Very little is known about human genes that can confer increased susceptibility or resistance to environmental carcinogens. Most exciting knowledge has been obtained from studies based on the much extensive experimental data obtained in laboratory animals. The studies proposed here are aimed at elucidating the genetic basis of the marked differences in the incidence of T-cell lymphoma among mice of certain inbred strains following percutaneous application of 3-methylcholanthrene (MA). The primary goal is to build upon our previous data indicating that a single dominant gene is the major determinant of relative resistance to MA lymphomagenesis and to map this gene. The goal will be studied first in an analysis of DNA from mice of a new set of recombinant inbred (RI) mice, SWXD1, by searching for correlations between MA lymphoma incidence and other genetic polymorphisms, primarily restriction fragment length polymorphisms detected by the use of probes for endogenous murine leukemia viruses, that are widely distributed among the chromosomes of mice. Similarly, this same approach will be applied to the analysis of DNAs from individual mice of a large backcross population segregating for the presence or absence of the MA resistance gene and observed for lymphoma after MA treatment. Another goal stems from experiments suggesting that this same resistance gene may play a role in resistance to lymphomagenesis by fractionated doses of whole body irradiation; this possibility will also be studied in the SWXD1 strains by comparing the lymphoma incidences in each strain after treatment with MCA vs. irradiation. A third goal involves the exploration of the genetic basis for the marked, genetically recessive hypersensitivity of mice of the RF/J strain to lymphomagenesis by a low total dose (200 rad) of fractionated irradiation, by comparison with other strains that are highly susceptible at higher doses but resistant at the low dose. We will pursue any suggestions of biological mechanisms that might be responsible for these differences in lymphoma resistance by attempting to correlate them with the distributions of the resistance genes.
| Kaelbling, M; Zhang, Y D; Dasgupta, U B et al. (1991) Nonrandom chromosome changes in methylnitrosourea (MNU) induced mouse T-cell lymphomas. Ann Genet 34:270-8 |
