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Circular DNA, chromosomal deletions and gene amplification
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Abstracts CIRCULAR DNA, CHROMOSOMAL DELETIONS AND GENE - 8 AMPLIFICATION, Geoffrey M. Wahl, Brad Windle and Bruce Draper, The Salk Institute for Biological Studies, La Jolla, CA A simple model for gene amplification will be presented in which molecular evidence for each step is provided. The model is likely to hold for many examples of gene amplification since the data have been obtained from studies of the amplification of endogenous genes in rodent and human cells. The first step involves a chromosomal deletion to generate an unstable extrachromosomal element. The elements replicate once per cell cycle, but are acentric and segregate randomly, The second step involves accumulation of these elements in cells in the presence of a selective environment. The initial elements can be submicroscopic, but they enlarge over time to form heterogeneously sized double minute chromosomes (DMs). The third step is integration of the DMs (or their precursors) to generate one or more expanded chromosomal regions. The model s compat b e w th a majority of the cytogenetic and molecular data concerning gone amolification in hamster, mouse and human cells. The deletion model for gene amplification suggests that loss of tumor suppressor genes by deletion and overproduction of protooncogenes by amplification may actually share common molecular intermediates.
*9
LOSS OF GENETIC INFORMATION IN CANCER. W.K. Cavenee, H.J. Scrable and C.D. James. Ludwig I n s t i t u t e f o r Cancer Research, Montreal, Quebec, Canada~ The determination and comparison of genotypic combinations at genomic l o c i in c o n s t i t u t i o n a l and tumor tissues from patients with various types of cancer have defined the chromosomal locations of l o c i in which recessive mutations play a r o l e in disease development. The predisposing nature of some of these mutant a l l e l e s is exemplified by studies of retinoblastoma and osteogenic sarcoma. These two c l i n i c a l l y associated diseases share a pathogenetic a l l y causal p r e d i s p o s i t i o n mapping to 13q14. A s i m i l a r mechanism i n v o l v i n g 11p15.5 is involved in the development of the embryonal v a r i a n t of rhabdomyosarcoma. Since the a l v e o l a r v a r i a n t does not share t h i s mechanism i t s use as a d i f f e r e n t i a l l y diagnostic i n d i c a t o r has been developed. F i n a l l y , genomic a l t e r a t i o n f o r chromosome 10 is apparent in glioblastomas and mixed tumors of glioblastoma/astrocytoma grade I I I but not in homogeneous astrocytoma grades I I or I I I ; suggesting the d e f i n i t i o n of a locus involved in tumor progression and, perhaps, an approach to molecular genetic staging of tumors.
Abstracts CIRCULAR DNA, CHROMOSOMAL DELETIONS AND GENE - 8 AMPLIFICATION, Geoffrey M. Wahl, Brad Windle and Bruce Draper, The Salk Institute for Biological Studies, La Jolla, CA A simple model for gene amplification will be presented in which molecular evidence for each step is provided. The model is likely to hold for many examples of gene amplification since the data have been obtained from studies of the amplification of endogenous genes in rodent and human cells. The first step involves a chromosomal deletion to generate an unstable extrachromosomal element. The elements replicate once per cell cycle, but are acentric and segregate randomly, The second step involves accumulation of these elements in cells in the presence of a selective environment. The initial elements can be submicroscopic, but they enlarge over time to form heterogeneously sized double minute chromosomes (DMs). The third step is integration of the DMs (or their precursors) to generate one or more expanded chromosomal regions. The model s compat b e w th a majority of the cytogenetic and molecular data concerning gone amolification in hamster, mouse and human cells. The deletion model for gene amplification suggests that loss of tumor suppressor genes by deletion and overproduction of protooncogenes by amplification may actually share common molecular intermediates.
*9
LOSS OF GENETIC INFORMATION IN CANCER. W.K. Cavenee, H.J. Scrable and C.D. James. Ludwig I n s t i t u t e f o r Cancer Research, Montreal, Quebec, Canada~ The determination and comparison of genotypic combinations at genomic l o c i in c o n s t i t u t i o n a l and tumor tissues from patients with various types of cancer have defined the chromosomal locations of l o c i in which recessive mutations play a r o l e in disease development. The predisposing nature of some of these mutant a l l e l e s is exemplified by studies of retinoblastoma and osteogenic sarcoma. These two c l i n i c a l l y associated diseases share a pathogenetic a l l y causal p r e d i s p o s i t i o n mapping to 13q14. A s i m i l a r mechanism i n v o l v i n g 11p15.5 is involved in the development of the embryonal v a r i a n t of rhabdomyosarcoma. Since the a l v e o l a r v a r i a n t does not share t h i s mechanism i t s use as a d i f f e r e n t i a l l y diagnostic i n d i c a t o r has been developed. F i n a l l y , genomic a l t e r a t i o n f o r chromosome 10 is apparent in glioblastomas and mixed tumors of glioblastoma/astrocytoma grade I I I but not in homogeneous astrocytoma grades I I or I I I ; suggesting the d e f i n i t i o n of a locus involved in tumor progression and, perhaps, an approach to molecular genetic staging of tumors.