We have recently reported the activation of a new oncogene in human papillary thyroid carcinomas. This oncogene, papillary thyroid carcinoma (PTC), is a novel rearranged version of the ret tyrosine-kinase protooncogene. Thyroid neoplasms include a broad spectrum of malignant tumors, ranging from well-differentiated tumors to undifferentiated anaplastic carcinomas. To determine the frequency of ret oncogene activation, we analyzed 286 cases of human thyroid tumors of diverse histologic types. We found the presence of an activated form of the ret oncogene in 33 (19%) of 177 papillary carcinomas. By contrast, none of the other 109 thyroid tumors, which included 37 follicular, 15 anaplastic, and 18 medullary carcinomas, and 34 benign lesions, showed ret activation. (J. Clin. Invest. 1992. 89:1517-1522
Cytogenetic studies have shown frequent clonal abnormalities in papillary carcinoma (PFC)
RET/PTC is a transforming seque cated by the fusion of the tyrosine inase domain of the RET protooncogene with the 5' end of the locus DIOS170 dI by probe H4 and is frequently found activated in human papillary thyroid carcinomas. RET and DIOS)70 have been mappe to us region of the long arm of chromosome 10: qll.2 and q21, respectively. To identify the mechanis leadin to the generation ofthe oncogenic seqe RET/PTC, a combined cytogenetic and molecular analysis of several cas of papillary thyroid cadnomas was done. In four cases the results ted that these tumors had RET/PTCactivatlon and a paracentric inversion of the long arm of chromosome 10, inv(lO)(qll.2q21), with breakpoints coinddent with the regions where RET and DIOSi70 are located.Therefore, a chromosome lOq inversion provides the stural basis for the DIOS170-RET fusion that forms the hybrid transform sequence RET/PTC.In some forms of cancer, chromosome rearrangements have provided the structural basis of their molecular pathogenetic mechanisms. In particular, in hematologic malignancies, chromosomal translocations result in deregulation of the expression ofthe cell-growth-related genes c-MYC and BCL2 in Burkitt and in follicular lymphomas, respectively (1-3). In other instances, the translocation may generate chimeric transforming transcripts as in the case of the BCR-ABL fusion protein found in chronic myelocytic leukemia (4).In solid tumors, however, only rarely have chromosome aberrations been analyzed at the molecular level. The most relevant examples include the chromosomal deletions found to inactivate one or both copies of tumor-suppressor genessuch as RB in retinoblastoma, WTI in Wilms tumor, and DCC in colon carcinoma (5).The only example of generation of chimeric transforming sequences in solid tumors is tie activation of c-MET on chromosome 7 by the TPR gene that maps to chromosome 1 (6). However, this event, most likely a chromosomal translocation, has been generated in vitro by treatment of the original human osteogenic sarcoma cell line (HOS) with a chemical carcinogen (7). In other cases the rearrangements giving rise to the transforming fusion products have been generated during the transfection procedures, as in the case of RET (8,9). When a similar genetic event occurred somatically in the original tumor DNA, like the fusion between the nonmuscle tropomyosin sequence and the tyrosine kinase domain of proto-TRK gene (10), no chromosomal aberrations were identified to provide a model for the relative mechanism.We have reported (11) the occurrence in papillary thyroid carcinomas of specific rearrangements of the tyrosine kinase domain of the proto-RET gene with an unknown "gene" DJOS170, identified by probe H4 and originally designated the chimeric transforming sequence as PTC11, but here designate it as RET/PTC. In two distinct sets of experiments, RET/PTC activation was found in =25% of papillary thyroid carcinomas (12, 13) and represented a tumor-specific somatic event, being detected in the original DNA of both primary tumors ...
State Supreme Courts require a minimum threshold of reliability and acceptance in the scientific community for all medical and similar evidence to be admitted at trial. In Florida and some other states, the courts adhere to what is known as the Frye standard, whereas in most states and in Federal Courts, it is the so-called Daubert standard. The jurisdiction of the present case is Hillsborough County (Tampa), Florida. Forensic pathologists seldom, if ever, are requested to participate in such hearings, unlike their toxicological and basic science colleagues who are more involved in research methodology and technical procedures. The burden is on the proponent of the evidence to prove the general acceptance of both the underlying scientific principle of the test and procedures used to apply that principle to the facts of the case at hand. The trial judge has the sole discretion to determine this question and general acceptance must be established by a preponderance of the evidence. The authors describe in detail a hearing in a case in which they were all involved. One author (WQS) had researched and documented the original scientific methodology in the literature. The situation involved a car and tractor trailer crash with the two occupants of the car dying of multiple trauma, whereas the truck driver was not injured. Autopsy of the auto driver revealed multiple injuries with exsanguination, and only vitreous humor and liver tissue, but not blood, were tested for ethyl alcohol. The estate of the driver of the automobile brought suit against the owner of the trucking company for wrongful death. The plaintiff requested a Frye hearing to question the reliability of testing other body specimens to translate to probable blood alcohol level. The testimony, submitted documents, and eventual decision by the judge are discussed.
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