The influence of the pituitary tumor transforming gene-1 (PTTG-1) on survival of patients with small cell lung cancer and non-small cell lung cancer

Abstract

Background: PTTG-1 (pituitary tumor transforming gene) is a novel oncogene that is overexpressed in tumors, such as pituitary adenoma, breast and gastrointestinal cancers as well as in leukemia. In this study, we examined the role of PTTG-1 expression in lung cancer with regard to histological subtype, the correlation of PTTG-1 to clinical parameters and relation on patients' survival.

Methods: Expression of PTTG-1 was examined immunohistochemically on formalin-fixed, paraffin-embedded tissue sections of 136 patients with small cell lung cancer (SCLC) and 91 patients with non-small cell lung cancer (NSCLC), retrospectively. The intensity of PTTG-1 expression as well as the proportion of PTTG-1 positive cells within a tumor was used for univariate and multivariate analysis.

Results: PTTG-1 expression was observed in 64% of SCLC tumors and in 97.8% of NSCLC tumors. In patients with SCLC, negative or low PTTG-1 expression was associated with a shorter mean survival time compared with patients with strong PTTG-1 expression (265 +/- 18 days vs. 379 +/- 66 days; p = 0.0291). Using the Cox regression model for multivariate analysis, PTTG-1 expression was a significant predictor for survival next to performance status, tumor stage, LDH and hemoglobin. In contrast, in patients with NSCLC an inverse correlation between survival and PTTG-1 expression was seen. Strong PTTG-1 expression was associated with a shorter mean survival of 306 +/- 58 days compared with 463 +/- 55 days for those patients with no or low PTTG-1 intensities (p = 0.0386). Further, PTTG-1 expression was associated with a more aggressive NSCLC phenotype with an advanced pathological stage, extensive lymph node metastases, distant metastases and increased LDH level. Multivariate analysis using Cox regression confirmed the prognostic relevance of PTTG-1 expression next to performance status and tumor stage in patients with NSCLC.

Conclusion: Lung cancers belong to the group of tumors expressing PTTG-1. Dependent on the histological subtype of lung cancer, PTTG-1 expression was associated with a better outcome in patients with SCLC and a rather unfavourable outcome for patients with NSCLCs. These results may reflect the varying role of PTTG-1 in the pathophysiology of the different histological subtypes of lung cancer.

Figure 1

Immunohistochemical staining of PTTG-1. (A + B) positive control of germ cells in testis; (C) negative control of uropoietic tubuli stroma cells and globuli of the kidney; SCLC with negative PTTG-1 expression (D); low PTTG-1 expression (E) and strong PTTG-1 expression (F). Adenocarcinoma (NSCLC) with negative PTTG-1 expression (G), low PTTG-1 expression (H) and strong PTTG-1 expression (I). Squamous cell carcinoma (NSCLC) with low PTTG-1 expression (J) and strong PTTG-1 expression (K). (L), note the positive cytoplasmatic staining of normal bronchial epithelium.

Figure 2

Proportion of PTTG-1 positive tumor cells and PTTG-1 staining intensities of SCLC (N = 136); white bar represents PTTG-1 negative cases; light grey and black bars represent PTTG-1 low and strongly stained SCLC tumors, respectively.

Figure 3

3A and 3B Association of PTTG-1 expression and survival in SCLC tumors. (A): no statistical differences in survival time between patients with SCLC of no, low or strong PTTG-1 expression were seen (p = 0.0843). (B): a statistical significant difference on survival time was observed (p = 0.0291), when comparing those patients with PTTG-1 negative/low expression (grey line) with those patients with strong PTTG-1 expression (black line). PTTG-1 strong expressing cases (black line) had a statistical longer mean survival time of 379 ± 66 days compared with 265 ± 18 days for those patients with no/low PTTG-1 expression (grey line).

Figure 4

Proportion of PTTG-1 positive tumor cells and PTTG-1 staining intensities of NSCLC (N = 91); white bar represents PTTG-1 negative cases; light grey and black bars represent PTTG-1 low and strongly stained NSCLC tumors, respectively.

Figure 5

5A and 5B Association of PTTG-1 expression and survival in NSCLC tumors. (A): statistical difference in survival time between patients with NSCLC (n = 91) of no/low PTTG-1 expression (black line) and strong PTTG-1 expression (grey line) was seen. Patients with strong PTTG-1 expression had a significant (p = 0.0386) shorter survival time. (B): looking at PTTG-1 expression for the subgroup of patients with advanced NSCLC receiving palliative chemotherapy (n = 76), a statistically significant difference on survival time between PTTG-1 no/low expressing group (black line) and PTTG-1 strong expressing group (grey line) was observed (p = 0.0229).