Microsatellite Instability in Adenomas as a Marker for Hereditary Nonpolyposis Colorectal Cancer

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC)is the most common of the well-defined colorectal cancer syndromes , accounting for at least 2% of the total colorectal cancer burden and carrying a greater than 80% lifetime risk of cancer. Significant reduction in cancer morbidity and mortality can be accomplished by appropriate clinical cancer screening of HNPCC patients with mutations in mismatch repair (MMR) genes. Thus , it is desirable to identify individuals who are mutation-positive. In individuals with cancer , mutation detection can be accomplished relatively efficiently by germline mutation analysis of individuals whose cancers show microsatellite instability (MSI). This study was designed to assess the feasibility of screening colorectal adenoma patients for HNPCC in the same manner. Among 378 adenoma patients , six (1.6%) had at least one MSI adenoma. Five out of the six patients (83%) had a germline MMR gene mutation. We conclude that MSI analysis is a useful method of prescreening colorectal adenoma patients for HNPCC. (Am J Pathol 1999, 155:1849 -1853) Germline mutations in DNA mismatch repair genes (MLH1, MSH2, PMS1, PMS2, and MSH6) 1 underlie HNPCC. Deficient DNA mismatch repair results in reduced replication fidelity. Cells deficient for both alleles of a mismatch repair gene acquire a mutator phenotype, leading to accumulation of somatic mutations, which can be demonstrated by analyzing microsatellite sequences in the tumor DNA. These sequences display frequent somatic deletions and insertions, often referred to as microsatellite instability (MSI). HNPCC patients form adenomas at a slightly but not strikingly increased rate as compared with the general population 2 (Jä rvinen HJ, Aarnio M, Mustonen H, Aktan-Collan LA, Peltomäki P, de la Chapelle A, Mecklin J-P, submitted). Adenomas in HNPCC tend to be large and show a villous architecture and high-grade dysplasia. 3 It is possible that the mutator or MSI phenotype characteristic of HNPCC tumors drives the promotion of adenoma to carcinoma.MSI can be seen at an early stage in HNPCC tumors, but usually at later stages in sporadic colorectal tumorigenesis. 4 Adenomas from patients with HNPCC frequently show MSI as opposed to 0 to 3% of apparently sporadic colorectal adenomas. 5,6 The frequency of the MSI is 80 to 95% in HNPCC cancers 6 -8 and 10 to 15% in sporadic colorectal cancers. [7][8][9][10] The fact that a considerable proportion of sporadic colorectal cancers displays MSI makes microsatellite analysis a relatively unspecific marker for HNPCC when applied to malignant tumors.

Loss of mismatch repair protein immunostaining in colorectal adenomas from patients with hereditary nonpolyposis colorectal cancer

“…10 Since adenomatous tissue must sometimes be used for assessment of mismatch repair defects in HNPCC investigations, we aimed at determining the frequency of loss of immunostaining for the mismatch repair proteins in adenomas from HNPCC-patients. Overall, loss of immunostaining was detected in 23/35 adenomas from 26 HNPCC-patients.…”

“…Consequently, a microsatellite instability-high phenotype has been reported in 0-4% of sporadic adenomas compared to 15-20% of sporadic carcinomas. [8][9][10][11] Whereas the mismatch repair defects in sporadic colorectal tumors are mainly associated with somatic hypermethylation of the MLH1 promoter, HNPCC tumors develop as a result of germline mutations in these genes. 7,12 Data on the frequency of microsatellite instability in HNPCC-associated adenomas are still quite scarce, but indicate that defective mismatch repair can be found in 24-93% of the adenomas.…”

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

“…The overall MSI frequency in adenomas has been reported to be much lower than in carcinomas. About 1-2% of sporadic and up to 67% of the HNPCC associated colorectal adenomas develop the MSI phenotype (Grady et al, 1998;Loukola et al, 1999;Iino et al, 2000;Sugai et al, 2003). The occurrence of MSI was described to be present at early stages and to persist during colorectal tumor progression by some authors (Shibata et al, 1994).…”

Challenges and Pitfalls in HNPCC Screening by Microsatellite Analysis and Immunohistochemistry

“…This is especially true for adenomas. 8 The correct classification of the case as MMR deficient by laser microdissection was confirmed by immunohistochemistry, revealing loss of MLH1 expression and subsequent detection of a germ-line mutation in the corresponding gene. However, laser microdissection cannot be used without the clinico-pathological context.…”