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IntroductionFigure 5. DNA methylation effects in normal and cancer cells. Methylation has important functions innormal development and normal cells as shown to the left. The effects of the loss of epigenetic control incancer are shown in right side of the figure.DNA methylation and cancerEver since the discovery of hypomethylation in human tumors in 1983[43], it has been clearthat epigenetics, and in particular methylation, plays an important role in cancerdevelopment. Even though hypomethylation triggered the interest of epigenetics and cancer,it is promoter hypermethylation that have stolen most of the headlines thereafter, andespecially subsequent to the finding of promoter hypermethylation of the RB gene, thesymbol of Knudson’s two-hit hypothesis from twenty years prior[44], when the link betweenmethylation and reduced transcription was found[45]. In spite of the reserved suggestion ofpromoter hypermethylation being an infrequent event in human cancers, the article pavedway for an even stronger focus on methylation as an important factor intumorigenesis[45;46].20
IntroductionA rapidly growing field is the epigenetic control of micro-RNA (miRNA). miRNAs areendogenous non-coding small RNAs which regulate gene expression in a sequence-specificmanner, and can function as either oncogenes or tumor suppressor genes[47]. Compellingevidence now show that miRNAs are subject to both hypo- and hypermethylation in atumor and tissue-specific manner[48]. New studies also suggest that hypermethylation canmimic small chromosomal deletions or loss of heterozygosity by means of long rangeepigenetic silencing (LRES)[49;50]. The concept of LRES is no longer “one methylated CpGisland – one silent gene”, but rather involves large regions which may include severalgenes[49]. In breast cancer, the HOXA cluster has been shown to be subject to LRES, inwhich approximately 100kb DNA undergoes epigenetic inactivation[51].Colorectal cancerIncidence, treatment and outcome – Nature versus NurtureEach year over 1 million people are diagnosed with colorectal cancer (CRC) worldwide[52],including 3500 new Norwegian cases. It is an age-related disease, in the sense that it primarilyaffects older individuals (Figure 6). CRC is the most common form of sex-independentcancer ‡ , and the incidence is increasing (Figure 6). The disease is more prevalent in theindustrialized countries (Figure 7) § . Understanding both the initial and progressive steps ofthe disease is important in order to learn how and who to treat as knowledge of earlyalterations will provide information on how to detect the disease at an early, curable stage,while the later changes may be exploited to give information on treatment response. Thesubstantial differences in CRC incidence between the industrialized and developing countriessuggest that the disease is strongly affected by life-style and environmental factors. Severalrisk factors have been suggested and include obesity, high-fat diet, tobacco, alcohol and lackof physical activity[53]. Other factors have a preventive effect on CRC, e.g. exercise, highintake of fiber and vegetables as well as sufficient amounts of different nutrients. However,the literature is inconsistent on the matter, and the different mechanisms of risk factorexposure are still unknown[54].‡ The Norwegian Cancer Registry – http://www.kreftregisteret.no§ International Agency for Research on Cancer web pages - Cancer Mondial – http://www-dep.iarc.fr21
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 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
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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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