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Molecular cytogenetic studies of soft tissue sarcoma : with focus on prognosis and acquired events

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posted on 2024-09-03, 05:46 authored by Wen-Hui Weng

Soft tissue sarcomas (STSs) constitute a heterogenous group of highly aggressive tumors of mesenchymal origin that account for approximately 1% of all human malignancies. With the aim of eventually improving the diagnostics and clinical handling of these patients, considerable research efforts have been invested to understand the natural history of these tumors. In this thesis, we applied both molecular and cytogenetic techniques to identify specific genetic events associated with clinical outcome, drug resistance and tumor progression in soft tissue sarcomas.

In paper I, a panel of 39 primary malignant fibrous histiocytomas (MFH) of high malignancy grade were characterized by comparative genomic hybridization (CGH) analyses. The genetic alterations were then evaluated in relation to the survival and the tumor recurrent during follow-up. Our results suggest that the clinical outcome of MFH is associated with the genetic profiles of the primary tumors. Importantly, a subgroup of MFHs characterized by a low risk of developing metastasis and local recurrence is recognized based on their frequent gains of 17q, and hence a better survival.

In paper II, we evaluated the prognostic role of ezrin in a series of 50 patients with primary highly malignant STSs using immunohistochemistry and correlated its expression to clinical outcome. Among the STSs analyzed, half of the cases showed positive ezrin immunoreactivity in the membrane and cytoplasm of the tumor cells. Positive expression was significantly associated with death from or with disease as well as development of metastasis. Our findings suggest that ezrin immunoreactivity could be valuable as an additional prognostic marker for this tumor type.

In paper III, we aimed to establish Picropodophyllin (PPP) resistance in human malignant cells and to investigate the involved mechanisms. Four established human cancer cell lines with documented IGF-1R function and responsiveness to PPP treatment were exposed to increasing concentrations of PPP for up to 80 weeks. Only two cell lines survived the selection process, and in both of them, the resistance development was remarkably slow and limited. During the first 40 weeks, these lines successively developed moderate increase of IGF-1R expression, whereafter the expression returned to normal levels. The increased IGF-1R expression was overlapped by some genetic changes, and the common alteration for both cell lines was gains in chromosome 11p12-q13. None of the resistant cell lines exhibited increase in the expression of multidrug-resistance related proteins MDR1 or MRP1.

In paper IV, we characterized the chromosomal composition of an MFH case using a combination of SKY, G-banding, CGH, and cDNA array-CGH.This MFH was shown to carry large chromosome markers with a high-level amplification at the regions of 6q21-23, 8p21-pter, 8q24-qter and 12q13-15, suggesting that these regions might harbor oncogenes that could play important role in the tumorigenesis.

In paper V, we performed CGH, mutation screening, SKY and Southern analyses in a series of 32 STSs from 26 patients. CGH analyses revealed frequent chromosomal imbalances involving several different chromosomes. The most common finding was deletions involving chromosome 13 that was seen in nearly half of the cases. Southern analyses excluded the involvement of candidate suppressors such as RB gene, which frequently deleted region in CLL, and pointed towards the involvement of a more telomeric target.

In paper VI, we reported a case of two synovial sarcomas occurring synchronously with biphasic feature in a 10-year old girl. Molecular and cytogenetic analyses were performed on these tumor samples, as well as the peripheral leukocytes. A SS18-SSX2 fusion was detected by both RT-PCR and FISH assays in the tumor samples, but not in the blood sample. An apparently normal karyotype was found in the leukocytes, suggesting that the SS18-SSX2 fusion detected in the tumor samples is an acquired event.

List of scientific papers

I. Weng WH, Ahlen J, Lui WO, Brosjo O, Pang ST, Von Rosen A, Auer G, Larsson O, Larsson C (2003). Gain of 17q in malignant fibrous histiocytoma is associated with a longer disease-free survival and a low risk of developing distant metastasis. Br J Cancer. 89(4): 720-6.
https://pubmed.ncbi.nlm.nih.gov/12915885

II. Weng WH, Ahlen J, Astrom K, Lui WO, Larsson C (2005). Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue sarcomas. [Manuscript]

III. Vasilcanu D, Weng WH, Girnita A, Lui WO, Axelson M, Girnita L, Larsson C, Larsson O (2005). Malignant cells exhibit limited resistance to the insulin-like growth factor receptor 1 inhibitor PPP. [Manuscript]

IV. Weng WH, Wejde J, Ahlen J, Pang ST, Lui WO, Larsson C (2004). Characterization of large chromosome markers in a malignant fibrous histiocytoma by spectral karyotyping, comparative genomic hybridization (CGH), and array CGH. Cancer Genet Cytogenet. 150(1): 27-32.
https://pubmed.ncbi.nlm.nih.gov/15041220

V. Weng WH, Lerner M, Grander D, Ahlen J, Villablanca A, Pang ST, Wejde J, Lui WO, Larsson C (2005). Loss of chromosome 13q is a frequently acquired event in genetic progression of soft tissue sarcomas in the abdominal cavity. Int J Oncol. 26(1): 5-16.
https://pubmed.ncbi.nlm.nih.gov/15586219

VI. Weng WH, Claviez A, Krams M, Larsson, Larsson C, Suttorp M (2005). A unique case of two synovial sarcomas occuring synchronously in a 10-year old girl. [Manuscript]

History

Defence date

2005-04-12

Department

  • Department of Molecular Medicine and Surgery

Publication year

2005

Thesis type

  • Doctoral thesis

ISBN-10

91-7140-241-1

Number of supporting papers

6

Language

  • eng

Original publication date

2005-03-22

Author name in thesis

Weng, Wen-Hui

Original department name

Department of Molecular Medicine

Place of publication

Stockholm

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