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Loss of p16(INK4a) is associated with reduced patient survival in soft tissue tumours, and indicates a senescence barrier
  1. Thomas Knösel1,
  2. Annelore Altendorf-Hofmann2,
  3. Lars Lindner3,
  4. Rolf Issels3,
  5. Heiko Hermeking4,
  6. Gesa Schuebbe3,
  7. Sebastian Gibis3,
  8. Helge Siemens4,
  9. Eric Kampmann3,
  10. Thomas Kirchner1
  1. 1Institute of Pathology, Ludwig-Maximilians-University (LMU), Munich, Germany
  2. 2Department of General, Visceral und Vascular Surgery, Friedrich-Schiller University, Jena, Germany
  3. 3Department of Internal Medicine III, Ludwig-Maximilians-University (LMU), Munich, Germany
  4. 4Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University (LMU), Munich, Germany
  1. Correspondence to Professor Thomas Knösel, Institute of Pathology, Ludwig-Maximilians-University (LMU), Thalkirchnerstr. 36, Munich 80337, Germany; Thomas.Knoesel{at}med.uni-muenchen.de

Abstract

Aims p16(INK4a) is an important factor in carcinogenesis, and its expression is linked to oncogene-induced senescence. Very recently it was shown that upregulation and downregulation of p16 indicates a senescence barrier in the serrated route of colorectal cancer. However, in soft tissue sarcoma (STS), the senescence mechanism is still not understood. In this study, we analysed a well characterised cohort of STS for p16(INK4a) expression and correlated the results with clinicopathological parameters including survival.

Methods Tissue microarrays (TMA) of 183 soft tissue and bone tumours were analysed immunohistochemically. Furthermore, mRNA expression of p16(INK4a) was evaluated in four sarcoma cell lines, and a demethylation test was performed by treatment with 5-aza-2′-deoxycytide.

Results On protein level, expression of p16(INK4a) was observed in undifferentiated pleomorphic sarcoma (UPS) in 69.1%, leiomyosarcoma in 85.7%, synovial sarcoma in 77.8%, liposarcoma in 88.9%, angiosarcoma in 60.9% and MPNST in 22.2%. Loss of p16(INK4a) was observed in high grade sarcomas and showed a significant correlation with reduced patient survival (p=0.032). On DNA level, one out of four sarcoma cell lines exhibited a methylated p16(INK4a) promoter analysed by methylation-specific PCR. p16(INK4a) mRNA and protein expression was restored after demethylation using 5-aza-2′-deoxycytide.

Conclusions Upregulation of p16(INK4a) might be associated with the induction of senescence and indicates a senescence barrier. Downregulation of p16(INK4a) is found in malignant progression, and is significantly correlated with reduced patient survival. Downregulation of p16(INK4a) may be explained by DNA-hypermethylation in sarcoma cells.

  • Soft Tissue Tumours
  • Tumour Biology
  • Molecular Pathology

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