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

Discussionmarkers with a very high specificity, such as SEPT9, are needed. Ideally, tissue specificmarkers should be included as well. One way of reducing the chance of non-specific positivehits is to use a combination of markers and apply stringent criteria for positive scoring.In addition to MAL (Paper I), five additional markers with similar potential of highsensitivity and specificity are recently identified and validated in colorectal tissue samples inour lab (Lind et al., unpublished). In combination, we may score a tumor as positive if two ofthe 6 markers are positive. By this we approach 93% of both carcinomas and adenomas arepositive and 96% of all normal samples are negative.Prognostic markersTumor features which can predict prognosis are valuable in the clinic. But to date none ofthe known molecular markers for colorectal cancer are in clinical use, with the exception ofmonitoring plasmatic CEA levels and genetic testing of known hereditarysyndromes[130;179]. One of the major problems with molecular marker studies is that manyhave limited power, analyzing only small numbers of tumors. Another factor is that the samemarkers are analyzed with different technologies, which may bias the end results. In spite ofthis, several markers have shown a prognostic potential, including APC, TP53 and MSIstatus. A study has shown that patients presenting tumors with an APC mutation beforecodon 1000 have a shorter cancer-related survival compared to the ones with mutation afterthis codon[180]. Most APC-mutations are truncating, and those that occur before codon1000 will cause all the ten -catenin binding sites to be lost. This will most likely result in astronger deregulation of the WNT-signaling pathway. A similar finding is seen for TP53where mutations within the L3 zinc-binding domain are associated with a worse patientprognosis compared to those with mutations outside this domain[181;182]. A largeinternational study has shown that among the twelve possible mutations at codon 12 inKRAS, only the G12V mutation is found to have a significant impact on failure-free andoverall survival[183]. The molecular marker closest to a prognostic role in the clinic isprobably MSI status. A meta-analysis of 32 studies and over 7500 cases confirmed that MSIis significantly associated with good prognosis[59].56