The application has as its primary long term objective the development of a generalizable technique for measuring minimal disease in human neoplasia. This will be accomplished through the combination of two techniques, DNA fingerprinting and polymerase chain reaction (pcr) amplification. The technique will exploit the genetic instability seen in neoplastic cells, which has already been demonstrated to yield differences between DNA fingerprint patterns from normal and neoplastic cells in the same patient. The studies will first focus upon acute non-lymphocytic leukemia (ANLL). ANLL has been chosen as it is a potentially curable disorder which has a great deal of genetic instability. The immediate specific aim of the project is to develop the technique for detection of minimal residual disease in ANLL. This will be accomplished by comparing fingerprint patterns from normal and leukemic cells from the same patient using probes for DNA sequences flanking iterated minisatellite sequences. Oligonucleotide primers will then be utilized to detect minimal residual disease in remission samples by pcr amplification. One can then determine whether detection of residual disease in ANLL is of prognostic significance. Following these initial studies we will then attempt to apply the technique to other tumor types, including solid tumors such as breast and colorectal carcinoma. These studies have both clinical and basic scientific implications. The technique may provide important prognostic information, and may help clinicians to determine the optimum timing of therapy. Important information regarding the sequences of recombination sites, the degree of genetic instability in neoplastic cells, and the contribution of the genetic instability to the tumor phenotype may be addressed.
| Mashal, R D; Koontz, J; Sklar, J (1995) Detection of mutations by cleavage of DNA heteroduplexes with bacteriophage resolvases. Nat Genet 9:177-83 |
| Mashal, R D; Fejzo, M L; Friedman, A J et al. (1994) Analysis of androgen receptor DNA reveals the independent clonal origins of uterine leiomyomata and the secondary nature of cytogenetic aberrations in the development of leiomyomata. Genes Chromosomes Cancer 11:1-6 |
| Mashal, R D; Lester, S C; Sklar, J (1993) Clonal analysis by study of X chromosome inactivation in formalin-fixed paraffin-embedded tissue. Cancer Res 53:4676-9 |
