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Novel genetic and epigenetic alterations in ... - Ous-research.no

Novel genetic and epigenetic alterations in ... - Ous-research.no Novel genetic and epigenetic alterations in ... - Ous-research.no

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11.07.2015 Views

Future PerspectivesMolecular risk assessmentIn addition to our protocol for identification of novel methylation markers, an ongoingproject is designed to allow for detection of markers rarely found in polyps but frequent incancer and as such may be used in risk assessment. A parallel study will analyze some of thenewly suggested biomarkers (including MAL) in a new clinical series obtained throughcollaboration with Stavanger University Hospital, including ~200 colorectal tumors and anaverage of 4 lymph nodes from each patient in order to examine the presence of thesebiomarkers in the lymph nodes. The aim of the study is to identify a subgroup of stage IIpatients with molecular evidence of lymph node metastases missed by conventionaldiagnostics. These will be designated high-risk stage II patients and are likely to benefit fromadjuvant chemotherapy.Quantitative and qualitative transcriptomics.The tumor transcriptome from patients in two prospective series from different time periodsare under analyses using in-lab Affymetrix Exon microarrays. The purpose is to compare thegene signatures of stage II and III colorectal carcinomas from a series collected during 1987-89 (n = 100), a period where no CRC patients received adjuvant chemotherapy, with thevalidation series from 1997-2003 (n = 100) in which stage III patients and some stage IIreceived adjuvant chemotherapy. The two groups of each series are stratified according toknown good or poor disease outcome. With this study design ethical issues regarding thedifferent use of treatment arms are avoided, and potentially we may identify those that willbenefit from surgery alone as well as those that will benefit from adjuvant treatment. Theexon arrays will also provide data for structural changes within individual genes, which maybe due to splice variants or fusion genes. Such changes may be cancer specific and incombination with epigenetic markers these may be used for cancer risk assessment after theinitial early tumor detection.The dynamic genetics and epigenetics of large bowel tumorigenesis.The challenge in analyses of large datasets obtained through high throughput technologies iseven more evident when integrating the various sets. However, such large data sets exist andmore will come. The biological value of the pinpointed genes and the transfer to clinicalapplications will depend on the quality of the study design, including the clinical sampling66

Future Perspectivesand follow up. Combining the molecular results with more detailed biology will improve ourunderstanding of the dynamics in genome stability during the development of a malignancyfrom a precursor lesion in the large bowel. The necessity of parallel functional studies can beexemplified by the last study of this thesis in which a marker is found associated with goodprognosis and currently we do not know why.67

Future Perspectives<strong>and</strong> follow up. Comb<strong>in</strong><strong>in</strong>g the molecular results with more detailed biology will improve ourunderst<strong>and</strong><strong>in</strong>g of the dynamics <strong>in</strong> ge<strong>no</strong>me stability dur<strong>in</strong>g the development of a malignancyfrom a precursor lesion <strong>in</strong> the large bowel. The necessity of parallel functional studies can beexemplified by the last study of this thesis <strong>in</strong> which a marker is found associated with goodprog<strong>no</strong>sis <strong>and</strong> currently we do <strong>no</strong>t k<strong>no</strong>w why.67

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