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ABSTRACTColorectal cancer (CRC) is one of the major cancer killers in the world, and any factor thatbetter pinpoint patients with a poor prognosis may result in a prolonged life expectancy for alarge number of cancer patients.In order to identify novel prognostic markers a literature survey followed by a criticalselection of tumorigenic genes were performed. We analyzed frameshift mutations in 41genes with mostly coding mononucleotide repeats in two tumor series with a total of 202microsatellite instable (MSI) colorectal tumors using capillary electrophoresis. The resultswere confirmed by sequencing in a random subset of the genes and tumors.In total, the two series of MSI-tumors carried a mean number of 17 and 19 mutations,respectively. A strong association was seen between low mutation load and rectal location,both for individual genes (ACVR2A, ASTE1, CASP5, MARCKS, MBD4, MRE11A,MSH3, TAF1B and TFGBR2) as well as across all genes (P = 0.008).Univariate survival analysis revealed that mutation in RCC2 was associated with an increasedfive-year disease-free survival in both tumor series (P = 0.035 and 0.011, respectively). Thisfinding was confirmed using multivariate analyses even with the inclusion of the strongestknown predictor of prognosis to date, tumor stage at time of diagnosis (P = 0.028 and 0.021,respectively).In conclusion, analysis of an (A)10 repeat in RCC2 using readily available technology refinesdetermination of prognosis in a group of MSI tumors. This may be useful in a future choiceof treatment for stage II MSI-tumors.2
INTRODUCTIONMicrosatellite instability (MSI) is a phenotype seen in approximately 15% of all colorectalcancers (CRC).[1] It is one of three commonly described phenotypes in CRC alongsidechromosomal instability (CIN), defined by large chromosomal rearrangements andaneuploidy, and CpG Island Methylator Phenotype (CIMP), which denotes tumors withpromoter hypermethylation of a large number of genes.[1] The CIMP tumors show a largedegree of overlap with the MSI tumors.[2] Under normal conditions the DNA mismatchrepair system (MMR) ensures high fidelity DNA replication by preventing insertions anddeletions (indels) of bases caused by replication slippages.[3] Replication slippage commonlyoccurs within microsatellites, which are small stretches of repetitive units varying from 1-6nucleotides scattered throughout the genome.[4] A defective MMR-system, which is theunderlying cause of MSI, will increase the possibility of indels in microsatellites as these arenot repaired successfully. If these microsatellites are located within the coding region of agene this will lead to frameshift mutations,[5] and since many genes have microsatelliteswithin the coding region, MSI is often referred to as the mutator phenotype.[4] There aretwo subgroups within MSI-tumors, those with a low and those with a high degree ofinstability. MSI-L tumors are usually acknowledged to have a phenotype analogous tomicrosatellite stable tumors (MSS).[6]The initial cause of MSI in CRC is most often promoter hypermethylation of the DNAmismatch repair gene MLH1.[7] It is not MSI per se which is the crucial aspect intumorigenesis, but the mutations it generates in genes that may be involved in importantregulatory signaling pathways. Because of the high background of genetic instability in MSI-3
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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,
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 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 127: Table W2. Detailed Somatic Events o
Page 131: Identification of RCC2 as a prognos
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
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TARGET GENES OF MSI COLORECTAL CANC
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