Novel genetic and epigenetic alterations in ... - Ous-research.no

More documents

Recommendations

Info

ACVR2 ASTE1 CASP5 MARCKS MBD4 MRE11A MSH3 TAF1B TGFBR2Right colon (n = 22) 100 % 82 % 77 % 77 % 59 % 91 % 73 % 91 % 96 %Left colon (n = 7) 71 % 57 % 43 % 29 % 0 % 57 % 57 % 57 % 57 %Rectum (n = 7) 57 % 29 % 29 % 29 % 14 % 29 % 0 % 29 % 29 %P -value 0.008 0.028 0.038 0.015 0.007 0.004 0.003 0.004 < 0.001Table 1. Mutation frequencies at different tumor sites. All 9 genes with significantly different mutationfrequencies in MSI-H tumors from different sites in the colon are listed.Survival analysesA univariate five year disease-free survival analysis of the mutation status of the 41 genes inthe test series indicated that mutations in AXIN2 and EP300 were significantly associatedwith a worse prognosis while mutations in MRE11A, OGT and RCC2 were associated with abeneficial prognosis (Table 2 top left). The positive association between survival andmutation in RCC2 was confirmed in the validation series (Figure 4 and Table 2 bottom left).In addition, mutation in GRK4 and RBBP8 was associated with poor survival in thevalidation series (Table 2 bottom).Figure 4. Survival and RCC2 mutation. Both in the test series (left plot) and the validation series (right plot)show a significant association between mutations in RCC2 and improved survival.16
Multivariate analysesA multivariate Cox proportional hazards model was created for both tumor series, based onall variables with a P-value better than 0.05 from the univariate analyses, as well as significantclinico-pathological variables (Table 2 top right). For the test series, low tumor stage at timeof diagnosis was the strongest predictor of disease-free survival, followed by mutated RCC2,AXIN2 wild-type and OGT mutation. Mutation status of EP300 and MRE11A did notprovide additional information. For OGT, no hazard ratio and confidence interval wascalculated from the multivariateanalysis as it lacks events in themutation group. Advancedtumor stage and wild-type RCC2remained the best identifiers ofpoor survival in the validationseries (Table 2 bottom right). Inaddition, wild-type GRK4 is alsoassociated with improvedsurvival in the analysis (P =0.029). The association betweenmutated RCC2 and improvedsurvival was evident only in stageI-II tumors and not in stage III-IV tumors (P = 0.004)Test seriesValidation seriesParameterSurvival %(SD)UnivariateNumberof casesAXIN2- wild-type 79 (6.9) 36- mutation 50 (20.4) 6EP300- wild-type 86 (6.6) 30- mutation 50 (14.4) 12MRE11A- mutation 88 (6.5) 27- wild-type 53 (12.9) 15OGT- mutation 100 (-) 15- wild-type 62 (9.5) 27RCC2- mutation 93 (6.4) 17- wild-type 64 (9.6) 25Tumor stage- Stage I-II 92 (5.5) 25- Stage III-IV 53 (12.1) 19GRK4- wild-type 66 (5.3) 83- mutation 41 (10.6) 23RBBP8- wild-type 65 (5.8) 72- mutation 50 (8.7) 35RCC2- mutation 68 (5.6) 75- wild-type 43 (9.0) 30Tumor stage- Stage I-II 75 (5.2) 73- Stage III-IV 27 (8.4) 34P -value HR 95% CI P -value0.0380.0070.0130.0110.0350.0030.0190.0240.0111.8x10 -61.8 - 6.80.0291.1 - 4.2 0.0535.6x10 -6Table 2. Prognostic factors for 5-year disease-free survival.Abbreviations: SD, standard deviation; HR, hazard ratio fordeath from disease, locally recurrent disease or distant metastasis;CI, confidence interval4.410.910.02.22.23.5Multivariate1.0 - 18.41.3 - 91.32.0 - 49.21.1 - 4.40.0670.0080.0090.00317
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 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
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
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 96 and 97: 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 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
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 TAF1B (0.50), ACVR2A and ASTE1
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
Page 191: TARGET GENES OF MSI COLORECTAL CANC
show all

Novel genetic and epigenetic alterations in ... - Ous-research.no

Create successful ePaper yourself

Delete template?

Save as template?