- Email: [email protected]
In search for a lung tumor suppressor gene.
228
Abstracts
26 MOLECULAR GENETICS OF LUNG CANCER Desmond N. Camey, M.D.,PH.D. The major advances over the past decade in lung cancer have been the greater understanding of the biological properties of both small cell (SCLC) and non-small cell (NSCLC) lung cancer. Studies of large panels of cell lines and fresh biopsy specimens have demonstrated the extreme heterogeneity which exists within these turnouts to a range of biologic properties and gives a better understanding of the molecular events which are present in this disease, including, chromosomal rearrangements and deletions; point mutations, gene amplifications and the altered gene expression. Detailed studies of SCLC cell lines have revealed two distinct subtypes, namely, classic and variant ceil lines. The latter cell lines are associated with a more aggressive growth behaviour both in vitro and in vivo; a selective loss of neuroendocdne markers; a relative resistance to radiotherapy; and cytogenic abnormalities including double minute chromosomes or HSR's. Studies of SCLC cell lines have revealed amplifications and/or overexpression of members of the myc-family of oncogenes - cmyc, N-myc and L-myc. Among variant SCLC cell lines amplication of C-myc was noted; while Nmyc and L-myc amplifications was more frequent in classic SCLC cells. No cell lines expressed both C-myc, N-myc or L-myc together, however, in studies of both fresh turnouts and cell lines, mycfamily oncogene abnormalities were more frequent in cell lines and in specimens obtained from heavily pretreated patients. The data suggests that the myc-family of oncogenes are not important eady events in the biology of SCLC, but may contribute to a more aggressive behaviour at relapse. A variety of other oncogenes have been detected in both SCLC and NSCLC (e.g. C-myb) but not in any high frequency. In NSCLC mutational ras activation has been found in 30% of adenocarcinomas, while overexpression of EGF receptors is common in all NSCLC cell types. A range of cytogenetic defects have been defined in lung cancer cells. In addition to many structural and numerical cytogenetic abnormalities, a comparison of tumour and normal tissue DNA's by RFLP probes has revealed loss of heterozygosity in chromosome regions 3p, 13q and 17p. Allele loss is highly suggestive of the presence of anti-oncogenes, and in both SCLC and NSCLC allele loss at both chromosome regions 3p and 17p is observed. In contrast inactlvations of the retinoblastoma gene on chromosome region 13q is found predominantly in SCLC. As studies have shown that the p53 gene located on chromosome 17p13 has many features of an antioncogene, a recent study of 30 cell lines of both SCLC and NSCLC has revealed functional inactivatlons of the p53 gene in 17 of 30 specimens, including both SCLC and NSCLC, including 20% of fresh biopsy specimens. While not unique, the findings of alterations in p53, and Rb gene in lung cancer cells suggests that these genes may be important in the pathogenesis of a range of human turnouts.
27 IN SEARCH
FOR A LUNG TUMOR S U P P R E S S O R
GENE.
K. Kok I, A. Jonas 2, A. vd Berg I, J. Osinga I, R. Hofstra I, K Gulati 2, B. Carritt 2, C.H.C.M. Buys I" iDeparment of Human Genetics, University of Groningen, The Netherlands. 2MRC Human Biochemical Genetics Unit, U n i v e r s i t y of London. Characteristic chromosome deletions, thought to be the location of tumor suppressor genes, are found in a number of d i f f e r e n t tumour types. In d i f f e r e n t forms of lung cancer we have c o n s i s t e n t l y found a d e l e t i o n of D3FISS2 at 3p21. We
Abstracts
26 MOLECULAR GENETICS OF LUNG CANCER Desmond N. Camey, M.D.,PH.D. The major advances over the past decade in lung cancer have been the greater understanding of the biological properties of both small cell (SCLC) and non-small cell (NSCLC) lung cancer. Studies of large panels of cell lines and fresh biopsy specimens have demonstrated the extreme heterogeneity which exists within these turnouts to a range of biologic properties and gives a better understanding of the molecular events which are present in this disease, including, chromosomal rearrangements and deletions; point mutations, gene amplifications and the altered gene expression. Detailed studies of SCLC cell lines have revealed two distinct subtypes, namely, classic and variant ceil lines. The latter cell lines are associated with a more aggressive growth behaviour both in vitro and in vivo; a selective loss of neuroendocdne markers; a relative resistance to radiotherapy; and cytogenic abnormalities including double minute chromosomes or HSR's. Studies of SCLC cell lines have revealed amplifications and/or overexpression of members of the myc-family of oncogenes - cmyc, N-myc and L-myc. Among variant SCLC cell lines amplication of C-myc was noted; while Nmyc and L-myc amplifications was more frequent in classic SCLC cells. No cell lines expressed both C-myc, N-myc or L-myc together, however, in studies of both fresh turnouts and cell lines, mycfamily oncogene abnormalities were more frequent in cell lines and in specimens obtained from heavily pretreated patients. The data suggests that the myc-family of oncogenes are not important eady events in the biology of SCLC, but may contribute to a more aggressive behaviour at relapse. A variety of other oncogenes have been detected in both SCLC and NSCLC (e.g. C-myb) but not in any high frequency. In NSCLC mutational ras activation has been found in 30% of adenocarcinomas, while overexpression of EGF receptors is common in all NSCLC cell types. A range of cytogenetic defects have been defined in lung cancer cells. In addition to many structural and numerical cytogenetic abnormalities, a comparison of tumour and normal tissue DNA's by RFLP probes has revealed loss of heterozygosity in chromosome regions 3p, 13q and 17p. Allele loss is highly suggestive of the presence of anti-oncogenes, and in both SCLC and NSCLC allele loss at both chromosome regions 3p and 17p is observed. In contrast inactlvations of the retinoblastoma gene on chromosome region 13q is found predominantly in SCLC. As studies have shown that the p53 gene located on chromosome 17p13 has many features of an antioncogene, a recent study of 30 cell lines of both SCLC and NSCLC has revealed functional inactivatlons of the p53 gene in 17 of 30 specimens, including both SCLC and NSCLC, including 20% of fresh biopsy specimens. While not unique, the findings of alterations in p53, and Rb gene in lung cancer cells suggests that these genes may be important in the pathogenesis of a range of human turnouts.
27 IN SEARCH
FOR A LUNG TUMOR S U P P R E S S O R
GENE.
K. Kok I, A. Jonas 2, A. vd Berg I, J. Osinga I, R. Hofstra I, K Gulati 2, B. Carritt 2, C.H.C.M. Buys I" iDeparment of Human Genetics, University of Groningen, The Netherlands. 2MRC Human Biochemical Genetics Unit, U n i v e r s i t y of London. Characteristic chromosome deletions, thought to be the location of tumor suppressor genes, are found in a number of d i f f e r e n t tumour types. In d i f f e r e n t forms of lung cancer we have c o n s i s t e n t l y found a d e l e t i o n of D3FISS2 at 3p21. We