Novel genetic and epigenetic alterations in ... - Ous-research.no
Novel genetic and epigenetic alterations in ... - Ous-research.no Novel genetic and epigenetic alterations in ... - Ous-research.no
IntroductionFigure 6. Incidence rate for colorectal cancer compared with other types of cancer and age.a) Age-adjusted incidence rate for CRC compared to cancer in general in a Norwegian population. b) Theincidence of CRC is plotted against age at diagnosis. Raw data was obtained from the Norwegian CancerRegistry – Cancer in Norway 2006.The majority (70%) of CRC occurs sporadically, and only ~5% of all registered CRC are dueto single hereditary components, such as Lynch syndrome (OMIM #120435), formerlyknown as hereditary non-polyposis colorectal cancer (HNPCC), and familial adenomatouspolyposis (FAP, OMIM #175100). The remaining ~25% of CRC account for families withan accumulation of cancer, but with no known clear-cut Mendelian inheritance[55], and maybe multifactorial. Some studies claim that the fraction of heritable CRCs are as much as35%[56].Both Lynch syndrome and FAP are autosomal dominant disorders with a relative life-timerisk of developing CRC of 80% and 100%, respectively[57]. Lynch syndrome is caused by agerm line mutation in one of the components of the DNA mismatch repair system (MMR),most commonly MSH2 or MLH1[14] (see page 28-30 for MMR details). FAP is caused bygerm line mutation in the APC gene, a central cytoplasmic complex involved in degradationof -catenin (CTNNB1) in the WNT signaling pathway.22
IntroductionFigure 7. Colorectal cancer age-standardized incidence rate per 100.000 for women. The map for malesshows an identical trend; that the industrialized part of the world has a high incidence compared to thedeveloping countries.Survival among CRC patients depend heavily on tumor stage at time of diagnosis (Figure 8).Localized disease is associated with a relatively good prognosis (88% five-year relativesurvival) while patients with distant metastasis have a five-year relative survival of only 8%.Across all stages the five-year relative survival is approximately 57%. Another factor whichpredicts patient survival is genetic instability in the tumor, which traditionally is divided intochromosomal instability (CIN) and microsatellite instability (MSI), and patients with a MSItumor is associated with a better - while those with CIN tumors have a worsenedsurvival[58-60]. A third more recently described instability, called CpG island methylatorphenotype (CIMP), includes a subgroup of CRC with epigenetic instability which drivestumorigenesis in a similar way as CIN and MSI[61]. A detailed description of thesephenotypes is presented on page 28-32.23
- 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 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
IntroductionFigure 7. Colorectal cancer age-st<strong>and</strong>ardized <strong>in</strong>cidence rate per 100.000 for women. The map for malesshows an identical trend; that the <strong>in</strong>dustrialized part of the world has a high <strong>in</strong>cidence compared to thedevelop<strong>in</strong>g countries.Survival among CRC patients depend heavily on tumor stage at time of diag<strong>no</strong>sis (Figure 8).Localized disease is associated with a relatively good prog<strong>no</strong>sis (88% five-year relativesurvival) while patients with distant metastasis have a five-year relative survival of only 8%.Across all stages the five-year relative survival is approximately 57%. A<strong>no</strong>ther factor whichpredicts patient survival is <strong>genetic</strong> <strong>in</strong>stability <strong>in</strong> the tumor, which traditionally is divided <strong>in</strong>tochromosomal <strong>in</strong>stability (CIN) <strong>and</strong> microsatellite <strong>in</strong>stability (MSI), <strong>and</strong> patients with a MSItumor is associated with a better - while those with CIN tumors have a worsenedsurvival[58-60]. A third more recently described <strong>in</strong>stability, called CpG isl<strong>and</strong> methylatorphe<strong>no</strong>type (CIMP), <strong>in</strong>cludes a subgroup of CRC with epi<strong>genetic</strong> <strong>in</strong>stability which drivestumorigenesis <strong>in</strong> a similar way as CIN <strong>and</strong> MSI[61]. A detailed description of thesephe<strong>no</strong>types is presented on page 28-32.23
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