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Genetics of human cancer
Proceedings of the 34th Annual ASTRO Meeting
KEYNOTE MONDAY,
NOVEMBER
ADDRESSES
9, 1992
LESSONS FROM OUR CHILDREN
Sarah S. Donaldson, M.D. Department of Radiation Oncology; Stanford University School of Medicine; Stanford, CA 94305
While the incidence of cancer is increasing among both children and adults, mortality rates have decreased for children, while they have increased for adults. Of children diagnosed with cancer today, 80% are predicted to be long-term survivors. Although there are ditferences between children and adults with respect to the tumor types, biology and outcome, there are common lessons which we can learn from our children regarding the genetics of cancer, its management and treatment, and the importance of longitudinal studies of the survivors. Specific pediatric cancers, such as retinoblastoma, have led to the recognition of tumor suppressor genes, now also observed among adult tumors including sarcomas, breast, lung and bladder cancer. The presence of the tumor suppressor gene provides an understanding for the incidence of second malignant tumors among patients with heritable diseases. Furthermote, cancer prone families, such as those with the Li-Fraumeni syndrome, also carry the p 53 tumor suppressor gene; the presence of which greatly increases the risk of developing invasive cancer. Childhood cancer is rare; it represents only 1% of the total US cancer problem. However, 35% of all children with cancer, but only 2% of all adults, are studied via the NC1 cooperative group mechanism. For some specific childhood tumors such as rhabdomyosarcoma and Wilms’ tumor, as many as 70-85% of all cases are managed via NC1 sponsored trials. Essentially all pediatric cancer is treated by interdigitating radiation with surgical resection and systemic chemotherapy. This approach has contributed to high cure rates. Finally, our understanding of the late effects of being a carter survivor have come from longitudinal studies of children. The most severe long term effects related to radiation in childhood pertain to growth and development, infertility and second malignant tumor induction. Here the children treated for Hodgkin’s disease have demonstrated the dose and volume effects on axial skeletal and soft tissue growth. Infertility issues are treatment related and may often be obviated by using gonadal shielding. The risk of secondary leukemia is related to dose and class of specific chemotherapeutic agents administered; it is 5.5% among children receiving 6 cycles of MOPP. There is a 22 fold risk at 30 years of solid tumor induction following radiotherapy for Hodgkin’s disease. These serious concerns have been offset by current therapeutic approaches of using lower doses and smaller volumes of radiation with fewer cycles of less toxic chemotherapeutic agents. Childhood cancer ranks high among number of person-years of potential life saved annually. Currently, l:lC00 persons aged 15-45 is a cancer survivor, and in a decade more than 1% of the country’s work force will be a cancer survivor. The genetics, management and treatment, and follow-up of childhood cancer serves as an ideal model for our approach to adult cancer.
TUESDAY,
NOVEMBER
lo,1992
DIAGNOSTIC AND THERAPEUTIC TOOLS OF THE 21ST CENTURY Leroy Hood Center for Molecular Biotechnology, California Institute of Technology, Pasadena, CA 91125 As we move into the 21st century, medicine will undergo a revolution fueled by the Human Genome Project. This project, a complete analysis of our 24 different chromosomes, will define the 100,000 or so human genes and will begin to establish the nature of the regulatory machinery that controls their expression. These insights will fuel striking new approaches to the diagnosis and prevention of disease and, as well, the evolution of novel therapeutic approaches to some of Man’s most common diseases. I will discuss the Human Genome Project, the technological innovations that will be necessary to accomplish this project and the revolution it will initiate in clinical medicine.
117
KEYNOTE MONDAY,
NOVEMBER
ADDRESSES
9, 1992
LESSONS FROM OUR CHILDREN
Sarah S. Donaldson, M.D. Department of Radiation Oncology; Stanford University School of Medicine; Stanford, CA 94305
While the incidence of cancer is increasing among both children and adults, mortality rates have decreased for children, while they have increased for adults. Of children diagnosed with cancer today, 80% are predicted to be long-term survivors. Although there are ditferences between children and adults with respect to the tumor types, biology and outcome, there are common lessons which we can learn from our children regarding the genetics of cancer, its management and treatment, and the importance of longitudinal studies of the survivors. Specific pediatric cancers, such as retinoblastoma, have led to the recognition of tumor suppressor genes, now also observed among adult tumors including sarcomas, breast, lung and bladder cancer. The presence of the tumor suppressor gene provides an understanding for the incidence of second malignant tumors among patients with heritable diseases. Furthermote, cancer prone families, such as those with the Li-Fraumeni syndrome, also carry the p 53 tumor suppressor gene; the presence of which greatly increases the risk of developing invasive cancer. Childhood cancer is rare; it represents only 1% of the total US cancer problem. However, 35% of all children with cancer, but only 2% of all adults, are studied via the NC1 cooperative group mechanism. For some specific childhood tumors such as rhabdomyosarcoma and Wilms’ tumor, as many as 70-85% of all cases are managed via NC1 sponsored trials. Essentially all pediatric cancer is treated by interdigitating radiation with surgical resection and systemic chemotherapy. This approach has contributed to high cure rates. Finally, our understanding of the late effects of being a carter survivor have come from longitudinal studies of children. The most severe long term effects related to radiation in childhood pertain to growth and development, infertility and second malignant tumor induction. Here the children treated for Hodgkin’s disease have demonstrated the dose and volume effects on axial skeletal and soft tissue growth. Infertility issues are treatment related and may often be obviated by using gonadal shielding. The risk of secondary leukemia is related to dose and class of specific chemotherapeutic agents administered; it is 5.5% among children receiving 6 cycles of MOPP. There is a 22 fold risk at 30 years of solid tumor induction following radiotherapy for Hodgkin’s disease. These serious concerns have been offset by current therapeutic approaches of using lower doses and smaller volumes of radiation with fewer cycles of less toxic chemotherapeutic agents. Childhood cancer ranks high among number of person-years of potential life saved annually. Currently, l:lC00 persons aged 15-45 is a cancer survivor, and in a decade more than 1% of the country’s work force will be a cancer survivor. The genetics, management and treatment, and follow-up of childhood cancer serves as an ideal model for our approach to adult cancer.
TUESDAY,
NOVEMBER
lo,1992
DIAGNOSTIC AND THERAPEUTIC TOOLS OF THE 21ST CENTURY Leroy Hood Center for Molecular Biotechnology, California Institute of Technology, Pasadena, CA 91125 As we move into the 21st century, medicine will undergo a revolution fueled by the Human Genome Project. This project, a complete analysis of our 24 different chromosomes, will define the 100,000 or so human genes and will begin to establish the nature of the regulatory machinery that controls their expression. These insights will fuel striking new approaches to the diagnosis and prevention of disease and, as well, the evolution of novel therapeutic approaches to some of Man’s most common diseases. I will discuss the Human Genome Project, the technological innovations that will be necessary to accomplish this project and the revolution it will initiate in clinical medicine.
117