Tumors develop and progress as a result of alterations in oncogene and tumor suppressor genes. Knudson's two hit model predicts that cancer arises when both alleles of a tumor suppressor gene are inactivated. The insulin-like growth factor 2 receptor gene (IGF2R) is known to be a tumor suppressor for breast cancer, as mutations inactivating both alleles have been found in these tumors, consistent with its known functions in degrading insulin-like growth factor 2 (IGF2) and activating transforming growth factor beta1 (TGF-beta1), a growth inhibitor. Tumor suppressors can be inactivated by several means, such as genomic imprinting (a preferential silencing of a particular parental chromosome), large deletions resulting in loss of heterozygosity (LOH), and point mutations. In both humans and mice, IGF2R has gamete-of-origin dependent methylation which results in exclusive maternal expression in mice, while in humans imprinted expression is seen only in rare individuals and could be a predisposing factor for cancer. Since it is known that LOH plays a role in the genesis of breast cancer, we hypothesized that in some cases the event inactivating the other gene copy is parental imprinting. Our hypothesis predicted that this LOH is preferentially maternal and, therefore, the remaining allele is unmethylated. We tested this prediction in 20 breast cancer samples, thirteen of which (65%) were heterozygous and 9/13 (69%) had LOH. Two of 9 tumors (~22%) showed complete lack of methylation, consistent with LOH of the maternal allele. However, surprisingly and potentially significantly, normal tissue from the breast cancer patients was completely methylated in 4 samples and completely unmethylated in 2. This suggests that IGF2R methylation disruption may be a pre-existing, cancer-predisposing molecular lesion in the breast of these patients. More work is needed to exclude technical artifacts in reaching this conclusion.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.82218 |
| Date | January 2004 |
| Creators | Demian, Marie |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Human Genetics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002198700, proquestno: AAIMR12429, Theses scanned by UMI/ProQuest. |
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