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
RØYRVIK ET AL.2plastic properties. Colorectal tumors develop through waves of clonal expansionfollowing events that confer a growth advantage upon a cell. 3-5 Some sort ofpronounced genetic or epigenetic instability is usually considered to be a prerequisitefor the development of tumors. 4,6 Sporadic cases of colorectal cancer canbe sub-classified according to their molecular phenotypes: one referred to aschromosomally unstable (CIN), and the other unstable in microsatellites (MSI),representing 85% and 15% of all cases, respectively. 7 The former type is characterizedby its widespread aneuploidy, 8 which may be a result of the instability, 9and is largely overlapping with the category of tumors designated as microsatellitestable (MSS). The MSI-type carcinoma, the focus of this review, is usuallydiploid or near-diploid, but exhibits instability in microsatellites, short DNA sequencesconsisting of a stretch of small repetitive units (1-6 nucleotides) flankedby unique sequences. MSI tumors are also prone to lymphocyte infiltration, havea higher incidence of proximal colonic location, and have poorer differentiationthan MSS tumors. 10-17 The largely proximal location of these tumors may be significantin that this area of the colon is of a different embryological provenancethan the distal portion, the proximal originating from the midgut and the distalfrom the hindgut. 18 In addition, there are differences in blood supply, metabolism,bacterial flora, antigenic profile, and gene expression between the two sections ofthe normal colon. 18-20 All of the above have led to the assumption that there are atleast two distinct pathways which may lead to colon cancer – each with their ownset of preferential, though not absolute, molecular alterations and locations. Athird pathway of colorectal tumorigenesis has been proposed, the CpG island methylatorphenotype (CIMP), based on concurrent promoter hypermethylation ofmultiple genes in a given tumor. 21 However, the existence of this phenotype iscontroversial, and no consensus regarding it has been reached.In the progression from adenoma to carcinoma, both the MSI and MSS phenotypesoften display early mutations in either the CRC “gatekeeper” genes APC(at a frequency as high as 80% 22 ) or CTNNB1 (-catenin), and in KRAS for thedevelopment of adenomas, but their genetic and epigenetic profiles diverge moresignificantly when they start to approach malignancy (Fig. 1). 4 Though subsequentgene targets may be disparate, mutations frequently affect the same pathwaysin MSI and MSS tumors, as is the case with the TGFRII-SMADs pairinginvolved in proliferation repression and TP53-BAX in apoptotic promotion (Fig.2). Signaling pathways such as MAPK, WNT, TGF, AKT, and the TP53 networkare affected in most CRCs, and they are all implicated in cell cycle control.Some common targets in these pathways are illustrated in Figure 2; their alterationsare the result of both genetic and epigenetic mechanisms.II. IDENTIFICATION OF THE INSTABILITY OF TUMORSThe hereditary non-polyposis colorectal cancer syndrome (HNPCC) accounts forless than 5% of all CRC. The position of a gene co-segregating with this disease230
TARGET GENES OF MSI COLORECTAL CANCERFIGURE 1. Adenoma-carcinoma sequence. Changes affecting CIN tumors in blue, MSItumors in red; those common to both are in green.FIGURE 2. Signaling pathways commonly affected in colorectal tumorigenesis. Proteins inred indicate genes often affected in MSI tumors due either to mutations or epigeneticevents; those in blue are genes targeted by other mutational or epigenetic mechanisms inMSS tumors.231
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TARGET GENES OF MSI COLORECTAL CANCERFIGURE 1. Ade<strong>no</strong>ma-carc<strong>in</strong>oma sequence. Changes affect<strong>in</strong>g CIN tumors <strong>in</strong> blue, MSItumors <strong>in</strong> red; those common to both are <strong>in</strong> green.FIGURE 2. Signal<strong>in</strong>g pathways commonly affected <strong>in</strong> colorectal tumorigenesis. Prote<strong>in</strong>s <strong>in</strong>red <strong>in</strong>dicate genes often affected <strong>in</strong> MSI tumors due either to mutations or epi<strong>genetic</strong>events; those <strong>in</strong> blue are genes targeted by other mutational or epi<strong>genetic</strong> mechanisms <strong>in</strong>MSS tumors.231
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