Transgeneration transmission of carcinogenic risk

Molecular analysis of human tumors suggests that multiple genetic changes are required for a normal cell to become malignant (1). The multistage nature of carcinogenesis implies that cells which contain one or a few genetic mutations may behave normally; several other genetic insults are required to confer the tumor phenotype. It can be postulated that genetic damage may occur in germ cells but not be expressed until further genetic events occur in postnatal life. This sequence is potentially relevant for cancer prevention. Transmission of carcinogenic risk is best demonstrated by cancer-prone families. The best-known cancer syndrome is hereditary retinoblastoma, for which germ cell alterations of the Rb gene have been identified (2). A recent study suggests that germ-line mutations of the p53 gene are responsible for the Li — Fraumeni syndrome, an association of tumors including breast cancer and soft tissue sarcomas (3). Transgenic mice that harbor activated oncogenes have been constructed (reviewed in 4). The appearance of multiple tumors in these mice suggests that transgenerational transmission of genetic alterations may lead to cancer. Genetic alterations of germ cells predisposing to cancer may result from intrinsic genetic instability or from exposure to mutagens (5). It is our principal aim to consider the possible effect of mutagenic carcinogens on germ cells as the origin of genetic predisposition to cancer. The possibility of germ-line transmission of the effects of exogenous carcinogens has attracted renewed attention due to the recent report by Gardner et al. (6) of a significant increase in leukemia incidence among children whose fathers had worked at the Sellafield nuclear plant. Transgenic transmission of carcinogenic action of exogenous agents in experimental animals has been described by several authors (reviewed in 5). In epidemiological and experimental animal studies, exposure to carcinogens prior to conception is emphasized. Little is said about the possible interactions of pre-and postnatal exposures, in spite of the currently accepted hypothesis of multistage and multifactorial carcinogenesis. We review here the current evidence for multigeneration carcinogenesis. The proceedings of a recent meeting on this subject are available as an IARC Scientific Publication (7).