Start of Main Content
Report on Research on Rare Diseases in Children: FY 2000 to FY 2005

National Cancer Institute (NCI)

Overview of NCI Rare Diseases in Children Research Activities, FY 2000–FY 2005

NCI conducts and supports research in cancer biology, models, causes, prevention, control, early detection, diagnosis, treatment, and care.

While childhood cancer is relatively uncommon, with an annual incidence of 150 new cases per 1 million children in the United States, it accounts for 10% of childhood deaths and is second only to accidents as a cause of death in U.S. children. Although the overall cure rate for pediatric cancer exceeds 70%, it remains the leading cause of death by disease in children and adolescents in North America.

In general, childhood cancers are more aggressive than adult cancers and derive from more primitive cell types. The ability of a cancer cell to metastasize represents the major challenge in the treatment of pediatric cancers, with prognosis for children with metastatic cancer remaining quite poor.

NCI efforts are focused on rare cancers in children to improve our understanding of the biology of specific cancers and to translate this improved understanding to novel and better interventions for preventing, detecting, and treating cancer in children. NCI's section of this report discusses selected major research advances and current research initiatives conducted by the NCI intramural and extramural programs.

Recent Scientific Advances in Rare Diseases in Children Research


Dietary Bioflavonoid-Induced Breaks in the MLL Gene and Infant Leukemia

Approximately 80% of infants with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) have chromosome translocations involving the MLL gene at 11q23. Also, some cancer patients treated with chemotherapeutic agents such as etoposide or doxorubicin develop therapy-related leukemia involving MLL. These agents are known inhibitors of eukaryotic topoisomerase II (topo II), an enzyme that alters the deoxyribonucleic acid (DNA) topology pivotal for various cell functions by catalyzing double-strand breakage and rejoining of DNA. In one NCI/Division of Cancer Biology (DCB)-supported study, the researcher identified bioflavonoids (natural substances in food as well as in dietary supplements) that caused site-specific DNA cleavage in the MLL breakpoint cluster region in vivo; this site co-localized with the MLL breakpoint cluster region cleavage site induced by etoposide or doxorubicin. Topo II was identified as the target in both cases. Based on a test of 20 bioflavonoids, a common structure essential for topo II-induced DNA cleavage was identified. The results obtained in this study suggest that maternal ingestion of bioflavonoids induces MLL breaks and translocations in utero, leading to infant and early childhood leukemia. This study supports conclusions from a preliminary epidemiological study in which it was demonstrated that maternal consumption of topo II inhibitor-containing foods (including bioflavonoids) led to an approximately 10-fold higher risk of infant AML. Although the increased consumption of flavonoid-containing foods is associated with a decreased risk of adult malignancies in most epidemiologic studies to date, the results from this study may lead to altered chemoprevention strategies in order to avoid leukemia induction in infants. (FY 1985 through FY 2002)

Mechanisms in Perinatal Carcinogenesis

Perinatal exposures may lead to increased risk of both childhood cancers and those occurring later in life. Carcinogenic nitrosamine (N-nitrosodimethylamine), which is present in tobacco smoke and other environmental sources, was examined in animal models to increase the understanding of cellular and molecular mechanisms of carcinogenesis. After administration to lactating rat mothers, N-nitrosodimethylamine caused, in tissues of suckling infants, formation of a DNA adduct known to be associated with tumor initiation. Furthermore, if the mother received ethanol simultaneously, there was a 10-fold increase in these adducts in some tissues. These results indicate that exposures to carcinogens via breast milk require further study. (Funding started FY 1983, duration is indefinite)

Mechanisms in Trans-generational Perinatal Carcinogenesis

Exposure of male mice to chromium(III), a chemical widely encountered in work settings, before mating leads to increased incidence of several types of neoplasms in the offspring. Preliminary results of tests to identify the mechanics of carcinogenesis indicate that paternal exposure is associated with changes in serum hormones in the offspring and altered expression of a number of hepatic genes, including insulin-like growth factor binding protein 1. (Funding started FY 1983, duration is indefinite)

Molecular Basis of Metastases in Osteosarcoma

Osteosarcoma is the most common bone cancer in children and young adults. The major cause of mortality in this tumor is metastatic spread, predominantly to the lungs. A mouse model of osteosarcoma that grows in a manner similar to the human tumor and metastasizes to the lung following amputation in a manner very similar to humans was developed. This model was used to apply gene expression profiling experiments to identify a limited group of genes that appear to play a major role in metastatic behavior. One such gene, called ezrin, has now been shown to be associated with metastatic behavior and poor outcome in osteosarcoma in dogs. Its expression and correlation with outcome in human osteosarcoma is currently being evaluated. Continued examination of the biology of ezrin in the mouse model found that it enhances cell motility and alters cell shape--features associated with metastatic behavior. Once the association of specific genetic changes with metastatic behavior in osteosarcoma is clearly established, drugs that inhibit activity can be identified, and genetic changes associated with metastatic behavior in other pediatric sarcomas can be identified and studied. (FY 1997 through FY 2003)


Childhood Leukemia

A large case-control study conducted in conjunction with the Children's Cancer Group (an NCI-funded clinical trials cooperative group) evaluated the role of exposures to extremely low frequency magnetic fields (50 or 60 Hertz) from power lines and electrical appliances in the risk of childhood leukemia. Neither high, directly measured residential magnetic field levels nor high wire code levels (a proxy measure for close distance of residence to power lines) were found to be associated with significantly increased risks of childhood ALL. A separate study showed no association of residential radon levels with childhood leukemia. Further analyses are being completed on other potential risk factors for childhood leukemia, including vaccinations and medical x-rays. (FY 1989 through FY 2001)

Pesticide Exposure in Children with Non-Hodgkin's Lymphoma (NHL)

The Children's Cancer Group conducted a study of children who developed NHL or leukemia and found a significant association between risk of NHL and increased frequency of reported pesticide use in the home, professional exterminations within the home, and postnatal exposure to pesticide. The results of the study provide further evidence linking pesticide exposure to the risk of NHL but do not implicate any specific agent. (FY 1996 though FY 2000)

Allergic Disorders & the Risk of Childhood Acute Lymphoblastic Leukemia (ALL)

Investigators compared the histories of selected allergic disorders (asthma, hay fever, food or drug allergies, eczema, and hives) in 1,842 cases of ALL. The results from this study, in agreement with most previous studies on adult cancer, suggested that allergic disorders are associated with a reduced risk of childhood ALL. Data from this study also suggested that genetic and/or environmental factors that cause allergic disorders may also be protective against ALL. (FY 1996 though FY 2002)


Development of Immunotherapy Treatment in Pediatric Sarcomas

Preclinical models demonstrated that small protein fragments (peptides) derived from chromosomal alterations could be specifically recognized by cytotoxic T lymphocytes (CTL), and in some cases the tumor could be eliminated from mice by these CTL. These findings led to the development of a clinical study in children with refractory or recurrent Ewing's rhabdomyosarcoma. Patients were given specific peptide vaccinations in an attempt to generate anti-tumor CTL. The preliminary findings provide some evidence that CTL can be generated using a targeted approach. Follow-up studies are needed to explore this new modality of treatment to further understand immune-mediated anti-tumor effects. (FY 1997 through FY 2003)

Cancer Control, Survivorship, and Outcomes

Studies of Families at High Risk of Cancer: Beckwith-Wiedemann Syndrome

Investigations of families and individuals at high risk of cancer often lead to etiologic clues that may be important in the general population. Families with multiple members who have an unusual pattern or number of cancers are evaluated clinically, and risk factor information is obtained. Current studies include research on Beckwith-Wiedemann syndrome, an overgrowth disorder that occurs approximately once in every 15,000 births. Children with this syndrome can be mildly to greatly affected and are at risk for developing hypoglycemia and various types of tumors. NCI recently published a brochure entitled "Living with Beckwith-Wiedemann Syndrome" that provides a brief overview of the disorder, explains the specialized care that these children may need, and outlines the resources available to help affected families. (FY 1994 through FY 2002)

Follow-Up of Childhood Cancer Survivors

To study the long-term impact of treatment for childhood cancer, children participating in clinical trials sponsored by the NCI-funded Children's Cancer Group were identified, and interviews were conducted with long-term survivors and their siblings. In this large cohort, younger female patients who received 1,800 cGy cranial radiation and those who received 2,400 cGy below the diaphragm experienced early or delayed menarche. Patients treated with 2,400 cGy cranial radiation experienced educational difficulties. Other long-term effects studied in this cohort include loss of fertility, birth defects, psychosocial outcomes, and general health problems. (Funding started FY 1990, duration is indefinite)

Heritable Retinoblastoma and Susceptibility to Radiation-Induced Bone Sarcoma

Bone sarcoma incidence data from patients treated for bilateral retinoblastoma by x-ray during early childhood are being analyzed and compared to that from patients treated by injection of 224Ra for tuberculosis and other benign diseases. Preliminary analyses suggest that heritable retinoblastoma patients, whose baseline risk of bone sarcoma is already high, are unusually susceptible to radiation-related bone sarcoma. (FY 1989 through FY 2002)

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children


Biology of Pediatric Hematopoietic Malignancies

Leukemias and lymphomas are among the most common pediatric malignancies. Although cure rates are excellent for a number of subtypes (e.g., ALL, Hodgkin's disease, Burkitt's lymphoma), long-term prognosis is poor for those who relapse or have disease that is refractory to standard therapy. A new collaborative analysis of gene expression patterns in pediatric leukemias was recently initiated to improve the understanding of the pathobiology of childhood leukemias. This effort could result in a better classification and risk stratification and will ultimately assist in the identification of novel therapeutic targets.

Pediatric Division of the Cooperative Human Tissue Network (CHTN)

Pediatric tumor specimens that have been carefully annotated with histopathologic and clinical data are critical to further research progress. The Pediatric Division of the CHTN collects tissue specimens and associated data from pediatric patients enrolled in trials nationwide, including trials involving rare pediatric tumors, and distributes them to qualified researchers throughout North America. Research made possible by the availability of these specimens includes:

  • The identification of p53 alterations as a molecular marker for anaplastic Wilms' tumor, a form of Wilms' disease with a very poor prognosis.

  • Studies to define novel genes and mechanisms associated with familial predisposition to Wilms' tumor.

  • Investigation of the diagnostic utility of cytogenetic abnormalities in primitive neuroectodermal tumors of the central nervous system.

  • Studies of the expression of the bcl-2 family of genes in neuroblastoma and their role in inhibiting chemotherapy-induced apoptosis.

  • Work to identify the molecular and prognostic significance of genetic translocations in rhabdomyosarcomas.
(FY 1988 through FY 2006)

Gene Expression Analysis in Sarcoma

NCI is supporting a comprehensive, population-based study of gene expression in high-risk bone and soft tissue sarcomas of children and adolescents, with the goal of constructing a "mesoderm-sarcoma" microchip array with genes relevant to diagnosis and treatment. This research is expected to define comprehensive molecular "signatures" associated with critical clinical questions in any cancer. (FY 2000 through FY 2005)

Molecular Classification of Leukemias

Research efforts are being conducted to identify cDNA microarray technology, multivariate clustering methods, and links to clinical databases to perform molecular classification of AML and acute lymphoid leukemia. Molecular signatures of therapeutic response or resistance, minimal residual disease, or the influence of specific genotypes or cytogenetic abnormalities will be sought. The Pediatric CHTN's partnership with the newly unified Children's Oncology Group (COG) should further facilitate pediatric cancer research by providing access to specimens from 94% of pediatric cancers in North America and up to two-thirds of all patients joining clinical protocols. (FY 2000 through FY 2005)

Oncogenes and Tumor Suppressor Genes in Childhood Malignancies

A chromosomal translocation, t(2;13), that creates the fusion protein PAX3-FKHR has been identified as an early event in the childhood cancer alveolar rhabdomyosarcoma. Activities are under way to determine how PAX3-FKHR functions as an oncogene and to identify the secondary genetic alterations that are required to induce a full tumor phenotype.

A novel germline p53 mutation (p53R337H) has been identified in a cluster of pediatric patients in southern Brazil who have adrenal cortical carcinoma (ACC). These patients lack features of the Li-Fraumeni syndrome, suggesting that p53R337H is functionally inactive only under the intracellular conditions found in the adrenal cortical cells, thus specifically predisposing patients to ACC. Planned studies will test this hypothesis by direct examination of the biochemical and biophysical properties of this mutant p53 protein. Transgenic mice that carry this mutation in the germline will be developed. (FY 1996 through FY 2006)


Swedish Childhood Cancer Study

Record-linkage of the Swedish Birth Registry and the Swedish Cancer Registry yielded 10,000 cases of childhood cancer (years 1973-1995). Nearly 2,000 cases of rare childhood cancers (500 lymphoma, 400 bone and connective tissue cancer, 300 Wilms' tumor, 250 neuroblastoma, 200 retinoblastoma, 130 germ cell tumors, and 50 hepatoblastoma) were matched to 10,000 controls with the same year of birth and same gender as their matched case. Analysis of perinatal variables will focus on conditions and characteristics of the mother (including cigarette use), conditions and characteristics of the newborn baby, and medical procedures in labor, delivery, and care of the newborn. (FY 1993 through FY 2003)

Fanconi Anemia (FA) and Other Hereditary Pediatric Bone Marrow Failure Syndromes as Models for Study of Carcinogenesis in Humans

A number of hereditary pediatric disorders predispose to bone marrow failure, acute leukemia, and unusual solid tumors (notably head/neck cancers and gynecological carcinomas) in adult survivors. This atypical pattern of second malignancies suggests that there may be important, but as yet uncharacterized, gene-environmental interactions in their pathogenesis. A new project will identify cancer-prone families before the appearance of cancer, by virtue of underlying genetic hematologic diseases. The prototype disorder will be FA, but other bone marrow failure syndromes such as Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita will also be studied. These disorders will be used as models of mechanisms of carcinogenesis in humans, and for investigation of the pathogenesis of neoplastic complications in these conditions. This project represents the first systematic, comprehensive, etiologically oriented, and epidemiologically grounded study of the cancers that complicate the hereditary bone marrow failure disorders of childhood. (FY 2001 through FY 2006)

The Pattern and Reproducibility of Recall for Past Exposures and Behavior for Two Different Intervals Between Childhood Cancer Diagnosis and Maternal Interview

Little is known about the etiology of most cancers occurring in children. In the past couple of decades, several environmental, occupational, and proxy factors for infections or immunological diseases have been linked with modest increases in risk of specific childhood cancers, but it is unclear whether these associations are etiologic or due in whole or part to recall bias or other forms of bias. The objective of this study is to establish the presence or absence of differential misclassification resulting from rumination bias by assessing the pattern of maternal responses to questions about prenatal and early infant diet, pre- and post-natal exposure to electrical appliances, maternal reproductive history, and other birth-related characteristics in relation to the timing of the maternal interview. A second objective is to assess the reproducibility of maternal responses to the topics listed above between two interviews of the mother approximately 6 months apart. The study will enroll 400 mothers of children newly diagnosed with leukemia, lymphoma, or brain tumors and randomize them into two groups: one to be interviewed within 14 days of diagnosis ("early") and the second to be interviewed 6 months after diagnosis ("late," as is currently done). Each group will also be interviewed using the same questionnaire six months after the initial interview. (FY 2002 through FY 2004)

Malignant Germ Cell Tumors (GCTs) in Children

The etiology of GCTs is poorly understood. Studies conducted among adult populations have suggested that certain prenatal exposures and parental occupational exposures may be associated with an increased risk of GCT. A proposed study will investigate risk factors for three types of GCT (testicular, ovarian, and non-gonadal) by utilizing resources available through the Children's Cancer Group. This study represents the first large epidemiologic investigation to study risk factors of childhood GCT and examines the interaction between genetic and environmental factors in the development of GCT. (FY 1996 through FY 2002)

Case-Control Study of Risk Factors for Wilms' Tumor

Wilms' tumor is the most common kidney tumor of childhood. Epidemiologic studies have suggested but not proven an environmental influence. A major aim of this study is to evaluate the role of specific paternal occupations and related exposures reported in previous studies as risk factors for Wilms' tumor. The most consistent associations have involved paternal employment as welders, mechanics, and machinists. Related exposures found in these and other occupations include metals and solvents. The study will evaluate maternal employment and related exposures to dyes, electromagnetic fields, solvents, and metals. (FY 1998 through FY 2003)

Epidemiology of Down Syndrome (DS) - Leukemia and DS

The environmental etiology of DS is largely unknown. DS children are run a nearly 20-fold increased risk of developing leukemia compared to children in the general population. Because only 1% of DS children ever develop leukemia, subsequent environmental exposures could be responsible for leukemia in this population. In the first case-control study (DS with leukemia compared to DS without leukemia), investigators will determine whether children with DS and leukemia share similar risk factors reported to be associated with childhood ALL and/or AML. In the second case-control study (DS compared to normal population), investigators will examine the potential risk factors for DS, including parental occupations, exposures, smoking, and alcohol use, among other factors. (FY 1997 through FY 2002)


Experimental Therapeutics of Pediatric Hematopoietic Malignancies

In an effort to develop new treatment strategies for pediatric hematopoietic malignancies, a number of clinical trials for patients with relapsed leukemias and lymphomas recently opened. These include phase I trials of arsenic trioxide and the farnesyl transferase inhibitor R115777, a phase II trial of intrathecal topotecan, and a pilot trial of non-myeloablative allogeneic stem cell transplantation. In addition, a trial is planned using a newly developed immunotoxin that targets CD22, a specific antigen found on the surface of approximately two-thirds of malignant cells in patients with ALL and NHL. These efforts promise to lead to the development of new, specific therapies for hematopoietic malignancies of childhood and adolescence. (Funding is indefinite)

Children's Oncology Group (COG) and Other Consortia

Nearly 90% of children with cancer in North America now have access to the state-of-the-art care provided by COG physician-researchers. Member institutions are located in almost every state, at more than 235 medical centers. These groups are currently achieving a cure rate of approximately 70% for children with cancer. The success of the pediatric cooperative group program can be measured by the continuing decline in childhood cancer mortality and by the continuing improvements in survival rates for many types of childhood cancer. Between 1989 and 1998, overall childhood cancer mortality declined by approximately 25%, with an approximately 30% decline in leukemia-related mortality and an approximately 50% decline in lymphoma-related mortality.

The primary objective of COG is to conduct clinical trials of new therapies for childhood cancer. Examples of research protocols under COG include: 1) a phase II randomized trial of standard versus dose-intensified chemotherapy for children younger than 3 years with central nervous system (CNS) malignancy, 2) development of intervention strategies to increase enrollments, 3) evaluation of topotecan given with cyclophosphamide to improve outcomes for children with rhabdomyosarcoma, and 4) evaluation of the duration of intensive chemotherapy required after remission is achieved in order to obtain a cure for ALL.

NCI also supports consortia of institutions conducting pediatric clinical trials to evaluate new agents in children with cancer. Of special note is the phase I evaluation of the Bcr-Abl tyrosine kinase inhibitor ST1571 for children with Philadelphia chromosome-positive leukemias. This group of leukemias has a particularly poor prognosis, and studies of ST1571 in adults have shown high levels of anti-leukemia activity at doses producing minimal toxicity. Several studies in this area are ongoing and others are planned. Examples include an upcoming pilot study that will combine ST1571 with conventional chemotherapy agents and a study that will evaluate the use of ST1571 combined with radiation therapy for children with high-grade gliomas.

Another very active consortium is the Pediatric Brain Tumor Clinical Trials Consortium. In 2000, this consortium's clinical trials included a phase I study of a molecularly targeted anti-angiogenic agent in children with recurrent brain tumors and a pilot study evaluating the use of intrathecal therapy given in combination with intensive chemotherapy as an alternative to radiation for infants. Future studies will focus on agents that target the molecular characteristics of cancer cells as well as neurosurgical approaches. (Funding started FY 1991, duration is indefinite)

Cancer Control, Survivorship and Outcomes

Genetic Epidemiology of Medulloblastoma

A study of patients with medulloblastoma was recently initiated in collaboration with researchers from NIH and the Children's National Medical Center, Washington, D.C. The study is clinically evaluating patients with this type of brain cancer, assessing risks for all types of cancer among family members; examining tumors for mutations in the PTCH, APC, or other candidate genes; and evaluating the relationship between molecular genetic alterations, tumor characteristics, response to chemotherapy and radiation treatment, and survival in

Previous Contents Next

Last Reviewed: February 1, 2005
Back to Top
Back to Top