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Cancer Genomics - Molecular Analysis of Epithelial Cells
KTH, Superseded Departments, Biotechnology.
2004 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Cancer is a disease involving multiple causal andsymptomatic genetic changes, collectively reflecting theselective pressures that occur during tumor development.Epithelial cancers are by far the most common type of cancerworldwide and investigation of the alterations associated withepithelial carcinogenesis will ultimately lead to improvementsin diagnosis, prognosis, prevention and treatment of thedisease.

This thesis describes structural and functional studies ofthe genome in minute amounts of defined cancerous material inorder to obtain accurate genetic profiles of heterogeneouscancer specimens. The focus has primarily been on the geneticanalysis of epithelial pre-cancers and cancers of the skin andcervix, including epidermal p53 clones, actinic keratosis (AK),cervical intraepithelial neoplasia (CIN), cancer in situ (CIS),squamous cell carcinoma (SCC), and basal cell carcinoma (BCC).In addition, normal and cancer cell lines of epithelial originwere utilized for in vitro studies. A range of genomictechniques were evaluated and applied toinvestigate theunderlying mechanisms that contribute to, or counteract, thecancer phenotype.

Comparisons between cancerous and normal conditions included(i) screening of non-synonymous polymorphisms in coding regions(cSNPs) of the tumor suppressor genes p53 and PTCH, whichpotentially confer an increased risks for developing epithelialcancer (ii) assessment of preferential allelic loss ofheterozygozity (LOH) (iii) determination of the infectionstatus by oncogenic human papilloma viruses of different types(iv) genetic analysis of the p53 mutation spectra in epidermalp53 clones (v) elucidation of functional genomic alterationsand mechanisms that underlie the proliferation arrest andaccelerated differentiation that is induced by antioxidanttreatment.

In these investigations the pyrosequencing technique wasevaluated for its utility in screening and scanning SNPs andwas subsequently applied along with Sanger DNA sequencing andviral allele-specific amplification in the case-control andmutational studies outlined above. Microarray technology,perhaps one of the most extensively utilized high-throughputformats for research purposes today, was used for global geneexpression analysis of treated and untreated cell cultures. Asdemonstrated in the studies included in this thesis, themultihit nature of cancer requires numerous methods tooptimally address all the various types of genetic andtranscriptional changes that may be involved.

Key words: SCC, BCC, HPV, p53, PTCH, single nucleotidepolymorphism (SNP), pyrosequencing, DNA sequencing, loss ofheterozygozity (LOH), functional genomics, transcriptionalprofiling, DNA microarray

Place, publisher, year, edition, pages
Stockholm: Bioteknologi , 2004. , 88 p.
Keyword [en]
DNA microarray, Pyrosequencing
URN: urn:nbn:se:kth:diva-3783ISBN: 91-7283-728-4OAI: diva2:9635
Public defence
2004-06-04, 00:00
Available from: 2004-06-02 Created: 2004-06-02 Last updated: 2012-03-20

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