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RØYRVIK ET AL.Another topic that deserves attention is the functional consequence of mutationof mutated target gene expression. Both on the transcriptomic and proteomiclevels, a large-scale approach to this area would be useful in understanding therole of MSI in oncogenesis.Considering the comparative wealth of untested putative MMR target genesamong cMNR-containing sequences alone, not to mention those harboring diandtrinucleotide or repeats in UTRs and introns, it seems clear that a highthroughputapproach to analysis is desirable. Ideally, if somewhat unrealistically,all potential targets—both those that have been assessed in MSI tumors and thosethat have not—should be evaluated for a large consecutive clinical series.In short, after 12 years of research into targeted genes of mismatch repair deficientcolorectal cancers, we believe that those identified scarcely constituteeven the tip of the iceberg.REFERENCES1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer statistics,2006. CA Cancer J Clin. 2006;56:106–30.2. Radtke F, Clevers H. Self-renewal and cancer of the gut: two sides of a coin.Science. 2005;307(5717):1904–9.3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell.1990;61:759–67.4. Grady WM. Genomic instability and colon cancer. Cancer Metastasis Rev.2004;23:11–27.5. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.6. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers.Nature. 1998;396(6712):643–9.7. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, BurtRW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN, Srivastava S. ANational Cancer Institute workshop on microsatellite instability for cancer detectionand familial predisposition: development of international criteria for thedetermination of microsatellite instability in colorectal cancer. Cancer Res.1998;58:5248–57.8. Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers.Nature. 1997;386(6625):623–7.9. Rajagopalan H, Nowak MA, Vogelstein B, Lengauer C. The significance ofunstable chromosomes in colorectal cancer. Nat Rev Cancer. 2003;3:695–701.242
TARGET GENES OF MSI COLORECTAL CANCER10. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of theproximal colon. Science. 1993;260(5109):816–9.11. Duval A, Hamelin R. Genetic instability in human mismatch repair deficientcancers. Ann Genet. 2002;45:71–5.12. Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP,Jarvinen H, Powell SM, Jen J, Hamilton SR, . Clues to the pathogenesis of familialcolorectal cancer. Science. 1993;260(5109):812–6.13. Lothe RA, Peltomaki P, Meling GI, Aaltonen LA, Nystrom-Lahti M, PylkkanenL, Heimdal K, Andersen TI, Moller P, Rognum TO, . Genomic instabilityin colorectal cancer: relationship to clinicopathological variables and familyhistory. Cancer Res. 1993;53:5849–52.14. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somaticmutations in simple repeated sequences reveal a new mechanism forcolonic carcinogenesis. Nature. 1993;363(6429):558–61.15. Bubb VJ, Curtis LJ, Cunningham C, Dunlop MG, Carothers AD, Morris RG,White S, Bird CC, Wyllie AH. Microsatellite instability and the role of hMSH2in sporadic colorectalcancer. Oncogene. 1996;20;12:2641–9.16. Kim H, Jen J, Vogelstein B, Hamilton SR. Clinical and pathological characteristicsof sporadic colorectal carcinomas with DNA replication errors in microsatellitesequences. Am J Pathol. 1994;145:148–56.17. Chung KY, Kim NG, Li LS, Kim H, Kim H, Nam CM, Kim H, Shin DH.Clinicopathologic characteristics related to the high variability of codingmononucleotide repeat sequences in tumors with high-microsatellite instability.Oncol Rep. 2003;10:439–44.18. Glebov OK, Rodriguez LM, Nakahara K, Jenkins J, Cliatt J, Humbyrd CJ, De-Nobile J, Soballe P, Simon R, Wright G, Lynch P, Patterson S, Lynch H, GallingerS, Buchbinder A, Gordon G, Hawk E, Kirsch IR. Distinguishing rightfrom left colon by the pattern of gene expression. Cancer Epidemiol BiomarkersPrev. 2003;12:755–62.19. Bufill JA. Colorectal cancer: evidence for distinct genetic categories based onproximal or distal tumor location. Ann Intern Med. 1990;113:779–88.20. Pocard M, Salmon RJ, Muleris M, Remvikos Y, Bara J, Dutrillaux B, PouponMF. Deux colons—deux cancers? Adenocarcinomes coliques proximal ou distal:arguments en faveur d'une cancerogenese distincte [Two colons--two cancers?Proximal or distal adenocarcinoma: arguments for a different carcinogenesis].Bull Cancer. 1995;82:10–21.21. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG islandmethylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A.1999;96:8681–6.243
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Novel genetic and epigenetic altera
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TABLE OF CONTENTSACKNOWLEDGEMENTS .
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ACKNOWLEDGEMENTSThe present work ha
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Prefacetechnology[3]. This new tech
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SummaryThe subgroup of carcinomas w
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Introduction“Epigenetic inheritan
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Introductionamino acid change it is
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Introductionmethylation during embr
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IntroductionDNA is most of the time
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IntroductionFigure 5. DNA methylati
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IntroductionFigure 6. Incidence rat
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IntroductionFigure 8. Tumor staging
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Introductioninasmuch as 80% of colo
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IntroductionInstabilities involved
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Introductionthere seems to be a fid
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Introductionsevere alterations are
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Introductionpopulation-wide screeni
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IntroductionFigure 12. Present and
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RESULTS IN BRIEFPaper Ia. “DNA hy
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Results in Briefinstability, and se
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Results in BriefUnivariate survival
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Discussionseveral factors, and full
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Discussionlow threshold, we increas
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DiscussionIt may seem like unnecess
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Discussionthan 96% DHPLC do not sta
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DiscussionFigure 13. Mutation detec
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DiscussionClinical impact of molecu
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Discussionmarkers with a very high
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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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684 RAS Signaling in Colorectal Car
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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
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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
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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
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