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SummaryThe subgroup of carcinomas with the MSI phenotype is known to have a better prognosisthan a consecutive unselected patient series. We analyzed 41 genes for mutations in twoclinically independent series of MSI-tumors and evaluated their prognostic information. Weidentified mutation status of RCC2 as an independent prognostic marker, which discriminatebetween good and poor prognosis among patients with a localized disease.10
GENERAL INTRODUCTIONGenetic and epigenetic inheritance“Genetic inheritance is the biological process wherebygenetic factors are transmitted from one generation tothe next”The principles behind genetic inheritance was elegantly described by Gregor Mendelin the mid 19 th century, where he showed that an offspring inherit one allele ofeach gene from each of its parents, and that the encoded information from thesemake out the phenotype[4]. Although it took 34 years until his work was re-discovered andappreciated, the Mendelian heritage has ever since been widely accepted as the default way ofgenetic inheritance. The fact that DNA is the crucial compound of this inheritance was notshown until 1952, almost a century later[5], a year before the DNA structure itself wasresolved[6]. Since then, the knowledge of inheritance has exploded. Some features are nowknown to be inherited in a non-mendelian manner, i.e. not according to Mendel’s laws ofinheritance. We also know that it is possible that information which is not coded by theDNA sequence itself can be passed to the next generation.This exception from the Hershey and Chase findings in 1952 is called epigenetics. There aretwo kinds of epigenetic inheritance; cellular/somatic, the one from a cell to its daughter cells;and transgenerational/germline, from one parent to its offspring, the latter a recent anddebated finding[7]. When epigenetic information is passed from a mother cell to its daughtercells, methylation marks are kept on the initial DNA strand during replication and celldivision, causing the epigenetic pattern to be re-established in the daughter cell[8].11
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 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 34 and 35: Introductionpopulation-wide screeni
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[
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DiscussionThese examples underline
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Discussiongenes. One is based on mu
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CONCLUSIONSWe have identified novel
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Future PerspectivesMolecular risk a
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REFERENCES1. Breasted J (1930) The
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References29. Deng G, Chen A, Pong
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References57. Al-Sukhni W, Aronson
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References84. Kunkel TA (1993) Nucl
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ReferencesLeggett B, Levine J, Kim
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References133. Lind GE, Thorstensen
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References156. Meling GI, Lothe RA,
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ReferencesT, Song X, Day RH, Sledzi
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References196. Honda S, Haruta M, S
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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
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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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