liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
Molecular genetic alterations in chemically-induced lymphomas
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lymphoma is one of the most common malignancies in humans. Its incidence has increased rapidly in the past 30 years. However, the molecular mechanisms underlying the development of lymphomas are largely unknown.

Environmental carcinogens play an important role in tumorigenesis. 1,3-butadiene (BD) and 2~,3-dideoxycytidine (ddC) are two carcinogens to which humans are exposed. Cancer bioassays in mice have revealed that both BD and ddC induce high frequencies of lymphomas. The present study provides a genetic dissection of these chemically-induced lymphomas, with a focus on identification of potential turner suppressor loci and genetic alterations in genes involved in the pRb, p53 and Ras/Raf pathways. These pathways are important in the control of cell proliferation.

Approximately 87% of BD-induced and 75% of ddC-induced lymphomas show allelic losses or mutations in genes examined. Similar frequencies for inactivation of the p53 pathway were observed in BD- and ddC-induced tumors, whereas disruption of the pRb pathway is more common in ddC-induced lymphomas. On the other hand, BD-induced tumors display more frequent activation of the Ras/Raf pathway. These data indicate the genotoxicity of both ddC and BD, and also confirm the carcinogenicity of these chemicals at a molecular level.

This study also reveals that different genetic alterations occur in distinct stages of the development of BD-induced lymphomas. Ras mutations were detected in tumors derived from mice exposed to BD for only 26 weeks or at a rather low concentration (20 ppm), suggesting that ras mutations may occur early in tumor formation. In contrast, all six tumors with aberrations of p53 occurred in the high dose (625 ppm), continuous long-term exposure group, and these tumors appear to have a more aggressive phenotype, indicating that inactivation of p53 may be a late event, associated with progression of BD-induced lymphomas. Furthermore, two or more genetic alterations were found in 67% of tumors from the 625 ppm dose group and in only 46% of lymphomas derived from mice exposed to s312 ppm of BD. In addition, more than five genetic aberrations occurred only in the 625 ppm dose group. These results support the contention that there is a dose-dependent increase of genetic alterations in BD-induced tumors.

The mutational pattern resulting from carcinogen-exposure has been observed in both human and animal turners. In the present study, the specific K-ras codon 13 CGC mutation and allelic loss of the Rafl locus on chromosome 6 were detected only in BD-induced lymphomas, while frequent allelic loss of the telomeric region of chromosome 2 was observed only in ddC-induced tumors, suggesting an agent-specific effect.

The genome-wide screen of allelic losses revealed that multiple potential tumor suppressor genes contribute to the development of BD- and ddC-induced lymphomas. Moreover, most of the identified regions with frequent allelic losses carry unknown tumor suppressor genes, whose isolation and identification are of great interest for further investigation.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1999. , 68 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 607
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-25725Local ID: 10102ISBN: 91-7219-561-4OAI: diva2:246273
Public defence
1999-11-11, Elsa Brändströmsalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)

Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.

Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-11-09Bibliographically approved

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Zhuang, Shi-Mei
By organisation
Cell biologyFaculty of Health Sciences
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 31 hits
ReferencesLink to record
Permanent link

Direct link