Limits...
Loss of 4q21.23-22.1 is a prognostic marker for disease free and overall survival in non-small cell lung cancer.

Uzunoglu FG, Dethlefsen E, Hanssen A, Wrage M, Deutsch L, Harms-Effenberger K, Vashist YK, Reeh M, Sauter G, Simon R, Bockhorn M, Pantel K, Izbicki JR, Wikman H - PLoS ONE (2014)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.

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.

Show MeSH

Related in: MedlinePlus

Loss of 4q21.23 in DTCs and tumor tissue of a NSCLC patient.Bone-marrow cells of the patient were immunocytochemically stained against cytokeratin using the APAAP method. A positive DTC (red) and a negative leukocyte (brown) are shown. B: Bone-marrow cells of the patient were stained fluorescently against cytokeratin (red signal) followed by FISH analysis in C) with RP11-1053C2 probe and Cen3 probe (RP11-1053C2 probe: 1 green signal; Cen3 probe: 3 spectrum orange signals; nuclear staining in DAPI). Cen7 probe (Cen7 probe: spectrum aqua displayed in the pseudo-color magenta) was in addition used for FISH analysis on D) primary tumor (2–5 orange signals/cell, 2–4 magenta signals/cell and 0–2 green signals/cell) and E) tumor relapse FFPE material (3–6 orange, 4–5 magenta and 1–3 green signals/cell).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4263470&req=5

pone-0113315-g003: Loss of 4q21.23 in DTCs and tumor tissue of a NSCLC patient.Bone-marrow cells of the patient were immunocytochemically stained against cytokeratin using the APAAP method. A positive DTC (red) and a negative leukocyte (brown) are shown. B: Bone-marrow cells of the patient were stained fluorescently against cytokeratin (red signal) followed by FISH analysis in C) with RP11-1053C2 probe and Cen3 probe (RP11-1053C2 probe: 1 green signal; Cen3 probe: 3 spectrum orange signals; nuclear staining in DAPI). Cen7 probe (Cen7 probe: spectrum aqua displayed in the pseudo-color magenta) was in addition used for FISH analysis on D) primary tumor (2–5 orange signals/cell, 2–4 magenta signals/cell and 0–2 green signals/cell) and E) tumor relapse FFPE material (3–6 orange, 4–5 magenta and 1–3 green signals/cell).

Mentions: Based on our earlier finding that 4q12-32 loss correlates with positive DTC status, we wanted to investigate whether a loss of this region is also present in DTCs from a patient with 4q loss in the primary tumor[14]. A loss of 4q22.1 was detected in 77% (17/22) of the patients DTCs. The range of RP11-1053C2 probe and centromere 3 signals were heterogeneous, varying from 1 to 5 signals (mean 1.7 and 2.7 respectively). FISH analysis was also performed on paraffin-embedded primary tumor and lung relapse material from the same patient (fig. 3). These results again revealed a loss of 4q22.1 and high degree of heterogeneity in the individual cells ranging from 0–4 signals in primary tumor and 0–5 in tumor relapse material.


Loss of 4q21.23-22.1 is a prognostic marker for disease free and overall survival in non-small cell lung cancer.

Uzunoglu FG, Dethlefsen E, Hanssen A, Wrage M, Deutsch L, Harms-Effenberger K, Vashist YK, Reeh M, Sauter G, Simon R, Bockhorn M, Pantel K, Izbicki JR, Wikman H - PLoS ONE (2014)

Loss of 4q21.23 in DTCs and tumor tissue of a NSCLC patient.Bone-marrow cells of the patient were immunocytochemically stained against cytokeratin using the APAAP method. A positive DTC (red) and a negative leukocyte (brown) are shown. B: Bone-marrow cells of the patient were stained fluorescently against cytokeratin (red signal) followed by FISH analysis in C) with RP11-1053C2 probe and Cen3 probe (RP11-1053C2 probe: 1 green signal; Cen3 probe: 3 spectrum orange signals; nuclear staining in DAPI). Cen7 probe (Cen7 probe: spectrum aqua displayed in the pseudo-color magenta) was in addition used for FISH analysis on D) primary tumor (2–5 orange signals/cell, 2–4 magenta signals/cell and 0–2 green signals/cell) and E) tumor relapse FFPE material (3–6 orange, 4–5 magenta and 1–3 green signals/cell).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263470&req=5

pone-0113315-g003: Loss of 4q21.23 in DTCs and tumor tissue of a NSCLC patient.Bone-marrow cells of the patient were immunocytochemically stained against cytokeratin using the APAAP method. A positive DTC (red) and a negative leukocyte (brown) are shown. B: Bone-marrow cells of the patient were stained fluorescently against cytokeratin (red signal) followed by FISH analysis in C) with RP11-1053C2 probe and Cen3 probe (RP11-1053C2 probe: 1 green signal; Cen3 probe: 3 spectrum orange signals; nuclear staining in DAPI). Cen7 probe (Cen7 probe: spectrum aqua displayed in the pseudo-color magenta) was in addition used for FISH analysis on D) primary tumor (2–5 orange signals/cell, 2–4 magenta signals/cell and 0–2 green signals/cell) and E) tumor relapse FFPE material (3–6 orange, 4–5 magenta and 1–3 green signals/cell).
Mentions: Based on our earlier finding that 4q12-32 loss correlates with positive DTC status, we wanted to investigate whether a loss of this region is also present in DTCs from a patient with 4q loss in the primary tumor[14]. A loss of 4q22.1 was detected in 77% (17/22) of the patients DTCs. The range of RP11-1053C2 probe and centromere 3 signals were heterogeneous, varying from 1 to 5 signals (mean 1.7 and 2.7 respectively). FISH analysis was also performed on paraffin-embedded primary tumor and lung relapse material from the same patient (fig. 3). These results again revealed a loss of 4q22.1 and high degree of heterogeneity in the individual cells ranging from 0–4 signals in primary tumor and 0–5 in tumor relapse material.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center of Hamburg-Eppendorf, Hamburg, Germany.

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.

Show MeSH
Related in: MedlinePlus