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.was, by reverse genetics, found to be located at chromosome bands 2p15-16 in1993. 23 Later that year, two groups isolated the gene in question, MSH2, which,if mutated in the germline, causes HNPCC. 24,25 Studies of HNPCC tumors revealeda ladder of novel alleles, rather than the expected loss of one allele expectedaccording to the two-hit hypothesis for the inactivation of a potential tumorsuppressor gene. 10,12-14 In this manner, colorectal carcinogenesis was tied to anovel mechanism—defective mismatch repair. A variety of tumor types arefound in patients with HNPCC, the most common being colorectal, endometrial,gastric, and ovarian tumors. 26Tumors with MSI were initially dubbed replication error tumors (RER+), andthe classification was often based on analyses of a variable number of dinucleotideloci. 10,12-14 Scoring of a tumor as RER+ or RER- was somewhat arbitrary asit depended on the total number of loci analyzed. A consensus panel of fivemono- and dinucleotide markers (BAT25, BAT26—mononucleotide; D2S123,D5S346, D17S250 - dinucleotide) was implemented later, and this so-called Bethesdapanel is now the current standard for assessing microsatellite instability inboth the hereditary and sporadic colorectal cancers. 27 The three dinucleotidemarkers depend on the availability of corresponding normal DNA in order toscore all affected tumors, whereas the BAT markers, being quasimonomorphic,can be more confidently used independent of non-tumor DNA. Furthermore, theBAT markers are highly informative, and therefore it has been suggested thatthese two, or even just BAT26, are sufficient for population-based diagnosticsaiming to identify cases with potential germline cancer predisposition. 28It has long been suspected that patients with MSI-CRC have a better overallsurvival than those with MSS, 10,13,15 and it now seems well-established that theformer phenotype is associated with an improved prognosis to the degree of atleast 15% compared to patients with the latter type. 29 Diploidy is also a markerfor positive prognosis, and though the majority of MSI-H tumors are diploid,ploidy and MSI status appear to be independent markers, as diploidy was indicativeof increased survival even within the MSI group. 30III. DEFECTIVE MMR: THE GENERATOR OF THE MSI PHENOTYPEThe MSI phenotype is caused by faulty or lacking mismatch repair proteins ofthe MutL, MutS homolog repair systems, which then fail to correct insertions anddeletions primarily caused by replication slippage in microsatellites with smallrepetitive units. Replication slippage is liable to occur at such sequences; followinga transient, local dissociation of the nascent parental DNA strand, reassociationoccurs between misaligned complementary repeat units, therebylengthening or shortening the newly synthesized strand. 31-33 If the MMR systemis defective, such errors will not be repaired and will accumulate in the cell.Most of the sporadic MSI tumors are caused by the silencing of MLH1 through232
TARGET GENES OF MSI COLORECTAL CANCERpromoter methylation, but some are caused by LOH/somatic mutation inMSH2. 34-40In the first step of eukaryotic mismatch repair, MSH2 recognizes the errorand forms a heterodimer with either MSH3 or MSH6, depending on the nature ofthe irregularity. MSH3 is specific for insertion/deletion (indel) loops of 2-4 nucleotides,while MSH6 is specific for single nucleotide loops or mismatches. Acomplex of DNA, MutS homologs, and ATP recruits a heterodimer of MLH1and PMS2, which displaces the main processive DNA polymerase and the slidingclamp PCNA, before recruiting base excision machinery to remove the tractin which the mismatch occurs. As the binding partners of MSH2 and MLH1 arecompletely dependent on them, any defect in MSH2, MSH3, and MSH6 will effectivelyinhibit the functions of PMS2 (as well as PMS1 and MLH3, of uncertainfunctional relevance) for MLH1. 41,42IV. CELLULAR CONSEQUENCES OF DEFECTIVE MMRDefects in the systems above are not in themselves carcinogenic, they simplyprovide the occasion for accumulation of indels in the existing microsatellites inthe genome—the resulting changes in some of the affected genes enables the incipienttumor to acquire necessary carcinomatous characteristics such as evasionof apoptosis, lack of dependency of extracellular/extratumoral growth signals, insensitivityto anti-growth signals, angiogenesis and unlimited scope for replication.43 The search for such target genes of MSI-CRC first bore fruit in the shapeof the tumor suppressor gene TGFRII in 1995, 44,45 two years after the MSI phenotypewas described for familial cancers, 10,12,14 to be followed by what were tobecome the other “canonical” target genes, partly by virtue of their early discoveryand subsequent frequent assessment: BAX, IGFIIR, MSH3, and MSH6.46 47 48In a stepwise model of tumorigenesis, the existence of “secondary mutators” likeMSH3 and MSH6 * has been suggested, given that they are DNA repair proteinsprone to frameshift mutations themselves, and may, when mutated, exacerbatethe phenotype. 49,50 MRE11, through its probable MLH1-related involvement in 3’nick-directed MMR, may have a similar effect. 51Cancers of the hereditary non-polyposis colorectal cancer (HNPCC) type, themost common being colorectal and endometrial, 26 also display microsatellite instability(see above), and have similar mutational spectra to the sporadic MSIcancers, though the initial genetic flaws in these cases are germline mutations inthe mismatch repair systems. 49V. LITERATURE SURVEY OF TARGET GENESIn order to survey known and putative target genes, a search was performed in* This, naturally, can only be the case if the tumor possesses functional MSH2.233
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TARGET GENES OF MSI COLORECTAL CANCERpromoter methylation, but some are caused by LOH/somatic mutation <strong>in</strong>MSH2. 34-40In the first step of eukaryotic mismatch repair, MSH2 recognizes the error<strong>and</strong> forms a heterodimer with either MSH3 or MSH6, depend<strong>in</strong>g on the nature ofthe irregularity. MSH3 is specific for <strong>in</strong>sertion/deletion (<strong>in</strong>del) loops of 2-4 nucleotides,while MSH6 is specific for s<strong>in</strong>gle nucleotide loops or mismatches. Acomplex of DNA, MutS homologs, <strong>and</strong> ATP recruits a heterodimer of MLH1<strong>and</strong> PMS2, which displaces the ma<strong>in</strong> processive DNA polymerase <strong>and</strong> the slid<strong>in</strong>gclamp PCNA, before recruit<strong>in</strong>g base excision mach<strong>in</strong>ery to remove the tract<strong>in</strong> which the mismatch occurs. As the b<strong>in</strong>d<strong>in</strong>g partners of MSH2 <strong>and</strong> MLH1 arecompletely dependent on them, any defect <strong>in</strong> MSH2, MSH3, <strong>and</strong> MSH6 will effectively<strong>in</strong>hibit the functions of PMS2 (as well as PMS1 <strong>and</strong> MLH3, of uncerta<strong>in</strong>functional relevance) for MLH1. 41,42IV. CELLULAR CONSEQUENCES OF DEFECTIVE MMRDefects <strong>in</strong> the systems above are <strong>no</strong>t <strong>in</strong> themselves carc<strong>in</strong>ogenic, they simplyprovide the occasion for accumulation of <strong>in</strong>dels <strong>in</strong> the exist<strong>in</strong>g microsatellites <strong>in</strong>the ge<strong>no</strong>me—the result<strong>in</strong>g changes <strong>in</strong> some of the affected genes enables the <strong>in</strong>cipienttumor to acquire necessary carc<strong>in</strong>omatous characteristics such as evasio<strong>no</strong>f apoptosis, lack of dependency of extracellular/extratumoral growth signals, <strong>in</strong>sensitivityto anti-growth signals, angiogenesis <strong>and</strong> unlimited scope for replication.43 The search for such target genes of MSI-CRC first bore fruit <strong>in</strong> the shapeof the tumor suppressor gene TGFRII <strong>in</strong> 1995, 44,45 two years after the MSI phe<strong>no</strong>typewas described for familial cancers, 10,12,14 to be followed by what were tobecome the other “ca<strong>no</strong>nical” target genes, partly by virtue of their early discovery<strong>and</strong> subsequent frequent assessment: BAX, IGFIIR, MSH3, <strong>and</strong> MSH6.46 47 48In a stepwise model of tumorigenesis, the existence of “secondary mutators” likeMSH3 <strong>and</strong> MSH6 * has been suggested, given that they are DNA repair prote<strong>in</strong>sprone to frameshift mutations themselves, <strong>and</strong> may, when mutated, exacerbatethe phe<strong>no</strong>type. 49,50 MRE11, through its probable MLH1-related <strong>in</strong>volvement <strong>in</strong> 3’nick-directed MMR, may have a similar effect. 51Cancers of the hereditary <strong>no</strong>n-polyposis colorectal cancer (HNPCC) type, themost common be<strong>in</strong>g colorectal <strong>and</strong> endometrial, 26 also display microsatellite <strong>in</strong>stability(see above), <strong>and</strong> have similar mutational spectra to the sporadic MSIcancers, though the <strong>in</strong>itial <strong>genetic</strong> flaws <strong>in</strong> these cases are germl<strong>in</strong>e mutations <strong>in</strong>the mismatch repair systems. 49V. LITERATURE SURVEY OF TARGET GENESIn order to survey k<strong>no</strong>wn <strong>and</strong> putative target genes, a search was performed <strong>in</strong>* This, naturally, can only be the case if the tumor possesses functional MSH2.233
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