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.
Highlights
Genomic instability is one of the key hallmarks of cancer [1]
Copy number aberrations in non-small cell lung cancer (NSCLC) can be found at multiple regions, some being specific for the histological subtype, and some being dependent on the severity of histopathological changes [5,6,7,8,9,10,11] the occurrence of copy number changes has shown to be an early event in lung cancer pathogenesis
This can be found in combination with a sequential pattern of loss of heterozygosity (LOH), which begins with the allelic loss on chromosome 8p, followed by 3p and 9p deletions [7, 12, 13]
Summary
Genomic instability is one of the key hallmarks of cancer [1]. Numerous studies on genomic instability in non-small cell lung cancer (NSCLC) have highlighted specific deletion patterns for both metastatic and primary tumors [2,3,4]. Copy number aberrations in NSCLC can be found at multiple regions, some being specific for the histological subtype, and some being dependent on the severity of histopathological changes (e.g. tumor stage or grading) [5,6,7,8,9,10,11] the occurrence of copy number changes has shown to be an early event in lung cancer pathogenesis This can be found in combination with a sequential pattern of loss of heterozygosity (LOH), which begins with the allelic loss on chromosome 8p, followed by 3p and 9p deletions [7, 12, 13]. We sought to analyze whether this loss could be detected in DTCs of a NSCLC patient
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