Abstract
Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR-DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients’ age, but not with patients’ gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients’ age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers.
Highlights
Lynch syndrome, occurring with an estimated allele frequency of up to 1:350, is one of the most common inherited cancer syndromes [1] and clinically often referred to as hereditary non-polyposis colorectal cancer (HNPCC) [2]
mismatch repair (MMR) protein immunohistochemistry was performed in 714 cm of mucosa (626 cm large bowel, 88 cm small bowel) from carriers of a Lynch syndrome mutation and 144 cm (129 cm large bowel, 15 cm small bowel) from patients without a germline mutation in the respective MMR gene, including 62 cm of mucosa (49 cm large bowel, 13 cm small bowel) from patients with sporadic MSI-H colorectal cancer
This corresponds to the following surface areas: 24.9 cm2 mucosa from Lynch syndrome mutation carriers (22.5 cm2 large bowel, 2.4 cm2 small bowel) and 5.1 cm2 from patients without an MMR gene germline mutation (4.7 cm2 large bowel, 0.4 cm2 small bowel), including 2.2 cm2 from sporadic MSI-H colorectal cancer patients (1.8 cm2 large bowel, 0.4 cm2 small bowel)
Summary
Lynch syndrome, occurring with an estimated allele frequency of up to 1:350, is one of the most common inherited cancer syndromes [1] and clinically often referred to as hereditary non-polyposis colorectal cancer (HNPCC) [2]. Lynch syndrome mutation carriers have a lifetime risk of about 40% to 80% to develop colorectal cancer [3,4]. Carriers of a germline mutation in one allele of the respective MMR gene acquire a second somatic mutation that inactivates the remaining functional allele of the MMR gene, following the classical two-hit hypothesis [6]. Inactivation of MMR genes leads to the loss of MMR protein expression in tumour cells and to an MSI-H phenotype. This phenomenon can be detected by immunohistochemistry [7,8] and point to the appropriate MMR gene for mutation analysis
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