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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RØYRVIK ET AL.2plastic properties. Colorectal tumors develop through waves of clonal expansionfollow<strong>in</strong>g events that confer a growth advantage upon a cell. 3-5 Some sort ofpro<strong>no</strong>unced <strong>genetic</strong> or epi<strong>genetic</strong> <strong>in</strong>stability is usually considered to be a prerequisitefor the development of tumors. 4,6 Sporadic cases of colorectal cancer canbe sub-classified accord<strong>in</strong>g to their molecular phe<strong>no</strong>types: one referred to aschromosomally unstable (CIN), <strong>and</strong> the other unstable <strong>in</strong> microsatellites (MSI),represent<strong>in</strong>g 85% <strong>and</strong> 15% of all cases, respectively. 7 The former type is characterizedby its widespread aneuploidy, 8 which may be a result of the <strong>in</strong>stability, 9<strong>and</strong> is largely overlapp<strong>in</strong>g with the category of tumors designated as microsatellitestable (MSS). The MSI-type carc<strong>in</strong>oma, the focus of this review, is usuallydiploid or near-diploid, but exhibits <strong>in</strong>stability <strong>in</strong> microsatellites, short DNA sequencesconsist<strong>in</strong>g of a stretch of small repetitive units (1-6 nucleotides) flankedby unique sequences. MSI tumors are also prone to lymphocyte <strong>in</strong>filtration, havea higher <strong>in</strong>cidence of proximal colonic location, <strong>and</strong> have poorer differentiationthan MSS tumors. 10-17 The largely proximal location of these tumors may be significant<strong>in</strong> that this area of the colon is of a different embryological provenancethan the distal portion, the proximal orig<strong>in</strong>at<strong>in</strong>g from the midgut <strong>and</strong> the distalfrom the h<strong>in</strong>dgut. 18 In addition, there are differences <strong>in</strong> blood supply, metabolism,bacterial flora, antigenic profile, <strong>and</strong> gene expression between the two sections ofthe <strong>no</strong>rmal colon. 18-20 All of the above have led to the assumption that there are atleast two dist<strong>in</strong>ct pathways which may lead to colon cancer – each with their ownset of preferential, though <strong>no</strong>t absolute, molecular <strong>alterations</strong> <strong>and</strong> locations. Athird pathway of colorectal tumorigenesis has been proposed, the CpG isl<strong>and</strong> methylatorphe<strong>no</strong>type (CIMP), based on concurrent promoter hypermethylation ofmultiple genes <strong>in</strong> a given tumor. 21 However, the existence of this phe<strong>no</strong>type iscontroversial, <strong>and</strong> <strong>no</strong> consensus regard<strong>in</strong>g it has been reached.In the progression from ade<strong>no</strong>ma to carc<strong>in</strong>oma, both the MSI <strong>and</strong> MSS phe<strong>no</strong>typesoften display early mutations <strong>in</strong> either the CRC “gatekeeper” genes APC(at a frequency as high as 80% 22 ) or CTNNB1 (-caten<strong>in</strong>), <strong>and</strong> <strong>in</strong> KRAS for thedevelopment of ade<strong>no</strong>mas, but their <strong>genetic</strong> <strong>and</strong> epi<strong>genetic</strong> profiles diverge moresignificantly when they start to approach malignancy (Fig. 1). 4 Though subsequentgene targets may be disparate, mutations frequently affect the same pathways<strong>in</strong> MSI <strong>and</strong> MSS tumors, as is the case with the TGFRII-SMADs pair<strong>in</strong>g<strong>in</strong>volved <strong>in</strong> proliferation repression <strong>and</strong> TP53-BAX <strong>in</strong> apoptotic promotion (Fig.2). Signal<strong>in</strong>g pathways such as MAPK, WNT, TGF, AKT, <strong>and</strong> the TP53 networkare affected <strong>in</strong> most CRCs, <strong>and</strong> they are all implicated <strong>in</strong> cell cycle control.Some common targets <strong>in</strong> these pathways are illustrated <strong>in</strong> Figure 2; their <strong>alterations</strong>are the result of both <strong>genetic</strong> <strong>and</strong> epi<strong>genetic</strong> mechanisms.II. IDENTIFICATION OF THE INSTABILITY OF TUMORSThe hereditary <strong>no</strong>n-polyposis colorectal cancer syndrome (HNPCC) accounts forless than 5% of all CRC. The position of a gene co-segregat<strong>in</strong>g with this disease230