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Introductionpopulation-wide screening program. The obstacles of this method are the cost andavailability of trained personnel, as well as reduced compliance over time. Randomized trailsdesigned to determine the efficacy with regards to incidence and mortality are thereforeneeded in order to justify the use of colonoscopy as a population based screeningprogram[123].The presence of occult blood in feces is considered an indication of CRC, and a fecal occultblood test (FOBT) is already in use as a screening program in several countries. FOBT isshown to reduce mortality by CRC with 15-33%, but the need for biannual testing hasresulted in a decrease in patient compliance over time and lower the effect of thescreening[123]. With different FOBT technologies, variable levels of sensitivity are obtained,ranging from 5%-99%, while specificity is somewhat higher 65%-99%[124;125]. Suchdiverse results indicate that the test is highly dependent on optimal sample preparation andanalysis. It also gives both a relatively high degree of false positive and false negativefindings. Positive predictive value, or precision rate, is the proportion of patients with whoare correctly diagnosed. It is the most important measure of a diagnostic method as itreflects the probability that a positive test reflects the underlying condition being tested for,and a high degree of false positives will make the precision rate decrease. On the contrary,negative predictive value is the proportion of patients with negative test results who arecorrectly diagnosed and in the same manner, a high rate of false negatives will impair thisnumber. A low precision rate results in unnecessary colonoscopies, hence reducing the costeffectiveness of FOBT screening. Also, FOBT will not detect benign precursor lesions[123].The requirement for better biomarkers is therefore needed from an early detection screeningperspective. A marker with both high sensitivity and specificity will not only prevent extracosts due to unnecessary colonoscopies, but may also increase the time-intervals betweenrepeated tests. Finally, optimal biomarkers should also be present in benign precursor stagesand thereby increase the time-window in which removing the polyp is considered curative.Prognostic and predictive markersSurvival is as mentioned associated with tumor phenotype, as patients with MSI tumorsgenerally have improved prognosis compared to patients with MSS tumors[59]. In addition,5-flurouracil (5-FU) based chemotherapy does not seem to provide survival benefits among34
Introductionpatients with MSI tumors, neither in stage II nor in stage III colon and rectal cancer [126-128]. There are also survival differences within the MSI-group. In order to further improveprognosis and treatment of this group as a whole it is important to identify those MSItumors with the worse prognosis which will benefit from non-5-FU based chemotherapy inthe future.In 1997, adjuvant chemotherapy was introduced in Norway for a subset of the CRC patients.Today, with some exceptions, patients with stage I or II receive surgery alone which isconsidered curative. Patients with metastasis to lymph nodes (stage III) receivechemotherapy in addition to surgery (adjuvant chemotherapy). Different regimes ofchemotherapy exist, and the most common is 5-FU/leucovorin in combination withoxaliplatin in patients under 75 years of age[129]. Some stage II patients are also offeredchemotherapy when an insufficient number of lymph nodes (< 8) are analyzed for presenceof cancer cells. In order to better pinpoint which patients within stage II and III that wouldbenefit from chemotherapy optimally designed studies are needed which can result inimproved markers. A flow-chart describing present and possible future elements in CRCdiagnostics and choice of treatment is illustrated in Figure 12.35
Page 1 and 2: Novel genetic and epigenetic altera
Page 3 and 4: TABLE OF CONTENTSACKNOWLEDGEMENTS .
Page 5 and 6: ACKNOWLEDGEMENTSThe present work ha
Page 7 and 8: Prefacetechnology[3]. This new tech
Page 10 and 11: SummaryThe subgroup of carcinomas w
Page 12 and 13: Introduction“Epigenetic inheritan
Page 14 and 15: Introductionamino acid change it is
Page 16 and 17: Introductionmethylation during embr
Page 18 and 19: IntroductionDNA is most of the time
Page 20 and 21: IntroductionFigure 5. DNA methylati
Page 22 and 23: IntroductionFigure 6. Incidence rat
Page 24 and 25: IntroductionFigure 8. Tumor staging
Page 26 and 27: Introductioninasmuch as 80% of colo
Page 28 and 29: IntroductionInstabilities involved
Page 30 and 31: Introductionthere seems to be a fid
Page 32 and 33: Introductionsevere alterations are
Page 36 and 37: IntroductionFigure 12. Present and
Page 38 and 39: RESULTS IN BRIEFPaper Ia. “DNA hy
Page 40 and 41: Results in Briefinstability, and se
Page 42 and 43: Results in BriefUnivariate survival
Page 44 and 45: Discussionseveral factors, and full
Page 46 and 47: Discussionlow threshold, we increas
Page 48 and 49: DiscussionIt may seem like unnecess
Page 50 and 51: Discussionthan 96% DHPLC do not sta
Page 52 and 53: DiscussionFigure 13. Mutation detec
Page 54 and 55: DiscussionClinical impact of molecu
Page 56 and 57: Discussionmarkers with a very high
Page 58 and 59: Discussionchromosomes in metaphase[
Page 60 and 61: DiscussionThese examples underline
Page 62 and 63: Discussiongenes. One is based on mu
Page 64 and 65: CONCLUSIONSWe have identified novel
Page 66 and 67: Future PerspectivesMolecular risk a
Page 68 and 69: REFERENCES1. Breasted J (1930) The
Page 70 and 71: References29. Deng G, Chen A, Pong
Page 72 and 73: References57. Al-Sukhni W, Aronson
Page 74 and 75: References84. Kunkel TA (1993) Nucl
Page 76 and 77: ReferencesLeggett B, Levine J, Kim
Page 78 and 79: References133. Lind GE, Thorstensen
Page 80 and 81: References156. Meling GI, Lothe RA,
Page 82 and 83: ReferencesT, Song X, Day RH, Sledzi
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References196. Honda S, Haruta M, S
Page 86 and 87:
ORIGINAL ARTICLESAPPENDIXAppendix I
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GASTROENTEROLOGY 2007;132:1631-1639
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Paper IbGuro E Lind, Terje Ahlquist
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Journal of Translational Medicine 2
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Paper IITerje Ahlquist, Guro E Lind
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BackgroundMost cases of colorectal
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ADAMTS1 CDKN2A CRABP1 HOXA9 MAL MGM
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pseudogene, leading to a high rate
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strands. Proc Natl Acad Sci U S A 1
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concomitant absence of transcript a
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Volume 10 Number 7 July 2008 pp. 68
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682 RAS Signaling in Colorectal Car
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Table W2. Detailed Somatic Events o
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Identification of RCC2 as a prognos
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INTRODUCTIONMicrosatellite instabil
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unselected series of primary tumors
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specificity, i.e. that they only am
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On the assumption that DNA repair a
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In order to ensure that gene mutati
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Figure 2. Mutation frequency differ
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and TAF1B (0.50), ACVR2A and ASTE1
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Multivariate analysesA multivariate
Page 149 and 150:
When comparing our findings of muta
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The test series included a low numb
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entering M-phase remains to be seen
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12. Duval A, Reperant M, Hamelin R
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34. Martineau-Thuillier S, Andreass
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AppendicesAppendix I:List of abbrev
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Critical Reviews TM in Oncogenesis,
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TARGET GENES OF MSI COLORECTAL CANC
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