Analysis of a candidate lung tumor suppressor gene at 3p21.3
Abstracts
Initial Award Abstract |
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Lung cancers are strongly associated with cigarette smoking. In order to understand how cigarette smoke components cause lung cancer and other smoking-related cancers, it is necessary to understand the sequence of molecular events that leads to formation of a tumor many years or decades later. According to current thinking, a number of genes need to be mutated or functionally disabled before a normal cell loses all normal growth control mechanisms and is brought onto a path of uncontrolled cell division eventually leading to a tumor. Gene mutation or inactivation has been found in genes such as p53, ras, and p16 at a relatively high frequency in human lung cancer.
However, the most common and earliest chromosomal change in the development of lung tumors has been mapped to the short arm of chromosome 3, in an area designated as 3p21.3. At this location, a specific chromosomal area is often deleted in lung cancer, and sometimes even both copies of this chromosomal material are lost. This phenomenon often hints at the presence of a tumor suppressor gene, which needs to be lost or inactivated completely in order for a tumor to arise.
We have cloned a new gene from the common chromosomal deletion area of chromosome 3p21.3. The gene has 50% homology to one other protein that interacts with the ras oncogene product. We do not know much about the function of this gene yet, except the following: 1) It is inactivated in a high percentage of human lung cancers (up to 100% of small cell carcinomas). 2) It suppresses cell growth when put back into lung cancer cells.
We will investigate further how this gene is inactivated in different types of lung cancers and in head and neck tumors. We will try to define its biochemical function in the cell. Finally, in order to test its presumed function as a tumor suppressor, we will delete this gene in the mouse and see if these mice develop tumors, either spontaneously or after exposure to cigarette smoke carcinogens.
The study should increase our understanding of the mechanisms of lung cancer initiation. If the causes of smoking-associated cancers are better understood at the molecular level, more efficient early screening procedures and future gene therapy approaches may be developed. |
Final Report |
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In order to understand how cigarette smoking causes lung cancer, it is necessary to understand the sequence of molecular events that leads to formation of a tumor. According to current thinking, a number of genes need to be mutated or functionally disabled before a normal cell loses all normal growth control mechanisms and is brought onto a path of uncontrolled cell division eventually leading to a tumor. Gene mutation or inactivation has been found in genes such as p53, ras, acid p16 at a relatively high frequency in human lung cancer. However, the most common and earliest chromosomal change in the development of lung tumors has been found at the short arm of chromosome 3, in an area designed as 3p21.3. At this location, a specific chromosomal area is often deleted in lung cancer, and sometimes even both copies of this chromosomal material are lost. This phenomenon often hints at the presence of a tumor suppressor gene, which needs to be lost or inactivated completely in order for a tumor to arise.
We have cloned a new gene from the common chromosomal deletion area of chromosome 3p21.3 named Ras association domain family 1 (RASSFI). The gene has 50% homology to one other protein that interacts with the ras oncogene product. Two major alternative transcripts originate from the RASSF1 locus, RASSFIA and RASSFIC.
The aim of this one-year award was to further investigate the role of RASSF 1 A in the pathogenesis of tobacco-related cancers. Towards this aim, we have initially focused on a small cell lung cancer, one of the most deadly forms of the disease. In small cell lung cancer, about 90% of the cases show loss of genetic material in 3p21.3 on one of the chromosomes. We found that, consistent with this high frequency of chromosomal aberration, there is inactivation of the RASSF 1 A gene by DNA methylation in 22 of 28 primary small cell lung carcinomas analyzed (=79%). These findings point to an important role of the RASSFIA gene in the pathogenesis of small cell lung cancer.
We have also made progress towards creating knockout mice for the RASSFI gene. We constructed the gene targeting vectors for selective knockout of isoforms RASSFIA and RASSFIC, as well as for the combined knockout of isoforms A and C. Homologous recombination was obtained in embryonic stem cells and these clones have been injected into the blastocysts of mice. The first mice with a deletion of RASSFI gene on one chromosome have been borne. They will be mated to produce homozygous knockout mice. |
Publications
| The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas |
| Periodical: Oncogene |
Index Medicus: |
| Authors: Dammann R, Takahashi T, Pfeifer GP |
ART |
| Yr: 2001 |
Vol: 20 |
Nbr: |
Abs: |
Pg: 3563-3567 |
| Hypermethylation of the CpG island of RASSF1A, a putative tumor suppressor gene from the 3p21.3 locus, occurs in a large percentage of human breast cancers |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: Dammann R, Yang G, Pfeifer GP |
ART |
| Yr: 2001 |
Vol: 61 |
Nbr: |
Abs: |
Pg: 3105-3109 |
| The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas |
| Periodical: Oncogene |
Index Medicus: |
| Authors: Dammann R, Takahashi T, Pfeifer GP |
ART |
| Yr: 2001 |
Vol: 20 |
Nbr: |
Abs: |
Pg: 3563-3567 |
| Hypermethylation of the CpG island of RASSF1A, a putative tumor suppressor gene from the 3p21.3 locus, occurs in a large percentage of human breast cancers |
| Periodical: Cancer Research |
Index Medicus: |
| Authors: Dammann R, Yang G, Pfeifer GP |
ART |
| Yr: 2001 |
Vol: 61 |
Nbr: |
Abs: |
Pg: 3105-3109 |
