title: Loss of 4q21.23-22.1 is a prognostic marker for disease free and overall survival in non-small cell lung cancer.
abstract: This study was performed to assess the prognostic relevance of genomic aberrations at chromosome 4q in NSCLC patients. We have previously identified copy number changes at 4q12-q32 to be significantly associated with the early hematogenous dissemination of non-small cell lung cancer (NSCLC), and now aim to narrow down potential hot-spots within this 107 Mb spanning region. Using eight microsatellite markers at position 4q12-35, allelic imbalance (AI) analyses were performed on a preliminary study cohort (n = 86). Positions indicating clinicopathological and prognostic associations in AI analyses were further validated in a larger study cohort using fluorescence in situ hybridization (FISH) in 209 NSCLC patients. Losses at positions 4q21.23 and 4q22.1 were shown to be associated with advanced clinicopathological characteristics as well as with shortened disease free (DFS) and overall survival (OS) (DFS: P = 0.019; OS: P = 0.002). Multivariate analyses identified the losses of 4q21.23-22.1 to be an independent prognostic marker for both DFS and OS in NSCLC (HR 1.64-2.20, all P<0.04), and especially in squamous cell lung cancer (P<0.05). A case report study of a lung cancer patient further revealed a loss of 4q21.23 in disseminated tumor cells (DTCs). Neither gains at the latter positions, nor genomic aberrations at 4q12, 4q31.2 and 4q35.1, indicated a prognostic relevance. In conclusion, our data indicate that loss at 4q21.23-22.1 in NSCLC is of prognostic relevance in NSCLC patients and thus, includes potential new tumor suppressor genes with clinical relevance.
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Faik G
authors.initials: FG
authors.lastname: Uzunoglu
authors.affiliation: Institute of Tumour Biology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ebba
authors.initials: E
authors.lastname: Dethlefsen
authors.affiliation: Institute of Tumour Biology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Annkathrin
authors.initials: A
authors.lastname: Hanssen
authors.affiliation: Institute of Tumour Biology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Wrage
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Deutsch
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany; Institute of Tumour Biology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Harms-Effenberger
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Yogesh K
authors.initials: YK
authors.lastname: Vashist
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Reeh
authors.affiliation: Department of Pathology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.affiliation: Department of Pathology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Bockhorn
authors.affiliation: Institute of Tumour Biology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.affiliation: Institute of Tumour Biology, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
mesh_terms: D000368:Aged; D022981:Allelic Imbalance; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor