title: Microsatellite instability in pulmonary adenocarcinomas: a comprehensive study of 480 cases.
abstract: A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency, leading to accumulation of numerous mutations at repetitive DNA sequence stretches (microsatellites), known as high-level microsatellite instability (MSI-H). In colorectal cancer, MSI-H tumors show a clinical behavior different from microsatellite-stable (MSS) tumors. Data about the prevalence of MSI among non-small cell lung cancer (NSCLC) are conflicting, and clinical relevance of MSI is largely unknown. We analyzed a series of 480 pulmonary adenocarcinomas (ADC) for MSI using a sensitive mononucleotide marker panel (BAT25, BAT26, and CAT25). Positive cases were further analyzed by immunohistochemical staining for DNA mismatch repair proteins. Results were correlated with clinicopathological variables. MSI-H was detected in 4/480 (0.8 %) cases. In none of these, a background of Lynch syndrome was found. Three of the patients developed a metachronous carcinoma (esophagus, pancreas, and kidney). All MSI-H cases were stage I and occurred in smokers/ex-smokers. Mutations were found in EGFR (n = 2), KRAS (n = 1), or BRAF (n = 1). MSI-H neoplasms had a higher proliferative activity (38.7 %) than MSS neoplasms (28.3 %). Mean overall survival for MSS and MSI-H cases was 64.8 (CI 60.4-69.1) and 47.1 (CI 21-73.2) months, respectively. When specific mononucleotide marker panels are applied, the MSI-H phenotype is rare and predominantly found in early stage ADC of smokers. However, the frequency of MSI-H is in the range of other relevant molecular alterations. In the era of precision therapy, associations with distinct clinicopathological variables merit further investigation.
authors.affiliation: Institute of Pathology, Heidelberg University, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany. arne.warth@med.uni-heidelberg.de.
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Körner
authors.affiliation: Institute of Pathology, Heidelberg University, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Translational Research Unit, Thoraxklinik at Heidelberg University, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.affiliation: Department of Thoracic Surgery, Thoraxklinik at Heidelberg University, Heidelberg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Dienemann
authors.affiliation: Institute of Pathology, Heidelberg University, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel-Doeberitz
authors.affiliation: Institute of Pathology, Heidelberg University, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany.|Clinical Cooperation Unit Applied Tumor Biology, DKFZ, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000473:pathology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging / Q000379:methods
keywords: Adenocarcinoma; Lung cancer; Microsatellite instability; Mismatch repair