Very low incidence of microsatellite instability in rectal cancers from families at risk for HNPCC

Abstract

In families at risk for hereditary non-polyposis colorectal cancer (HNPCC) that do not fulfill all clinical criteria for HNPCC, additional evidence is sought by testing cancer specimens for microsatellite instability (MSI). We investigated whether the location of a colorectal cancer (CRC) predicts the result of MSI-testing in these families. One hundred and seven patients suspected for HNPCC were offered MSI-testing. MSI-testing was positive in 6/7 patients with endometrial carcinoma and in 22/100 patients with CRC. Only one out of 22 (4%) rectal cancers was MSI-positive, and in this patient no mismatch repair (MMR) gene mutation was found. Right-sided colon carcinomas were more likely to be MSI-positive (14/37 or 38%), followed by left-sided colon carcinomas (7/4 or 17%) (p < 0.05), with 6/14 and 4/7 MMR gene mutations, respectively. The likelihood that a tumor would be MSI-positive was 3.3 times greater for right-sided than for left-sided colon cancer (OR 3.3, p < 0.05). Microsatellite instability was 8.1 times more frequent in colon cancers than in rectal cancers (p < 0.05). The presence of MSI was independently related to fulfillment of the Bethesda criteria (OR 7.0, p = 0.01). In families with multiple cases of colorectal cancer, the rectal cancers are only rarely MSI-positive. This indicates that even in families with multiple colorectal cancers, rectal cancers are most commonly of sporadic origin.

Colorectal Carcinoma in Malaysians: DNA Mismatch Repair Pattern in a Multiethnic Population

“…This rate is comparable to those generally observed, except for being on the lower end of the range (Koopman et al, 2009;Kanthan et al, 2012;Legolvan et al, 2012). This could be due to inclusion of rectal carcinoma, which have been observed to show lower incidence of MSI (Hoogerbrugge et al, 2003), in this study. That dMMR was significantly associated with right sided location and poor differentiation of the CRC has been demonstrated by others (Yearsley et al, 2006;Iacopetta et al, 2010).…”

Patients with an unexplained microsatellite instable tumour have a low risk of familial cancer

“…Mutation analysis of MLH1, PMS2, MSH2, and MSH6 was performed in DNA from peripheral blood lymphocytes by a combination of either single-strand conformation polymorphism analysis or denaturing gradient gel electrophoresis and direct sequence analysis essentially as described elsewhere (Wu et al, 1997;Hoogerbrugge et al, 2003). Only mutations resulting in a premature termination codon, the recurrent amino-acid deletion in MLH1 c.1852_1854del (p.Lys618del) and the amino-acid deletion c.211_213del (p.Glu71del) in MLH1, which has been shown to abort the function of MLH1 (Raevaara et al, 2002), were considered pathogenic.…”

“…Tumours were scored as MSI positive if at least two of the five Bethesda markers showed instability; they were scored MSI negative if none of the Bethesda markers showed instability. In case of one instable marker, additional markers were included, and immunohistochemistry (IHC) of MMR proteins was performed (Hoogerbrugge et al, 2003). In 273 tumours, the mononucleotide marker BAT40 was added to the standard set of markers and in 558 of 667 tumours IHC of MSH6 was performed irrespective of the MSI status to minimise the chance of missing a tumour that was due to an MSH6 germline mutation.…”

Compound heterozygosity for two MSH2 mutations suggests mild consequences of the initiation codon variant c.1A>G of MSH2

“…Molecular studies MSI analysis was performed in duplicate in four colorectal, one small bowel and one endometrial tumour using formalin-fixed paraffin-embedded tissue essentially as described by Hoogerbrugge et al 14 Areas with 60 -80% tumour cells were used for analysis. The Bethesda panel of microsatellite markers 15 was used together with the additional markers D1S158, D9S63, D18S58, D18S61, D8S199 and BAT40.…”