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Discussionchromosomes in metaphase[189], and loss of expression has been shown to cause G2/Marrest[190]. Indels in the 5’UTR region of this gene, a site of major translational regulation,may affect translational efficiency and stability, leading to cancer cell arrest and reducedproliferation. Knocking out RCC2 therefore seems like a bad strategy for a cancer cell, andone would expect a strong negative selection pressure. Still, we see a mutation frequencyabove 50%, indicating that this is not the case.Figure 15. Study sizesanalyzing coding repetitiveunits in MSI-tumors. Allstudies included in the reviewfrom 2007[90] are included.Sample size and number ofgenes analyzed are plottedagainst each other. Moststudies analyze a small numberof samples for a restrictednumber of genes. The starindicates the size of the studypresented in paper IV.Predictive markersWhile some biomarkers are well suited for diagnostic purposes, others can be used todetermine, or predict, response to a certain therapy. Such markers are called predictivemarkers. In paper III we showed that mutations in KRAS and BRAF were common in CRCas they were present in 62% of the tumors. Mutations in these genes have in other studiesbeen shown to predict response to cetuximab, a monoclonal antibody therapy targeting theepidermal growth factor receptor (EGFR). About 30-40% of non-responders to this therapycarry a KRAS mutation. Mutations in BRAF is significantly associated with lack of treatmentresponse as none of the patients with BRAF mut responded, while none of the responders58
Discussionwere mutated[191]. The reason for this lack of response is that cetuximab targets EGFR,which is located upstream of both KRAS and BRAF. Both these oncogenes are known tobecome constitutively active when mutated, meaning that they will sustain signaling even inabsence of receptor activation[112;192]. In addition to the potential diagnostic use ofpromoter hypermethylation it may also contribute with predictive information for choice oftreatment. This is also the case for MGMT, which is an enzyme involved in direct DNArepair. It works by irreversibly transferring alkyl groups from an O6-guanine to an internalcysteine[193]. Alkylation at the O6-position of guanine is a common point of attack formany carcinogens, and hypermethylated and inactivated MGMT makes the cancer cell moresusceptible to damage induced by alkylating agents as the damage is left unrepaired.Hypermethylated MGMT is associated with prolonged overall and disease-free survival aftercarmustine treatment compared to the ones without hypermethylation in gliomas[194].Hence, hypermethylation of MGMT serves as a predictive marker for positive response tochemotherapy consisting of alkylating agents. Even though no such agents are used in thestandard treatment regime of CRC, a study has shown that hypermethylation of MGMT maypredict non-recurrence after chemotherapy with 5-FU as these patients have a betteroutcome[195]. Hypermethylation of RASSF1A, a gene commonly hypermethylated in CRC,has been associated with a worse response to cisplatin treatment in both germ cell tumorsand hepatoblastomas[196;197]. Cisplatin is a platinum-based cytostatica similar to oxaliplatin,which is used for treating stage III and IV CRC patients. It may be that RASSF1A exerts thesame negative effect on oxaliplatin treatment in CRC patients, but to my knowledge this hasyet to be shown.Although debated, MSI, caused by hypermethylation of MLH1 in sporadic CRC, isassociated to worse response to 5-FU treatment[59;126-128]. One possible explanation ofthis cytostatic resistance is that the lack of MMR might allow incorporated 5-FU to causeharmful effects to DNA synthesis and replication, but with no recognition by thedysfunctional MMR system and no inhibition of cell growth. On the other hand, an intactMMR system may trigger a cell death program in MSS colorectal tumors treated with 5-FU,making this agent more effective in this subtype of tumors[128].59
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Novel genetic and epigenetic altera
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TABLE OF CONTENTSACKNOWLEDGEMENTS .
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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 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 105: 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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