Several fusion genes identified by whole transcriptome sequencing in a spindle cell sarcoma with rearrangements of chromosome arm 12q and MDM2 amplification

Abstract

Spindle cell tumors are clinically heterogeneous but morphologically similar neoplasms that can occur anywhere, mostly in adult patients. They are treated primarily with surgery to which is often added adjuvant or neoadjuvant radiation. Sub-classification of spindle cell sarcomas requires integration of histology, clinicopathological parameters, immunohistochemistry, cytogenetics (including fluorescence in situ hybridization) and/or molecular genetics. Some of the tumor subtypes are characterized by the presence of distinct chromosomal translocations and fusion genes. When no signs of differentiation are seen, the diagnosis by exclusion becomes undifferentiated spindle cell sarcoma. Cytogenetic, RNA sequencing and RT-PCR analyses were performed on a case of spindle cell sarcoma. The karyotype of the primary tumor was 46,X,del(X)(p?11p?22), der(12)(12pter→12q?22::12q?15→ q?22::16p11→16pter),-16,+r(12). MDM2 was found amplified in both the primary tumor and a metastasis. RNA-Seq of the primary tumor identified four fusion genes, PTGES3-PTPRB, HMGA2-DYRK2, TMBIM4-MSRB3 and USP15-CNTN1, in which all the partner genes map to the q arm of chromosome 12. In material from the metastasis, RT-PCR detected the PTGES3-PTPRB, HMGA2-DYRK2 and TMBIM4-MSRB3 whereas no USP15-CNTN1 fusion transcript was found. Because MDM2 amplification and the fusion transcripts PTGES3-PTPRB, HMGA2-DYRK2 and TMBIM4-MSRB3 were found both in the primary tumor and in the metastasis, they are components of the same clone and may be involved both in initiation and progression of the tumor. Which of them is pathogenetically primary remains unknown.

Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer

“…Thus, variants in MSRB3 could be related with the pathogenesis of thyroid cancer. The fusion of MSRB3 was found in the primary and metastasis tumour spindle cells42. Although we could not find any association between the variant of MSRB3 and MSRB3 expression or clinical phenotypes, there was an association with FTC as well as with PTC.…”

MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies

“…The MDM2 gene has been found to be amplified in several human tumors, including in situ and invasive breast adenocarcinomas [ 20 ], esophageal cancer [ 21 ], sarcomas (either common bone and soft tissue forms) [ 22 , 23 , 24 ], and endometrial stromal tumors [ 25 ]. Importantly, MDM2 gene amplification and TP53 mutation are usually exclusive events [ 24 ].…”

MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer

“…1 ). The MDM2 gene is overexpressed, mainly by gene amplification, in several solid cancers [ 22 ] including in situ and invasive breast adenocarcinomas [ 23 ], sarcomas (either common bone and soft tissue forms) [ 24 – 26 ], esophageal cancer [ 27 ], and endometrial stromal tumor [ 28 ]. It is of interest that, while amplification of the MDM2 gene is a major mechanism of MDM2 overexpression, MDM2 gene amplification and mutation of P53 are commonly mutually exclusive events [ 26 ].…”