Involvement of the PI3K/Akt pathway in myxoid/round cell liposarcoma

Elizabeth G. Demicco, Keila E. Torres, Markus P. Ghadimi, Chiara Colombo, Svetlana Bolshakov, Aviad Hoffman, Tingsheng Peng, Judith V M G Bovée, Wei Lien Wang, Dina Lev, Alexander J. Lazar

Research output: Contribution to journalArticlepeer-review

Abstract

The molecular determinants involved in the progression of myxoid liposarcoma to increased cellularity/round cell change are poorly understood. We studied the PI3K/Akt pathway in myxoid and round cell liposarcomas using a tissue microarray composed of 165 tumors from 111 patients, and mutational analysis of PIK3CA in 44 cases. Activating PIK3CA mutations were found in 6/44 cases, 14%; mutations were more frequent in round cell vs myxoid tumors (5/15, 33% vs 1/29, 3%; P=0.013). Complete loss of PTEN, an alternative mechanism for PI3K/Akt activation, was found in 13/111 (12%) cases and was mutually exclusive with PIK3CA mutation. Strong IGF1R expression was demonstrated in 14/39 (36%) of round cell and 11/58 (19%) of myxoid tumors (P=0.062). Activation of the PI3K pathway was confirmed using immunohistochemical analysis for downstream targets phospho-S6 ribosomal protein and phospho-4EBP1. Phospho-4EBP1 was increased in round cell tumors compared with myxoid tumors (24/30, 80% vs 25/44, 57%; P=0.038) or tumors with treatment effect (10/24, 42%; P=0.02). Phospho-S6 was highly expressed in both myxoid and round cell tumors (29/47, 62% and 14/30, 47%, respectively; P0.2). In tumors with PIK3CA mutation, any IGF1R expression, or loss of PTEN expression, phospho-4EBP1 was more frequently elevated compared with tumors without a known activating event in the PI3K pathway (55/72; 76% vs 3/8, 38%; P=0.033). These findings suggest that activation of the PI3K/Akt pathway via activating mutation of PIK3CA, loss of PTEN, or IGF1R expression have a role in round cell transformation. The PI3K/Akt pathway may therefore provide a therapeutic target in round cell liposarcoma.

Original languageEnglish
Pages (from-to)212-221
Number of pages10
JournalModern Pathology
Volume25
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • IGF1R
  • myxoid liposarcoma
  • PI3K
  • PTEN
  • round cell liposarcoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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