Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-09-06
1999-09-21
Myers, Carla J.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 912, 536 231, 536 2431, 536 2433, C12Q 168, C07H 2104, C12P 1934
Patent
active
059552735
DESCRIPTION:
BRIEF SUMMARY
There is provided an extremely sensitive assay for the early detection of human cancer, of various types. The assay is based on the use of a molecular marker, designated as Gene H19, which is used for in-situ hybridization of a tissue sample and for indicating the absence or presence of a cancer and its grading by a suitable marker (probe). Also, a kit for carrying out such an assay is provided.
Despite intensive therapeutic efforts cancer death rates are increasing. In the US they went up by 7 percent between 1975 and 1990. Should this trend continue, by the year 2000 every third individual in the western countries will harbor a potentially fatal malignancy. A major reason accounting for treatment failure is its administration to patients with a biologically advanced disease. A deceivingly small one cubic centimeter of tumor contains about a billion cancer cells. As a rule, patient prognosis--i.e., risk of recurrence and death, is directly correlated with the extent of the disease at the time of diagnosis: the more advanced the disease, the poorer the patient's chances are. Only a strategy leaning heavily on a) prevention and b) early detection could result in substantial gains. Tile leads indicating the importance of an early diagnosis come from analysis of US as well as of Japanese statistics. In the former, cancers of the urinary bladder (TCC) and of the uterine cervix and in the latter stomach cancer have shown reduced mortality. These achievements are due to early diagnosis and to screening of populations at risk. Current diagnostic tools, besides physical examination, are mainly imaging by (conventional or CT) X-rays and ultrasonography. Usually, their resolution power can detect lesions only if larger than one cubic cm. Biochemical testing of tumor products released into the blood stream, tumor "markers", is considerably more sensitive. Likewise, specific staining of biopsied tissues can detect minimal disease.
Genomic imprinting--the uniparental transmittance of a genetic trait--plays a pivotal role in embryogenesis and fetal development, and has been linked to tumorigenesis and human disease. H19 is an imprinted gene in human, expressed from the maternal allele. It is extensively transcribed early in embryogensis and in certain fetal tissues, and its expression is shut off in postnatal life. The expression of H19 parallels, in general, the expression of insulin-growth-factor 2, to which it is tightly linked on chromosome 11pl5.5. The H19 gene does not encode for a protein and functions on an RNA molecule. Relaxation of imprinting of H19 has been demonstrated in Wilms' tumor as well as in troplioblastic neoplasia. We have studied the expression of H19 in several types of human cancer exhibiting features of tissues which expresses H19 in fetal life: transitional cell bladder tumors. Wilms' tumor and rhabdomayosarcoma, as well as gynogenetic germ cell tumors. Two low-grade transitional cell tumors of the urinary bladder did not express the gene, like in bladder mocosa of the adult. Prominent expression of H19 was evident in 3 intermediate-grade and 4 high-grade transitional cell carcinomas and in in-situ bladder carcinoma adjacent to invasive tumor. H19 was found to be expressed in nephrogenic rests in a kidney of aniridia syndrome and in Wilms' tumor, as well as in 4/6 cases of embryonal rhabdomyosarcoma. Expression of H19 was noted in epithelial and mesenchymal elements of immature ovarian teratoma which developed after excision of dermoid cyst, while the original tumor did not express the gene. Prominent expression of this gene was also noted in certain elements of testicular germ cell and stromal-sex cord tumors. Genomic imprinting is a newly discovered mechanism in genetics by which certain traits are selectively expressed either from the maternal or from the paternal genome. Genomic imprinting plays a pivotal role in early stages of embryogensis and implantation as well as in fetal development.
Am. J. Hum. Genet., (1993), 53: pp 1096-1102 discloses an assay for indicating the presence or absen
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Ariel Ilana
Hochberg Abraham
Hadasit & Medical Research Services & Development Company, Ltd.
Myers Carla J.
Yissum Research Development Company of the Hebrew University of
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