title: Microsatellite instability at chromosome 8p in non-small cell lung cancer is associated with lymph node metastasis and squamous differentiation.
abstract: Genetic alterations at chromosome arm 8p are associated with advanced disease and poor patient outcome in several types of malignant tumors. We studied the frequency of microsatellite instability (MSI) and loss of heterozygosity (LOH) at chromosome 8p in early stage non-small cell lung cancer (NSCLC) of 47 patients with stage I or II disease (25 squamous cell carcinomas and 22 adenocarcinomas). Microsatellite analysis was performed after laser microdissection using 5 polymorphic tetranucleotide microsatellite markers and 4 dinucleotide markers at chromosome 8p. A pentanucleotide repeat marker at the chromosomal locus 17p13.1 (TP53.Alu) was also analyzed. Expression of the mismatch repair (MMR) proteins hMSH2, hMSH6 and hMLH1 was evaluated by immunohistochemistry. Microsatellite instability (MSI) in at least 2 markers was detected in 9 of 47 patients (19.1%) and was predominantly found at tetranucleotide repeats. Sixteen of 47 (34.0%) NSCLC demonstrated LOH at chromosome 8p. All MSI-positive tumors showed normal expression of the MMR proteins. The presence of MSI at chromosome 8p was associated with lymph node metastasis (p=0.02), squamous differentiation (8/25; 32%-p=0.03), and the presence of LOH at the p53 locus (p=0.06). None of the other investigated clinical, pathologic or molecular factors correlated with MSI. Our study showed that an elevated MSI at selected tetranucleotide sequences (EMAST) on chromosome 8p is frequent in early stage squamous cell carcinomas of the lung with lymphatic spread. The tetranucleotide marker panel used in this study was able to indicate lymph node metastasis and high risk disease in patients with resectable squamous cell lung cancer.
authors.affiliation: Department of Pathology, University of Regensburg, Regensburg, Germany. matthias.woenckhaus@klinik.uni-regensburg.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Woenckhaus
authors.forename: Robert
authors.initials: R
authors.lastname: Stoehr
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zieglmeier
authors.forename: Julia
authors.initials: J
authors.lastname: Foerster
authors.forename: Johannes
authors.initials: J
authors.lastname: Merk
authors.forename: Hagen
authors.initials: H
authors.lastname: Blaszyk
authors.forename: Michael
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstaedter
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002898:Chromosomes, Human, Pair 8; D004247:DNA / Q000737:chemistry; D004260:DNA Repair; D043243:DNA Sequence, Unstable; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics*; D008207:Lymphatic Metastasis; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D014176:Protein Biosynthesis; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C118481:MSH5 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D004247:DNA; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein