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