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A prognostic profile of hypoxia-induced genes for localised high-grade soft tissue sarcoma.

ABSTRACT: For decades, tumour hypoxia has been pursued as a cancer treatment target. However, prognostic and predictive biomarkers are essential for the use of this target in the clinic. This study investigates the prognostic value of a hypoxia-induced gene profile in localised soft tissue sarcoma (STS).The hypoxia-induced gene quantification was performed by real-time quantitative PCR (RT-qPCR) of formalin-fixed, paraffin-embedded tissue samples. The gene expression cut-points were determined in a test cohort of 55 STS patients and used to allocate each patient into a more or a less hypoxic group. The cut-points found in the test cohort were applied to a cohort of 77 STS patients for validation.For patients with localised high-grade STS treated with surgery with or without postoperative radiation therapy, the prognostic value of the hypoxia-induced gene profile was proved in the test cohort and confirmed in the validation cohort. After adjustment for confounders, the hazard ratio (HR) was 3.2 (95% CI: 1.5; 7.0) for patients with more hypoxic tumours compared with patients with less hypoxic tumours regarding disease-specific survival. Moreover, for the development of metastatic disease, the HR was 2.61 (95% CI: 1.27; 5.33).The hypoxia-induced gene profile is a validated independent prognostic marker that may help identify STS patients needing more aggressive or different adjuvant treatment.

SUBMITTER: Aggerholm-Pedersen N

PROVIDER: S-EPMC5117798 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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A prognostic profile of hypoxia-induced genes for localised high-grade soft tissue sarcoma.

Aggerholm-Pedersen Ninna N Sørensen Brita Singers BS Overgaard Jens J Toustrup Kasper K Baerentzen Steen S Nielsen Ole Steen OS Maretty-Kongstad Katja K Nordsmark Marianne M Alsner Jan J Safwat Akmal A

British journal of cancer 20161004 9

<h4>Background</h4>For decades, tumour hypoxia has been pursued as a cancer treatment target. However, prognostic and predictive biomarkers are essential for the use of this target in the clinic. This study investigates the prognostic value of a hypoxia-induced gene profile in localised soft tissue sarcoma (STS).<h4>Methods</h4>The hypoxia-induced gene quantification was performed by real-time quantitative PCR (RT-qPCR) of formalin-fixed, paraffin-embedded tissue samples. The gene expression cut ...[more]

PMID: 27701385

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Project description:High-grade soft-tissue sarcoma (STS) is a highly malignant neoplasm with a poor overall prognosis. Numerous prognostic factors determine tumor progression and patient outcomes. Various immune-associated cells identified in the tumor microenvironment have important roles in various tumor types. The present study was performed to evaluate the expression of immune-associated genes and to elucidate the association between these genes and the prognosis in high-grade STS. A total of 12 formalin-fixed, paraffin-embedded tissue samples of high-grade STS were subjected to gene expression analysis using the NanoString nCounter® System and another 35 samples were used for immunohistochemistry. For comparative analysis, the patients were divided into two groups according to overall survival (OS). The expression levels of 770 genes were first analyzed using the nCounter® PanCancer Immune Profiling Panel. Immunohistochemistry was then performed for the most significantly altered genes. Subsequently, the association between gene expression and prognosis of high-grade STS was evaluated. Of the 770 immune-associated genes analyzed, several genes were identified as being differentially expressed between the two groups. Based on gene expression levels and fold change, 13 representative genes were identified; 7 of the 13 candidate genes (C3, CD36, DOCK9, FCER2, FOS, HLA-DRB4 and NCAM1) were significantly overexpressed in the poor prognosis group, while the other 6 immune-associated genes (BIRC5, DUSP4, FOXP3, HLA-DQA1, HLA-DQB1 and LAG3) were increased in the good prognosis group. By immunohistochemistry, the expression of the 13 immune-associated genes was confirmed to be significantly different between the two groups. Expression of HLA-DQA1, HLA-DQB1 and HLA-DRB4 was observed in 74.3, 34.3 and 48.6% of tumors, respectively. HLA-DQA1 and HLA-DQB1 were significantly decreased, whereas HLA-DRB4 was significantly increased in the poor prognosis group. Of note, expression of HLA-DQA1 was associated with a significantly longer OS (P=0.028). In conclusion, HLA-DQA1 expression was significantly associated with long-term survival and may therefore be an immune biomarker for good prognosis in high-grade STS.

Project description:BackgroundStandard treatment of soft tissue sarcoma (STS) of the extremities includes limb-sparing surgery combined with pre- or postoperative radiotherapy (RT). The role of perioperative chemotherapy (CTX) remains uncertain. STS patients with high-risk features for local recurrence, distant metastases, and increased mortality may require additional systemic therapy. The objective of this study was to evaluate predictors of outcome regarding local control (LC), overall survival (OS), and freedom from distant metastases (FFDM) in a large single-center cohort of patients suffering from localized high-grade STS (grade 2/3, G2/G3). Special emphasis was put on a subgroup of patients who received combined neoadjuvant radiochemotherapy (RCT).MethodsOverall, 115 adult STS patients were included in this retrospective study. The median follow-up was 34 months. Twenty-three patients (20.0%) were treated with neoadjuvant RCT, 92 (80.0%) received other therapies (adjuvant RT alone (n = 58); neoadjuvant CTX + adjuvant RT (n = 17); adjuvant RCT (n = 10), neoadjuvant RT alone (n = 7)). To assess potential prognostic factors on LC, OS, and FFDM, univariate (UVA) and multivariable (MVA) Cox proportional hazards models were applied.ResultsUVA showed significantly better LC rates in the neoadjuvant RCT group (p = 0.025), with trends in MVA (p = 0.057). The 3-year LC rate was 89.7% in the neoadjuvant RCT group vs. 75.6% in the "other therapies" group. UVA also showed significantly better OS rates in the neoadjuvant RCT group (p = 0.049), however, this was not confirmed in MVA (p = 0.205), the 3-year OS rate was 85.8% for patients treated with neoadjuvant RCT compared to 73.5% in the "other therapies" group. UVA showed significantly better FFDM rates in (p = 0.018) and a trend towards better FFDM rates in MVA (p = 0.059). The 3-year FFDM rate was 89.7% for patients treated with neoadjuvant RCT compared to 65.9% in the "other therapies" group. In the subgroup of patients with G3 STS, neoadjuvant RCT was a significant positive predictor of LC and FFDM in MVA (p = 0.047, p = 0.027) but not for OS. Overall grade 3 and 4 toxicities were significantly higher (p = 0.019) in the neoadjuvant RCT group and occurred in 73.9% vs. 38.0% in patients receiving other therapies.ConclusionsThe results suggest that neoadjuvant RCT might improve LC and FFDM in patients with localized G3 STS while also being associated with increased acute complication rates. Further prospective research is warranted to confirm these findings.

Dataset Information

A prognostic profile of hypoxia-induced genes for localised high-grade soft tissue sarcoma.

Publications

A prognostic profile of hypoxia-induced genes for localised high-grade soft tissue sarcoma.

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