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000127549 1001_ $$0P:(DE-HGF)0$$aStaffa, Laura$$b0$$eFirst author
000127549 245__ $$aMismatch repair-deficient crypt foci in Lynch syndrome--molecular alterations and association with clinical parameters.
000127549 260__ $$aLawrence, Kan.$$bPLoS$$c2015
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000127549 520__ $$aLynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR-DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm2 mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients' age, but not with patients' gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients' age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers.
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000127549 650_7 $$2NLM Chemicals$$aAIM2 protein, human
000127549 650_7 $$2NLM Chemicals$$aASTE1 protein, human
000127549 650_7 $$2NLM Chemicals$$aAdaptor Proteins, Signal Transducing
000127549 650_7 $$2NLM Chemicals$$aBAX protein, human
000127549 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000127549 650_7 $$2NLM Chemicals$$aMLH1 protein, human
000127549 650_7 $$2NLM Chemicals$$aNuclear Proteins
000127549 650_7 $$2NLM Chemicals$$aProteins
000127549 650_7 $$2NLM Chemicals$$abcl-2-Associated X Protein
000127549 650_7 $$0EC 3.6.1.3$$2NLM Chemicals$$aMSH2 protein, human
000127549 650_7 $$0EC 3.6.1.3$$2NLM Chemicals$$aMutL Protein Homolog 1
000127549 650_7 $$0EC 3.6.1.3$$2NLM Chemicals$$aMutS Homolog 2 Protein
000127549 7001_ $$0P:(DE-HGF)0$$aEchterdiek, Fabian$$b1
000127549 7001_ $$0P:(DE-He78)af4b1091bd23a160b527ee39101ed100$$aNelius, Nina$$b2$$udkfz
000127549 7001_ $$0P:(DE-He78)e15dfa1260625c69d6690a197392a994$$aBenner, Axel$$b3$$udkfz
000127549 7001_ $$0P:(DE-HGF)0$$aWerft, Wiebke$$b4
000127549 7001_ $$aLahrmann, Bernd$$b5
000127549 7001_ $$aGrabe, Niels$$b6
000127549 7001_ $$aSchneider, Martin$$b7
000127549 7001_ $$aTariverdian, Mirjam$$b8
000127549 7001_ $$0P:(DE-He78)11747cd1dc061b9333c0e3a3ff31bf2f$$avon Knebel Doeberitz, Magnus$$b9$$udkfz
000127549 7001_ $$aBläker, Hendrik$$b10
000127549 7001_ $$0P:(DE-HGF)0$$aKloor, Matthias$$b11$$eLast author
000127549 773__ $$0PERI:(DE-600)2267670-3$$a10.1371/journal.pone.0121980$$gVol. 10, no. 3, p. e0121980 -$$n3$$pe0121980 -$$tPLoS one$$v10$$x1932-6203$$y2015
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