases of childhood
AML designed to test a series of hypotheses relating to pesticide exposures
and maternal marijuana use. In the future, it is anticipated that followup
studies will be proposed based on the results of previous CCG epidemiologic
investigations to test specific hypotheses relating to childhood brain tumors,
HD, non-Hodgkin's lymphoma, and ALL.
In future studies there will be more integration of direct measurements
of exposure. While important associations can be identified using self-reported
information obtained through interviews, it is recognized that there are
limitations inherent in data collected in this manner. Accordingly, whenever
possible, there will be expanded use of more direct measures of exposure.
In the current leukemia studies, direct measurements are being made of electromagnetic
field radiation, indoor radon, and pesticide residues, PAH, and heavy metals
from housedust. While recognizing the financial and logistical issues involved
in these types of measurements, experience to date clearly indicates the
utility and feasibility of this approach within CCG.
When investigating etiologic hypotheses, studies of childhood cancer
must be prepared to assess the potential role of biologic data, particularly
in combination with exposure data. With regard to the conduct of epidemiologic
studies, one of the many strengths of utilizing the cooperative clinical
trials group is the availability of biologic and/or clinical information
on ascertained cases. While the type of biologic information is often disease-
and protocol-specific, the information generally is collected in a uniform
manner at centralized resource laboratories. Previous CCG epidemiology studies
have incorporated into the study design the use of data on morphology, phenotype,
and cytogenetics. The current case-control study of neuroblastoma uses the
information on n-myc amplification and ploidy. Other CCG studies
have included collecting specific biologic data such as EBV. Depending on
the type of biologic data available, this information can be used to stratify
cases into potentially more homogeneous subgroups (i.e., morphology, phenotype,
etc.) or to assess the biologic parameters as potential risk factors, either
solely or in combination with other possible risk factors (i.e., EBV, p53).
Since genetics, and possible genetic-environment interactions, may be
important in the etiology of childhood cancers, the CCG plans to expand
the assessment of family history. While most of the previous CCG epidemiology
studies have included selected information on family history, the majority
have not been able to obtain a detailed family pedigree. Recognizing the
potential importance of family medical history, the Epidemiology Committee
plans to investigate the feasibility of systematically collecting more detailed
data in future studies. One of the major deterrents to obtaining family
history is the amount time required. By building upon the experience of
the CCG Genetics Registry, the committee will investigate various approaches
to collecting family history through self-administered and interview formats.
Because of the large proportion of childhood cancer cases that are diagnosed
and treated at an institution affiliated with a clinical trials cooperative
group, it is possible to investigate etiologic hypotheses in less common
childhood cancers. While from a public health perspective it may be argued
that these rare forms of malignancies may not warrant investigation, it
is clear that rare tumors have provided some of the most important information
concerning cancer etiology (i.e., retinoblastoma). In the near future the
Epidemiology Committee will consider studies of rare childhood cancers including
a) Burkitt's lymphoma to investigate environmental and genetic factors
through a case-control interview study that will correlate findings with
studies relating to evidence for EBV infection and occurrence of chromosomal
translocations, and b) germ cell tumors to investigate, in a case-control
study design, issues relating to congenital anomalies and in utero hormone
exposure.
Based on information compiled on the distribution of childhood cancers
registered with the pediatric cooperative groups (11), it has been
estimated that over 95% of patients diagnosed in the United States before
10 years of age could be ascertained. Therefore, when appropriate, CCG plans
to promote the conduct of intergroup epidemiologic studies to approximate
a population-based sample. This possibly would allow the use of alternative
methodologic approaches and promote interactions with regional cancer registries.
Lastly, the epidemiologic and biologic studies conducted by CCG and other
investigators are continually providing information relating to the possible
etiology of childhood cancers. It is important that this information be
communicated in the most effective manner to health care professionals who
interact with the population of childhood cancer patients. The CCG Epidemiology
Committee, in collaboration with the CCG Nursing Committee, plans to provide
a series of educational programs to facilitate the exchange of epidemiologic
and etiologic information to CCG investigators, including physicians, nurses
and data managers.
Summary
The experience of the CCG Epidemiology Committee demonstrates the advantages
in conducting epidemiologic research within an existing clinical trials
network. The detailed clinical and biologic data available on patients diagnosed
within the cooperative groups facilitates the transfer of state-of-the-art
technology to epidemiologic research. Discussions are underway in CCG for
future studies to correlate environmental exposures with biologic parameters
including 11q23 mutations in leukemia, ras gene mutations in childhood
AML, V-D-J recombinase in leukemia and lymphoma, tyrosine kinase activity
in ALL, and parent of origin of +21 in Downs' syndrome cases with leukemia.
With the emphasis on cancer biology within CCG and other cooperative groups,
the outlook for further integrating biologic measures into epidemiologic
research in the future looks very promising.
REFERENCES
1. Miller BA, Ries LAG, Hankey FR, Kosary FL, Harras A,
Devesa SS, Edwards BK, eds. SEER Cancer Statistics Review: 1973-1990. National
Cancer Institute, NIH Pub. No. 93-2789 (1993).
2. National Center for Health Statistics: Vital Statistics
of the United States, 1988, vol II, Mortality, part A. Washington: Public
Health Service, 1991.
3. Bleyer WA. What can be learned about childhood cancer
from "Cancer Statistics Review 1973-1988". Cancer 71:3229-3236
(1993).
4. Miller BA, Ries LAG, Hankey BF, Edwards BK, eds. Cancer
Statistics Review: 1973-1989. National Cancer Institute, NIH Pub. No. 92-2789
(1992).
5. Gurney JG, Davis S, Severson RK, Robison LL. The influence
of subsequent neoplasms on incidence trends in childhood cancer. Cancer
Epidemiol Biomarkers Prev 3:349-351 (1994).
6. Knudson AG. Hereditary cancer, oncogenes, and anti-oncogenes.
Cancer Res 45:1437-1443 (1985).
7. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rappaport
JM, Albert DM, Dryja TP. A human DNA segment with properties of the gene
that predisposes to retinoblastoma and osteosarcoma. Nature 323:643-646
(1986).
8. Ponder B. Gene losses in human tumors. Nature 335:400-402
(1988).
9. Birch JM, Hartley AI, Marsden HB, Harris M, Swindell
R. Excess risk of breast cancer in the mothers of children with soft tissue
sarcomas. Br J Cancer 49:325-331 (1984).
10. Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE,
Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, Friend SH. Germ line
p53 mutation in a familial syndrome of breast cancer, sarcomas and other
neoplasms. Science 250:1233-1238 (1990).
11. Ross JA, Severson RK, Robison LL, Pollock BH, Neglia
JP, Woods WG, Hammond GD. Pediatric cancer in the United States. A preliminary
report of a collaborative study of the Childrens Cancer Group and Pediatric
Oncology Group. Cancer 71:3415-3421 (1993).
12. Robison LL, Daigle A. Control selection using random
digit dialing for cases of childhood cancer. Am J Epidemiol 120:164-166
(1984).
13. Ambinder RF, Browning PJ, Lorenzana I, Leventhal BG,
Cosenza H, Mann RB, MacMahon EME, Medina R, Cardona V, Grufferman S, Olshan
A, Levin A, Peterson EA, Blattner W, Levine PH. Epstein-Barr virus and childhood
Hodgkin's disease in Honduras and the United States. Blood 81:462-467 (1993).
14. Buckley JD, Hobbie WL, Ruccione K, Sather HN, Woods
WG, Hammond D. Maternal smoking during pregnancy and the risk of childhood
cancer. Lancet 2:519-520 (1986).
15. Buckley JD, Robison LL, Swotinsky R, Garabrant D, LeBeau
M, Manchester P, Nesbit ME, Odom L, Peters J, Woods WG, Hammond GD. Occupational
exposures of parents of children with acute nonlymphocytic leukemia: a report
from the Childrens Cancer Study Group. Cancer Res 49:4030-4037 (1989).
16. Buckley JD, Sather H, Ruccione K, Rogers PCJ, Haas
JE, Henderson BE, Hammond GD. A case-control study of risk factors for hepatoblastoma.
A report from the Childrens Cancer Study Group. Cancer 64:1169-1176 (1989).
17. Buckley JD, Gilchrist GS, Ruccione K, Sather HN, Woods
WG, Hammond GD. Multiple sclerosis in mothers of children with acute lymphoblastic
leukemia. Leukemia 3:736-739 (1989).
18. Bunin GR, Emanuel BS, Meadows AT, Buckley JD, Woods
WG, Hammond GD. Frequency of 13q abnormalities among 203 patients with retinoblastoma.
JNCI 81:370-374 (1989).
19. Bunin GR, Meadows AT, Emanuel BS, Buckley JD, Woods
WG, Hammond GD. Pre- and post-conception factors associated with sporadic
heritable and non-heritable retinoblastoma. Cancer Res 49:5730-5735 (1989).
20. Bunin GR, Petrakova A, Meadows AT, Emanuel BS, Buckley
JD, Woods WG, Hammond GD. Occupations of parents of children with retinoblastoma:
a report from the Childrens Cancer Study Group. Cancer Res 50:7129-7133
(1990).
21. Olshan AF, Breslow NE, Falletta J, Grufferman S, Pendergrass
T, Robison L, Strong L, Waskerwitz M, Woods W, Hammond D. A case-control
study of risk factors for Wilms' tumor: report from the National Wilms'
Tumor Study. Med Pediat Oncol 16:413 (1988).
22. Olshan AF, Breslow NE, Daling J, Falletta J, Grufferman
S, Robison L, Waskerwitz M, Hammond D. Wilms' tumor and paternal occupation.
Cancer Res 50:3212-3217 (1990).
23. Robison LL, Buckley JD, Daigle AE, Benjamin D, Wells
R, Arthur DC, Hammond GD. Maternal drug use and risk of childhood acute
non-lymphoblastic leukemia: an epidemiologic investigation implicating marijuana.
Cancer 63:1904-1911 (1989).
24. Kuijten RR, Strom SS, Rorke LB, Boesel CP, Buckley
JD, Meadows AT, Bunin GR. Family history of cancer and seizures in young
children with brain tumors. Cancer Causes Control 4:455-464 (1993).
25. Bunin GR, Kuijten RR, Buckley JD, Rorke LB, Meadows
AT. Relation between maternal diet and subsequent primitive neuroectodermal
brain tumors in young children. New Engl J Med 329:536-541 (1993).
26. Olshan AF, Breslow NE, Falletta JM, Grufferman S, Pendergrass
T, Robison LL, Waskerwitz M, Woods WG, Vietti TJ, Hammond GD. Risk factors
for Wilms' tumor. Cancer 72:938-944 (1993).
27. Severson RK, Buckley JD, Woods WG, Benjamin D, Robison
LL. Cigarette smoking and alcohol consumption of parents of children with
acute myeloid leukemia: an analysis within morphologic subgroups. Cancer
Epidemiol Biomarkers Prev 2:433-439 (1993).
28. Bunin GR, Buckley JD, Boesel CP, Rorke LB, Meadows
AT. Risk factors for astrocytic glioma and primitive neuroectodermal tumor
of brain in young children. Cancer Epidemiol Biomarkers Prev (in press)
1994.
29. Buckley JD, Versteeg CM, Ruccione K, Sather HN, Waskerwitz
MJ, Woods WG, Robison LL. Epidemiologic characteristics of childhood acute
lymphocytic leukemia: Analysis by immunophenotype. Leukemia (in press) 1994.
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Last Update: September 15, 1998
