BACKGROUND & AIMS: Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in hereditary nonpolyposis colon cancer (HNPCC). However, nonneoplastic tissues from patients inheriting defects in human MSH2 or human MLH1 do not show significant genetic instability. The aim of this study was to determine whether acquisition of genetic instability at the adenoma stage promotes malignant transformation by studying adenoma-carcinoma progression in HNPCC. METHODS: Dinucleotide repeat loci were analyzed by polymerase chain reaction from microdissected adenoma and/or carcinoma stages from formalin-fixed paraffin-embedded HNPCC tumors. RESULTS: Although genetic instability was observed at some loci in almost all cases, the proportion of microsatellite loci altered was significantly less (P < 0.01) in completely benign adenomas (24%) than in benign areas of adenomas with malignancy (54%). Molecular fingerprints indicated intratumor heterogeneity, with evolution of related subclones of neoplastic cells. However, in all cases of tumor progression, at least one subclone from the adenoma stage was closely related to the carcinoma. CONCLUSIONS: Some genetic instability develops at the benign adenoma stage in most HNPCC tumors. Adenomas with a greater rate of genetic instability are more likely to progress to carcinoma. Topographic genotyping data provides evidence supporting the hypothesis of adenoma-carcinoma progression in HNPCC.
BACKGROUND & AIMS: Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in hereditary nonpolyposis colon cancer (HNPCC). However, nonneoplastic tissues from patients inheriting defects in humanMSH2 or humanMLH1 do not show significant genetic instability. The aim of this study was to determine whether acquisition of genetic instability at the adenoma stage promotes malignant transformation by studying adenoma-carcinoma progression in HNPCC. METHODS:Dinucleotide repeat loci were analyzed by polymerase chain reaction from microdissected adenoma and/or carcinoma stages from formalin-fixed paraffin-embedded HNPCC tumors. RESULTS: Although genetic instability was observed at some loci in almost all cases, the proportion of microsatellite loci altered was significantly less (P < 0.01) in completely benign adenomas (24%) than in benign areas of adenomas with malignancy (54%). Molecular fingerprints indicated intratumor heterogeneity, with evolution of related subclones of neoplastic cells. However, in all cases of tumor progression, at least one subclone from the adenoma stage was closely related to the carcinoma. CONCLUSIONS: Some genetic instability develops at the benign adenoma stage in most HNPCC tumors. Adenomas with a greater rate of genetic instability are more likely to progress to carcinoma. Topographic genotyping data provides evidence supporting the hypothesis of adenoma-carcinoma progression in HNPCC.
Authors: G Marra; S D'Atri; C Corti; L Bonmassar; M S Cattaruzza; P Schweizer; K Heinimann; Z Bartosova; M Nyström-Lahti; J Jiricny Journal: Proc Natl Acad Sci U S A Date: 2001-06-19 Impact factor: 11.205
Authors: G Togo; M Okamoto; Y Shiratori; H Yamaji; J Kato; M Matsumura; T Sano; T Motojima; M Omata Journal: Dig Dis Sci Date: 1999-09 Impact factor: 3.199
Authors: T Fujiwara; J M Stolker; T Watanabe; A Rashid; P Longo; J R Eshleman; S Booker; H T Lynch; J R Jass; J S Green; H Kim; J Jen; B Vogelstein; S R Hamilton Journal: Am J Pathol Date: 1998-10 Impact factor: 4.307
Authors: Annegret Müller; Carmen Beckmann; Gabriela Westphal; Tina Bocker Edmonston; Nicolaus Friedrichs; Wolfgang Dietmaier; Frank E Brasch; Matthias Kloor; Christoph Poremba; Gisela Keller; Daniela E Aust; Jürgen Fass; Reinhard Büttner; Heinz Becker; Josef Rüschoff Journal: Int J Colorectal Dis Date: 2006-03-02 Impact factor: 2.571