title: 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.
authors: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany.
authors: Laura
authors: L
authors: Staffa
authors: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany.
authors: Fabian
authors: F
authors: Echterdiek
authors: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany.
authors: Nina
authors: N
authors: Nelius
authors: Department of Biostatistics, DKFZ (German Cancer Research Center), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors: Axel
authors: A
authors: Benner
authors: Department of Biostatistics, DKFZ (German Cancer Research Center), Im Neuenheimer Feld 280, Heidelberg, Germany.
authors: Wiebke
authors: W
authors: Werft
authors: Bioquant, Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Heidelberg, Germany.
authors: Bernd
authors: B
authors: Lahrmann
authors: Bioquant, Hamamatsu Tissue Imaging and Analysis (TIGA) Center, Heidelberg, Germany.
authors: Niels
authors: N
authors: Grabe
authors: Department of General, Visceral and Accident Surgery, University Hospital Heidelberg, Heidelberg Germany.
authors: Martin
authors: M
authors: Schneider
authors: Department of General, Visceral and Accident Surgery, University Hospital Heidelberg, Heidelberg Germany.
authors: Mirjam
authors: M
authors: Tariverdian
authors: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany.
authors: Magnus
authors: M
authors: von Knebel Doeberitz
authors: University Hospital Charité, Department of General Pathology, Berlin, Germany.
authors: Hendrik
authors: H
authors: Bläker
authors: Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany, and Clinical Cooperation Unit Applied Tumour Biology, DKFZ (German Cancer Research Center) Heidelberg, Im Neuenheimer Feld 280, Heidelberg, Germany.
authors: Matthias
authors: M
authors: Kloor
mesh_terms: D058739:Aberrant Crypt Foci / Q000235:genetics* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000367:Age Factors; D000368:Aged; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000473:pathology*; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D055815:Young Adult; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C410167:AIM2 protein, human; C000601355:ASTE1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C494826:BAX protein, human; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D051028:bcl-2-Associated X Protein; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein