Molecular Search for Germ Cell Mutagenesis

Principal Investigator: John J. Mulvihill, MD

Abstract:

To date, no environmental agent has been proved to cause heritable germ cell mutation in human beings, not even in the long-time, multifaceted search for genetic effects among the offspring of the Japanese exposed to the US atomic bombs.  Yet, many persons with genetic disease are the first affected persons in their families.  Various environmental agents may cause germ cell mutation.  One suspected agent is cancer treatment.  We are attempting to determine whether or not cancer treatment causes germ cell mutation.  To accomplish this, we are recruiting adults between 18 and 55, who have children and had cancer in childhood or adolescence.  Their children and the other parent of their children will also be asked to participate and donate DNA.  Comparative genomic-wide mutation detection will eventually be done to identify any new mutation seen in offspring, but not in either parent.  Since the exact laboratory method has not been devised as yet, this proposal is for a repository of specimens.

Specific Aims

The null hypothesis is that available or future molecular, genome-wide assays will not detect any evidence of germ cell mutation that could reasonably be attributed to prior exposure of the parent to potentially mutagenic cancer therapy.  The alternative hypothesis and expected outcome is that such assays will reveal germ cell mutation that could be associated with the parent's cancer experience.  This outcome would confirm experimental germ cell mutagenesis in mice and evidence of persistent somatic cell mutation in human cancer survivors.  To begin addressing the issue of human germ cell mutagenesis through molecular genetic methods, we will collect and store blood, lymphocytes, and/or nucleic acid extracts from long-term survivors of cancer in childhood or adolescence, as well as on natural children they have had and the other parent of those children in the University of Oklahoma Genetics Laboratory under the direction of Dr. Shibo Li, Room BSEB 224.  Pari passu, we will collect and abstract information on the family medical history, the relevant details of therapy (types and doses of chemotherapy and radiotherapy), and other potential confounders.  Directly or via collaborations, we will apply genome-wide assays for comparative mutation detection within the triads of samples, to search for any genetic change that is present in the offspring's sample but not found in either parent.  Correlative evidence of somatic and germ cell mutation will be sought in blood and sperm cells from men who sired children.  This is expected to be a long-term project akin to the studies involving survivors of the atomic bomb exposure in Japan.  Studies are still being conducted on these individuals 60 years after the event.  Our suspected timeline after the 5 year data collection phase is between 10 and 20 years.

Participant Inclusion Criteria:

Having had a histopathologically proved malignant neoplasm (or clinically diagnosed central nervous system tumor), diagnosed under the age of 21 years, survived at least 5 years from date of diagnosis, showed no evidence of disease at last follow up, not known to have died, and born before 1987 (i.e., now over 17 years of age).

Participant Compensation:

No

Contact Information:

Matthew Grim  405/271-8685 Ext 42179 or e-mail matthew-grim@ouhsc.edu