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IntroductionFigure 8. Tumor staging and survival. Colorectal tumors are staged based on degree of localization. Stage 0is often referred to as carcinoma in situ and has not penetrated the mucosa boundaries. Stage I is consideredlocalized as the tumors has not penetrated the serosa. Stage II tumors are also considered local, but havepenetrated serosa and may have grown into pericolic fat tissue. Patients with localized tumors have a 5-yearsurvival of 88%. Stage III tumors are considered regional as local lymph nodes are infiltrated. Five-year survivalamong such patients is 68%. Patients with a stage IV tumor have metastasis to distant organs such as the liver,and have the worst prognosis as only 8% survive. Survival data has been added to this illustration by NationalCancer Institute.Genetics and epigenetics of CRC – a timelineColorectal cancer is one of the most extensively studied cancer types over the last centuryresulting in small and bigger leaps of knowledge. The timeline in Figure 9 presents some ofthe most important discoveries for this disease as well as for cancer in general.24
IntroductionFigure 9. A timeline of (colorectal cancer) genetics. The left hand side of the helix (in red) lists generalgenetic hallmarks while the right hand side (in black) includes hallmarks in colorectal cancer research.Molecular and morphological developmental pathways in colorectalcancerThe adenoma-carcinoma model was first presented by Muto and co-workers in 1975[62]. Itdescribed how colorectal cancer developed through different histopathological steps, fromthe first abnormality, via increasingly dysplastic adenomas to carcinomas, and has ever sincebeen a widely accepted paradigm for colorectal carcinogenesis. In 1990, Fearon andVogelstein added genetic information to this model and suggested that alterations in at leastfour of the presented genes were sufficient for developing cancer[63]. It has later beenshown that the order of events is just as important for the cancer development as thenumber of alterations[64;65].According to the adenoma-carcinoma model, adenomas can develop into eithermicrosatellite- or chromosome instable tumors depending on the genetic makeup of thetumor[64]. Mutation in the tumor suppressor gene APC is considered to be the initiatingevent, or “gatekeeper mutation” in colorectal tumorigenesis, and has been reported25
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 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
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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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