APC mutations in colorectal tumors with mismatch repair deficiency.

Abstract

We have investigated the influence of genetic instability [replication error (RER) phenotype] on APC (adenomatous polyposis coli), a gene thought to initiate colorectal tumorigenesis. The prevalence ofAPC mutations was similar in RER and non-RER tumors, indicating that both tumor types share this step in neoplastic transformation. However, in a total of 101 sequenced mutations, we noted a substantial excess ofAPC frameshift mutations in the RER cases (70% in RER tumors versus 47% in non-RER tumors, P < 0.04). These frameshifts were characteristic of mutations arising in cells deficient in DNA mismatch repair, with a predilection for mononucleotide repeats in the RER tumors (P < 0.0002), particularly (A). tracts (P < -0.00007). These findings suggest that the genetic instability that is reflected by the RER phenotype precedes, and is responsible for, APC mutation in RER large bowel tumors and have important implications for understanding the very earliest stages of neoplasia in patients with tumors deficient in mismatch repair.Instability at simple repetitive DNA sequences has been observed in a subset of sporadic colorectal cancers (1, 2) and in essentially all tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) (3-5). Deficiency in binding and repair of DNA mismatches has been demonstrated in tumor cell lines exhibiting such instability (6-10), and studies show an increased spontaneous mutation rate in selectable genes (8,(11)(12)(13). In most HNPCC tumors and in many of the sporadic cases, the underlying basis of this mutator or RER (replication error) phenotype is mutational inactivation of a human mismatch repair gene, five of which have so far been described (10,(14)(15)(16)(17)(18). With the exception of GTBP/pl60 (19), germ-line mutations have been identified in each of these genes in HNPCC families (5, 15-18, 20, 21

Tumor-infiltrating lymphocytes in colorectal cancers with microsatellite instability are correlated with the number and spectrum of frameshift mutations

“…The frequency of the frameshift mutations that we found for the 19 targets (Table 1) is in agreement with previous studies, except for APC and BAX. 8,38 The discrepancy that we observed for the latter genes is probably explained by the fact that our analysis was restricted to one repeat per gene, whereas previous reports had carried out a complete analysis of the corresponding targets. Although some of the mutations that we detected might only reflect the intrinsic genetic instability of tumors with microsatellite instability and may therefore be considered as passenger mutations, this study provides the following arguments confirming that some of these frameshift mutations, such as those affecting ACVR2, ASTE1/HT001 and TGFBR2, could play a key role in malignant transformation resulting from microsatellite instability: (i) their frequency, (ii) their presence in all malignant cells, suggesting that these alterations occur early and provide a selective advantage for tumor growth and (iii) the significant association of these mutations with other frameshift mutations (such as ASTE1/HT001 and TAF1B), which argues that they are not at random.…”

“…With these criteria, we selected 19 genes (Table 1), involved in signal transduction, apoptosis, DNA repair, transcription regulation or protein modification. In genes such as APC, containing several nucleotide repeats subjected to frameshift mutations in tumors with microsatellite instability, 38 we analyzed the sequence corresponding to the alteration that has been reported to be the most frequent one. For the PTEN, SEC63 and PRDM2 genes, we analyzed two distinct repeats, which had been shown to be both frequently altered.…”

Base transitions dominate the mutational spectrum of a transgenic reporter gene in MSH2 deficient mice

“…Thus, in addition to mutations in genes containing mononucleotide repeats, such as that encoding TGF-b receptor , MMR de®ciency potentially increases the frequency of damage to key growth control genes typically inactivated by point mutations. Indeed, in HNPCC tumors, mutations within APC and p53 genes are 40% frameshifts and 60% point mutations (Lazar et al, 1994); 70% of APC mutations in another study are frameshifts, with the remainder being point mutations (Huang et al, 1996).…”

Role of BAX mutations in mismatch repair-deficient colorectal carcinogenesis

“…All the samples were tested at ®ve microsatellite loci including the highly unstable BAT-26 locus, claimed to be su cient alone for identifying the RER status (Zhou et al, 1998;Hoang et al, 1997). The other 4 loci included L-myc, TGFbRII, D13S160, and D2S123 using the primers and conditions described elsewhere (Young et al, 1995;Huang et al, 1996).…”