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

More documents

Recommendations

Info

Introductionthere seems to be a fidelity threshold for homopolymer tracts, where those longer than 7base pairs are considered much less stable than those of seven or fewer units[80].With well over a thousand genes containing eight or more mononucleotide repeats in thegenome[90] it is obvious that mutations in these genes will accumulate at a much higher rateamong MSI tumors compared to tumors with a functional MMR-system. MSI is thereforeoften referred to as the mutator phenotype[91].CpG island methylator phenotype – CIMPWhile CIN tumors have a defect in the chromosomal segregation and MSI tumors have adefective MMR-system, the CIMP-tumors have a methylation machinery that has gone awry,causing epigenetic instability[92]. Tumors with CIMP are therefore associated with promoterhypermethylation of a large number of genes. It has previously been shown that 38% ofCRC display neither CIN nor MSI, and it has been speculated whether this group hasepigenetic events as the malignant driving force[93]. The CIMP phenotype overlaps in alarge degree with MSI, resulting in many of the same clinical associations, such as proximallocation and female gender of old age[92]. Overall, CIMP is associated with a poor prognosiscompared to CIMP-negative tumors[94;95]. In addition, it has been shown to be anindependent (from MSI and TP53 mut ) positive predictor of survival benefit from 5-FUtreatment[96]. On the genetic level, CIMP is strongly associated with the V600E mutation inBRAF, KRAS mut , and TP53 wt [97;98], which has led to the suggestion of two CIMP-groups;CIMP1 which is associated with extensive hypermethylation, V600E mutation in BRAF andMSI; CIMP2, an intermediate group with less frequent hypermethylation than CIMP1 as wellas KRAS mutation; and the CIMP negative group which contains very scarce methylation,microsatellite stable and wild-type TP53 tumors[98](Figure 11). CIMP is inversely associatedwith mutations in APC, the hallmark of early events in adenomas[99], thus supporting thehypothesis that CIMP and MSI tumors originate from the sessile serrated polyps and notadenomas[100]. CIMP is not exclusive for CRC. It has also been shown in gastric-, lung-,liver- and ovarian cancer as well as leukemia[95].30
IntroductionFigure 11. Integrated genetic and epigenetic analyses identify CIMP. With an integrative analysis ofmutation status of BRAF, KRAS and TP53, MSI status and methylation status of a panel of genes, Shen andco-workers identified three distinct subgroups of CRC. CIMP1 carry BRAF mutation, MSI and wide-spreadhypermethylation, CIMP2 carry KRAS mutation and intermediate degree of hypermethylation, while the CIMPnegative group carry TP53 mutations and scarce methylation (from [98]).CIMP was first described in 1999[61] and became immediately an area of great dispute.Toyota and colleagues identified a group with concurrent methylation of several loci andanother group with very little methylation. The group with frequent methylation was namedCIMP. Several studies supported this new phenotype[97;101;102], while other studies failedto verify the bimodal distribution of methylated genes, thus turning down the CIMPphenotype[103-105].Much of the discrepancies seen between the different studies are likelydue to both the panel of genes determining CIMP as well as the methodology[106;107].Today, CIMP is accepted as a third phenotype, and the effort has turned to how to correctlyclassify the CIMP tumors[98;108;109], as well as determining the initial cause. CIMP markerswill have to go through a similar process as the MSI marker panel (which initially wasdifferent from publication to publication) to reach a consensus marker panel [110].Among the original objections against CIMP was that it overlapped extensively with the MSIphenotype, and that CIMP was plainly a subclass of MSI-tumors with extensive promoterhypermethylation[105]. In fact, according to the sessile serrated polyp-model described onpage 26, it may prove to be the other way around, namely that CIMP precedes MSI, asCIMP may cause MLH1 to be hypermethylated, which again leads to MSI.The underlying cause of CIMP is still uncertain. Initially, the DNA methyl transferases(DNMT1, 2, 3a and 3b) were considered good candidates, but to date, no mutations or31
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 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:
Page 98 and 99:
Page 100 and 101:
Page 102 and 103:
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 123 and 124:
Page 125 and 126:
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 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
Page 167 and 168:
Page 169 and 170:
Page 171 and 172:
Page 173 and 174:
Page 175 and 176:
Page 177 and 178:
Page 179 and 180:
Page 181 and 182:
Page 183 and 184:
Page 185 and 186:
Page 187 and 188:
Page 189 and 190:
Page 191:
show all

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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?