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

More documents

Recommendations

Info

© Terje Cruickshank Ahlquist, 2009Series of dissertations submitted to theFaculty of Medicine, University of OsloNo. 766ISBN 978-82-8072-325-3All rights reserved. No part of this publication may bereproduced or transmitted, in any form or by any means, without permission.Cover: Inger Sandved Anfinsen.Printed in Norway: AiT e-dit AS, Oslo, 2009.Produced in co-operation with Unipub AS.The thesis is produced by Unipub AS merely in connection with thethesis defence. Kindly direct all inquiries regarding the thesis to the copyrightholder or the unit which grants the doctorate.Unipub AS is owned byThe University Foundation for Student Life (SiO)
TABLE OF CONTENTSACKNOWLEDGEMENTS .............................................................................................................5PREFACE.............................................................................................................................................6LIST OF PAPERS...............................................................................................................................8SUMMARY...........................................................................................................................................9GENERAL INTRODUCTION ....................................................................................................11Genetic and epigenetic inheritance .............................................................................................11Cancer as a genetic and epigenetic disease.................................................................................12DNA mutations in cancer ............................................................................................................13DNA methylation..........................................................................................................................15DNA methylation and cancer .................................................................................................20Colorectal cancer ...........................................................................................................................21Incidence, treatment and outcome – Nature versus Nurture.............................................21Genetics and epigenetics of CRC – a timeline......................................................................24Molecular and morphological developmental pathways in colorectal cancer ..................25Instabilities involved in colorectal cancer..............................................................................28Chromosomal instability – CIN.........................................................................................28Microsatellite instability – MSI ...........................................................................................28CpG island methylator phenotype – CIMP......................................................................30Signaling pathways ....................................................................................................................32Clinical challenges for CRC.....................................................................................................33AIMS....................................................................................................................................................37RESULTS IN BRIEF .......................................................................................................................38DISCUSSION....................................................................................................................................43Fresh-frozen versus formalin embedded tissue....................................................................43Methodological considerations....................................................................................................43DNA methylation analyses......................................................................................................43Bisulfite treatment ................................................................................................................43Methylation specific PCR (MSP)........................................................................................44Scoring of MSP results ........................................................................................................45Bisulfite sequencing..............................................................................................................46Mutation analyses......................................................................................................................47Denaturing high performance liquid chromatography ...................................................48Direct sequencing.................................................................................................................50Fragment analysis .................................................................................................................51Multiplex-dependent probe amplification ........................................................................52Clinical impact of molecular biology ..........................................................................................54Early tumor markers.................................................................................................................54Prognostic markers ...................................................................................................................56Predictive markers.....................................................................................................................58Survival analyses........................................................................................................................60Driver and passenger (epi)mutations..........................................................................................61Different origins of colorectal cancer contribute to a non-uniform disease ........................63CONCLUSIONS...............................................................................................................................64
Page 1: Novel genetic and epigenetic altera
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 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[
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
Page 84 and 85:
References196. Honda S, Haruta M, S
Page 86 and 87:
ORIGINAL ARTICLESAPPENDIXAppendix I
Page 89 and 90:
GASTROENTEROLOGY 2007;132:1631-1639
Page 91:
Paper IbGuro E Lind, Terje Ahlquist
Page 94 and 95:
Journal of Translational Medicine 2
Page 96 and 97:
Page 98 and 99:
Page 100 and 101:
Page 102 and 103:
Page 105:
Paper IITerje Ahlquist, Guro E Lind
Page 108 and 109:
BackgroundMost cases of colorectal
Page 110 and 111:
ADAMTS1 CDKN2A CRABP1 HOXA9 MAL MGM
Page 112 and 113:
pseudogene, leading to a high rate
Page 114 and 115:
strands. Proc Natl Acad Sci U S A 1
Page 116 and 117:
concomitant absence of transcript a
Page 119 and 120:
Volume 10 Number 7 July 2008 pp. 68
Page 121 and 122:
682 RAS Signaling in Colorectal Car
Page 123 and 124:
Page 125 and 126:
Page 127:
Table W2. Detailed Somatic Events o
Page 131 and 132:
Identification of RCC2 as a prognos
Page 133 and 134:
INTRODUCTIONMicrosatellite instabil
Page 135 and 136:
unselected series of primary tumors
Page 137 and 138:
specificity, i.e. that they only am
Page 139 and 140:
On the assumption that DNA repair a
Page 141 and 142:
In order to ensure that gene mutati
Page 143 and 144:
Figure 2. Mutation frequency differ
Page 145 and 146:
and TAF1B (0.50), ACVR2A and ASTE1
Page 147 and 148:
Multivariate analysesA multivariate
Page 149 and 150:
When comparing our findings of muta
Page 151 and 152:
The test series included a low numb
Page 153 and 154:
entering M-phase remains to be seen
Page 155 and 156:
12. Duval A, Reperant M, Hamelin R
Page 157 and 158:
34. Martineau-Thuillier S, Andreass
Page 159:
AppendicesAppendix I:List of abbrev
Page 163 and 164:
Critical Reviews TM in Oncogenesis,
Page 165 and 166:
TARGET GENES OF MSI COLORECTAL CANC
Page 167 and 168:
Page 169 and 170:
Page 171 and 172:
Page 173 and 174:
Page 175 and 176:
Page 177 and 178:
Page 179 and 180:
Page 181 and 182:
Page 183 and 184:
Page 185 and 186:
Page 187 and 188:
Page 189 and 190:
Page 191:
show all

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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?