Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer

Abstract

Tumorigenesis of colorectal cancer in patients with hereditary non-polyposis colorectal cancer (HNPCC) has been postulated to follow a different pathway from that of sporadic colorectal tumors. A characteristic of HNPCC-associated tumors is the replication error phenotype. We studied tumorigenesis in 8 fresh-frozen and 67 paraffin-embedded colorectal tumors derived from 29 families with HNPCC or a familial aggregation of colorectal cancer. By using intragenic markers, inactivation of the wild-type allele of hMLH1 was shown to occur through loss of heterozygosity and not through a somatic point mutation. Microsatellite instability is very common and occurs early in almost all colorectal tumors from HNPCC patients. Transforming growth factor beta type II receptor (T beta RII) mutations occur in these tumors at a high frequency. Of colorectal cancers from families with HNPCC, 63% have frameshift mutations in T beta RII, compared with 10% of sporadic colorectal cancers. APC and K-RAS mutations appear to be as frequent in the HNPCC tumors as in the sporadic counterpart.

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

“…MLH1 (MutL homolog 1) is the most important susceptibility gene for HNPCC (Peltomaki and Vasen, 2004) and also accounts for a major share of sporadic colorectal cancers (CRC) with microsatellite instability (MSI) (Kuismanen et al, 2000). In HNPCCrelated CRCs, the residual wild-type (wt) allele is often silenced by loss of heterozygosity (LOH) (Tannergard et al, 1997;Kuismanen et al, 2000;Potocnik et al, 2001;Yuen et al, 2002), whereas (biallelic) methylation of the MLH1 promoter primarily underlies sporadic microsatellite-unstable CRCs (Cunningham et al, 1998;Veigl et al, 1998;Kuismanen et al, 2000). Considerably less data are available on the mechanisms of inactivation of the wt allele in HNPCC spectrum tumors other than CRC, notably endometrial cancer (EC) that is the most common extracolonic malignancy in HNPCC.…”

“…Sporadic EC resembles sporadic CRC, in that MLH1 promoter methylation appears to be the primary mechanism of MSI (Esteller et al, 1998;Simpkins et al, 1999). In general, somatic point mutations rarely explain MMR gene inactivation in CRC (Tannergard et al, 1997;Kuismanen et al, 2000;Potocnik et al, 2001;Yuen et al, 2002) or EC (Chadwick et al, 2001).…”

Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers

“…There is good reason to believe that the MSI-H phenotype requires bi-allelic ('two hit') inactivation of the responsible MMR gene. In practice, however, only a single inactivating event was identified in up to 65% of currently reported MSI-H colorectal tumours (Hemminki et al, 1994;Konishi et al, 1996;Tannergard et al, 1997;Leung et al, 1998;Chan et al, 1999b). This may reflect the restricted number of inactivation mechanisms that were directly investigated.…”

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

“…We have previously reported wild-type allele loss in six out of 17 MLH1-linked tumors (Hemminki et al, 1994). Similarly, Tannerga˚rd et al (1997) showed LOH in six out of seven tumors, of which two could be shown to affect the wild-type allele. In MSH2-linked tumors, Lu et al (1996) detected LOH in four out of eight (50%) tumors and two wild-type allele losses were seen.…”

“…Loss of the wild-type allele in HNPCC tumors was proposed by Hemminki et al (1994) and it has been found to be the major mechanism for somatic second hits in most of the studies. Frequency of LOH in published studies varies between 33 and 86% (Hemminki et al, 1994;Lu et al, 1996;Tannerga˚rd et al, 1997;Kuismanen et al, 2000;Potocnik et al, 2001;Yuen et al, 2002), although the lost allele has not always been specified. In contrast, sporadic MMR-deficient tumors are most commonly due to bi-allelic inactivation of MLH1 by promoter hypermethylation, and these tumors rarely show LOH or somatic mutations in MLH1 (Kane et al, 1997;Cunningham et al, 1998;Herman et al, 1998;Veigl et al, 1998;Wheeler et al, 1999;Kuismanen et al, 2000).…”