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

Abstract

The molecular determinates 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 to 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; p=0.2). In tumors with PIK3CA mutation, any IGF1R expression, or loss of PTEN expression, phospho-4EBP1 was more frequently elevated compared to 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 play a role in round cell transformation. The PI3K/Akt pathway may therefore provide a therapeutic target in round cell liposarcoma.

Extensive Survey of STAT6 Expression in a Large Series of Mesenchymal Tumors

“…Specimens included in the study included whole tumor sections at 4 μm obtained from UMMC and ISMMS (n= 33 and 3 respectively, including 33 solitary fibrous tumors and 3 other sarcomas), sections from a diverse array of previously published sarcoma-specific tissue microarrays, including: soft tissue and uterine leiomyosarcomata, 28, 29 miscellaneous, predominately complex karyotype sarcomas, 30, 31 desmoid tumors, 32, 33 malignant peripheral nerve sheath tumors, 34 angiosarcomas, 35 , alveolar soft part sarcomas, 36 epithelioid sarcoma, 37 myxoid liposarcoma, 38 pleomorphic liposarcoma, 39 well-differentiated/ de-differentiated liposarcoma, 40 and 5 previously unpublished tumor-specific tissue microarrays, including: solitary fibrous tumors (2 arrays, from UTMDACC and ISMMS, respectively, including meningeal hemangiopericytomas), clear cell sarcoma, an additional well-differentiated/de-differentiated liposarcoma array, and neurofibromatosis-associated malignant peripheral nerve sheath tumors.…”

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

“…16 From MDACC, myxoid liposarcoma tissue microarrays contained untreated tumors and tumors pre-treated with chemotherapy, radiation, or a combination of both. 17,18 From the LUMC, tissue microarrays were selected containing chondrosarcomas, 19,20 osteosarcomas, 21 myxoid liposarcomas, and a variety of benign and malignant soft tissue tumors. 22,23 Immunohistochemistry Immunohistochemical staining was performed with an autostainer for tissue microarrays of the UBC and MDACC following protocols as described previously.…”

Establishment and characterization of a new human myxoid liposarcoma cell line (DL-221) with the FUS-DDIT3 translocation

“…8;20;21 Activating mutations in PIK3CA are found in 14–18% of MLS and loss of expression of PTEN is found in 12% of the tumors and is mutually exclusive from PIK3CA mutations. 22;23 Increased PI3K/Akt signalling has been demonstrated by high expression of downstream targets like phosphorylated 4EBP1, PRAS40 and S6. The PIK3CA mutation rate, IGFR expression and loss of PTEN were higher in tumors with a round cell component suggesting that this pathway might be involved in round cell transformation and tumor progression.…”