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Introductionsevere alterations are described in human cancer that can confirm this. On the contrary,germ line mutation in DNMT3B are known to cause ICF syndrome (Immunodeficiencycentromericinstability- facial anomalies syndrome, OMIM #242860), a disease associatedwith hypomethylation of small percentage of the genome[111], but without elevated cancerrisk. Overexpression of DNMT1 has been another suggestion for CIMP development, butdifferent technologies give inconsistent results[95]. Also it has also been speculated whetherloss of methylation boundaries may cause CIMP as methylation naturally increases with age.This age-specific methylation is under normal circumstances kept within its boundaries. Incancer, these boundaries can be lost, leading to spreading of methylation and so-calledcancer-specific methylation[92] ‡‡ .In summary, MSI is the only of the three different instabilities in CRC of which we know thecause, although it seems that the real cause of sporadic MSI is CIMP and that MSI is a mereconsequence of CIMP. (refer Figure 10).Signaling pathwaysThe critical feature in tumorigenesis is often not the altered gene per se, but rather itsinvolvement in a complex signaling network. Alteration in one gene may therefore trigger acascade of signaling factors, such as when KRAS activate the mitogen activated protein(MAP) kinase pathway[112]. Hence, from a cancer cell perspective, it is more beneficial toalter a gene involved in signaling networks instead of a “lonesome wolf”.Some pathways play a more prominent role in tumorigenesis than others, possibly because itis easier for the cell to “highjack” them. The WNT pathway is an example of this. It controlsmany events during embryogenesis, including regulation of proliferation, morphology,motility and cell fate[113]. It is believed to be dysregulated inasmuch as 90% of colorectalcancers and APC, AXIN2, CTNNB1 and TCF7L2 are the most frequently alteredcomponents[114;115]. The MAP kinase pathway, involving KRAS, BRAF, RASSF1A andEGFR as common targets in cancer is another example and is deregulated in at least one‡‡ Jingmin Shu – unpublished – presented on Cancer Epigenetics, AACR Special Conference, Boston, USA,May 200832
Introductionthird of human cancers[112;116]. PI3K – AKT pathway is a key regulator of many importantcellular activities, including proliferation, cell growth, survival, and metabolism. It is highlyconserved from C.elegans to humans, indicating an essential function in the cell [117]. Thepathway is overactive in 30% of human cancers and pathway members, including AKT2,IRS2, PIK3CA, PTEN, and PDK1 have been found altered in different kinds of cancer(reviewed in ([118]). Transforming growth factor (TGF) evolved to regulate epithelial andneural tissues, the immune system, and wound repair in vertebrates[119]. This two-facedpathway is of special interest in a cancer perspective as it works in both an anti- and a protumorigenicfashion. The anti-tumorigenic effects of TGF is exerted via the downstreamsignaling targets which includes important cell-cycle checkpoint genes such as CDKN1A(p21), CDKN1B (p27) and CDKN2B (p15)[120], genes with tumor suppressive activity. Thepro-tumorigenic function is due to TGF being a potent inducer of epithelial-mesenchymaltransition (EMT). Cells undergoing EMT acquire motility and invasive properties, traitsessential for metastasizing cancers[121]. This leaves two possibilities. One is to inactivatedthe whole pathway, and in that way get rid of the tumor suppressing activity. The other is tospecifically knocking out just the tumor suppressing arm of TGF-signaling: As with the firstpossibility this will eliminate the suppressing activity, but in addition the cell may exploit thepro-tumorigenic phenotype of the pathway to enhance tumor growth and invasion[119]. It istherefore of no surprise that TGF signaling is among the most commonly altered signalingpathways in human cancers[120].Clinical challenges for CRCEarly detection and screening programsThere are several clinical challenges with colorectal cancer. The disease is equally frequentamong men and women and that the overall patient survival is poor. The fact that survivaldepends heavily on stage at time of diagnose indicate that great effort should be made inorder to diagnose patients as early as possible in the tumor time-line. Different approachesare suggested in order to improve early detection. Population-wide colonoscopy orsigmoidoscopy has been shown to reduce the relative risk of developing CRC by 80%[122].Even though colonoscopy is considered the golden standard in colon cancer screening withestimated benefits as high as 90% in reducing mortality, only a few countries have a33
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 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
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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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