Mismatch Repair-Deficient Crypt Foci in Lynch Syndrome – Molecular Alterations and Association with Clinical Parameters

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.

Mismatch repair deficiency in Lynch syndrome‐associated colorectal adenomas is more prevalent in older patients

“…A recent study showed that the number of MMR-deficient crypt foci in the colorectal epithelium increased with age. 29 Because adenomas arising from MMR-deficient crypt foci are expected to lack MMR protein expression consistently, this observation appears to provide a reasonable explanation for the correlation between the prevalence of MMR deficiency and patient age as well as for the absence of adenomas with focal loss of MMR proteins. We suggest that a significant proportion of LS-associated adenomas, particularly those in older patients, may arise from MMR-deficient crypt foci ( Figure 2).…”

“…Conversely, these findings seem to be well explained when considering tumorigenesis via MMR‐deficient crypt foci. A recent study showed that the number of MMR‐deficient crypt foci in the colorectal epithelium increased with age . Because adenomas arising from MMR‐deficient crypt foci are expected to lack MMR protein expression consistently, this observation appears to provide a reasonable explanation for the correlation between the prevalence of MMR deficiency and patient age as well as for the absence of adenomas with focal loss of MMR proteins.…”

High numbers of PDCD1 (PD-1)-positive T cells andB2Mmutations in microsatellite-unstable colorectal cancer

“…This suggests that the recurrent exposure of immune cells towards MSIrelated antigens in Lynch syndrome, e.g. through mismatch repair-deficient crypts 1,40,41 may lead to T cell activation and consequently an enhanced number of activated T cells in clinically manifest tumors. The recurrent stimulation of the immune system with MSIinduced FSP neoantigens in Lynch syndrome may thus be the reason for the higher frequency of B2M mutations in Lynch syndrome-associated compared to sporadic MSI colorectal cancers 42 This supports the concept that stimulating the immune system against MSI-related FSP antigens, e.g.…”

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

“…Losing the expression of MMR proteins via inactivation of MMRTezcan G et al . Molecular aspects of early-onset colorectal cancer deficient crypt foci genes causes an MSI phenotype [30] . In these patients, the mutation rates of ACVR2, TAF1B and ASTE1, microsatellite-bearing target genes are higher than 80% [29][30][31][32][33] .…”

“…Molecular aspects of early-onset colorectal cancer deficient crypt foci genes causes an MSI phenotype [30] . In these patients, the mutation rates of ACVR2, TAF1B and ASTE1, microsatellite-bearing target genes are higher than 80% [29][30][31][32][33] . Recent studies indicated that in MSI cases, frameshift mutations of apoptotic genes, such as APAF1, BAX and FLASH, lead to intratumoral heterogeneity [28] .…”