Cloning of the X Chromosome's Putative Tumor Suppressor Gene
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Determining the genetic changes that occur in breast tumors should help to understand the mechanism of breast cancer, which in turn should elucidate novel approaches for cancer treatment. Nonrandom recurrent losses and gains of chromosomal segments in tumors are a consequence of mutational selection during the development and progression of abnormal cell growth.
 
 
 
 
 
 
 
 Chromosomal deletions play a role in the loss of tumor suppressor gene function and are generally thought to reflect the existence of a tumor suppressor gene within the lost region. In our previous studies, we observed losses of the q25 region of the X chromosome, which occurred in as many as 50% of breast tumors (the project was sponsored by the CA BCRP). The major part of one of the two X chromosomes is silent in females. Interestingly, the chromosomal segment losses we found occurred preferentially on the inactive X chromosome. The loss of the Xq25 region was significantly associated with the larger tumor size, higher histologic grade (the higher the "grade" the more abnormal the cell is) and axillary lymph node metastasis. 
 
 
 
 
 
 
 
 Our observation that the q25 region of the X chromosome is so frequently deleted in tumors means that this event provides the tumor cells with growth advantage necessary for cancer development. This indicates that the region contains a negative cell growth regulator, a so-called tumor suppressor gene, whose inactivation is required for the progression of the majority (at least 50%) of breast cancers. This is our central hypothesis. In addition, the gene inactivation seems to increase (or at least associate with) the tumor cells' ability to metastasize, and hence can be potentially used as a prognostic marker for metastasis. Obviously, identification of such a gene, which is involved in the development and progression of large number of breast tumors, is very important for understanding of tumor formation and progression (tumorigenesis), prognosis, and treatment of breast cancer.
 
 
 
 
 
 
 
 The general methodology in non-technical terms:
 
 
 
 We will use a candidate gene approach in the identification of the tumor suppressor gene. The human genome project provided chromosome maps with the positions of known and hypothetical genes. We know the X chromosome region (the one found deleted in breast tumors) where our gene is located, and because of the achievements of the human genome project, we have a list of genes located within this region. Now the goal is to find out which of those genes is the tumor suppressor gene. A basic criterion for a gene to be a putative tumor suppressor gene is its inactivation in tumor cells by means of mutational events or events that lead to the gene silencing. We will check the candidate genes in the region for the presence of such events.
 
 
 
 
 
 
 
 Innovative elements of the project in non-technical terms:
 
 
 
 The approach proposed in this study has previously been used for identification of tumor suppressor genes. The difference is that during the pre-human genome era the approach was very laborious and time consuming due to the absence of the complete knowledge of the human genome map and sequence. Currently, the approach has much more potential and promise for identification of cancer genes. Thus, it should rather be considered as "just in time" approach that may yield very important information.