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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.

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Estimated probability of disease free survival.A: Copy number loss at position 4q21.23 (RP11-570L13) revealed a trend towards shorter median disease free survival (DFS) in univariate analysis (12.5 months versus 28.0 months, P = 0.056). B: Copy number loss at position 4q21.23 (RP11-570L13) in the squamous cell carcinoma (SqCC) subgroup showed strong correlations with shorter DFS (11.2 months versus 39.1 months) P = 0.031. C: Copy number loss at position 4q22.1 (RP11-1053C2) showed significant correlations with shorter DFS (12.5 months versus 32.7 months), P = 0.010. D: Copy number loss at position 4q22.1 (RP11-1053C2) showed significant correlations with shorter DFS in SqCC subgroup (11.7 months versus 35.5 months), P = 0.027. Survival plots for gain aberrations were faded out for the sake of clarity.
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pone-0113315-g001: Estimated probability of disease free survival.A: Copy number loss at position 4q21.23 (RP11-570L13) revealed a trend towards shorter median disease free survival (DFS) in univariate analysis (12.5 months versus 28.0 months, P = 0.056). B: Copy number loss at position 4q21.23 (RP11-570L13) in the squamous cell carcinoma (SqCC) subgroup showed strong correlations with shorter DFS (11.2 months versus 39.1 months) P = 0.031. C: Copy number loss at position 4q22.1 (RP11-1053C2) showed significant correlations with shorter DFS (12.5 months versus 32.7 months), P = 0.010. D: Copy number loss at position 4q22.1 (RP11-1053C2) showed significant correlations with shorter DFS in SqCC subgroup (11.7 months versus 35.5 months), P = 0.027. Survival plots for gain aberrations were faded out for the sake of clarity.

Mentions: In the context of a univariate analysis, copy number loss at position 4q21.23 (RP11-570L13)revealed a non-significant trend towards shorter median DFS (12.5 months versus 28.0 months, P = 0.056). Subgroup analyses, however, showed a strong correlation with DFS in SqCC subgroup (11.2 months versus 39.1 months, P = 0.031; fig. 1, S6 Table). A similar effect on OS was reported for the whole study cohort (23.9 months versus 42.6 months, P = 0.033) and SqCC subgroup (12.5 months versus 41 months, P = 0.031, fig. 2, S6 Table).


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)

Estimated probability of disease free survival.A: Copy number loss at position 4q21.23 (RP11-570L13) revealed a trend towards shorter median disease free survival (DFS) in univariate analysis (12.5 months versus 28.0 months, P = 0.056). B: Copy number loss at position 4q21.23 (RP11-570L13) in the squamous cell carcinoma (SqCC) subgroup showed strong correlations with shorter DFS (11.2 months versus 39.1 months) P = 0.031. C: Copy number loss at position 4q22.1 (RP11-1053C2) showed significant correlations with shorter DFS (12.5 months versus 32.7 months), P = 0.010. D: Copy number loss at position 4q22.1 (RP11-1053C2) showed significant correlations with shorter DFS in SqCC subgroup (11.7 months versus 35.5 months), P = 0.027. Survival plots for gain aberrations were faded out for the sake of clarity.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0113315-g001: Estimated probability of disease free survival.A: Copy number loss at position 4q21.23 (RP11-570L13) revealed a trend towards shorter median disease free survival (DFS) in univariate analysis (12.5 months versus 28.0 months, P = 0.056). B: Copy number loss at position 4q21.23 (RP11-570L13) in the squamous cell carcinoma (SqCC) subgroup showed strong correlations with shorter DFS (11.2 months versus 39.1 months) P = 0.031. C: Copy number loss at position 4q22.1 (RP11-1053C2) showed significant correlations with shorter DFS (12.5 months versus 32.7 months), P = 0.010. D: Copy number loss at position 4q22.1 (RP11-1053C2) showed significant correlations with shorter DFS in SqCC subgroup (11.7 months versus 35.5 months), P = 0.027. Survival plots for gain aberrations were faded out for the sake of clarity.
Mentions: In the context of a univariate analysis, copy number loss at position 4q21.23 (RP11-570L13)revealed a non-significant trend towards shorter median DFS (12.5 months versus 28.0 months, P = 0.056). Subgroup analyses, however, showed a strong correlation with DFS in SqCC subgroup (11.2 months versus 39.1 months, P = 0.031; fig. 1, S6 Table). A similar effect on OS was reported for the whole study cohort (23.9 months versus 42.6 months, P = 0.033) and SqCC subgroup (12.5 months versus 41 months, P = 0.031, fig. 2, S6 Table).

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