Disputation and trial lecture - Terje Cruickshank Ahlquist

Cand.scient. Terje Cruickshank Ahlquist from Ragnhild A. Lothe's group at the Department of Cancer Prevention defended his PhD thesis entitled "Novel genetic and epigenetic alterations in colorectal tumors and their potential as biomarkers" on Wednesday May 13th.

His trial lecture - on the subject "Globale undersøkelser av genomforandringer i human cancer" was held the day before - on Tuesday May 12th.

Both lectures are available on web-TV:
Click here for PhD Thesis Presentation

Click here for Trial Lecture
Summary of the thesis:

Colorectal cancer (CRC) is the most common sex-independent cancer type in the world, and has a relatively poor 5-year survival of ~60%. The present study includes four papers presenting novel genetic and epigenetic changes during development of CRC. Some of these are suitable biomarkers for use in early detection and prognosis determination.

Using methylation-specific PCR, hypermethylation of three genes, ADAMTS1, MGMT and MAL was frequently found in precursor lesions as well as in carcinomas independent of microsatellite instability (MSI) status, but rarely in normal mucosa, making them promising early diagnostic biomarkers. In addition, hypermethylation of CRABP1, MLH1, NR3C1, RUNX3 and SCGB3A1 was shown to be identifiers of MSI tumors.

Alteration of the mitogen activated protein (MAP) kinase pathway is a hallmark of human cancer. A negative regulator of KRAS, NF1 encoding neurofibromin, is here for the first time examined in a series of CRC. By combining several techniques the whole coding region and flanking sequences were analyzed (>19kb), identifying alteration in >40% of CRCs. The majority of the mutations was found close to the intron-exon boundaries, and might cause alternative splicing. Overall, >70% of all CRC showed changes in one or more of the 4 analyzed genes (KRAS, BRAF, RASSF1A, and NF1) of the MAP kinase pathway

Patients with carcinomas of the MSI phenotype are known to have a better prognosis than those with microsatellite stable tumors. In order to identify a high-risk group among these patients, mutation analyses of 41 downstream genes were performed in MSI-tumors. The mutation status of gene, encoding a protein critical for correct spindle apparatus assembly, was found as an independent prognostic marker among patients with a localized disease, a finding also validated in an independent clinical series.
 
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