Dataset Information

Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas.

ABSTRACT: Bone and soft tissue sarcomas are a group of histologically heterogeneous and relatively uncommon tumors. To explore their genetic origins, we sequenced the exomes of 13 osteosarcomas, eight myxoid liposarcomas (MLPS), and seven synovial sarcomas (SYN). These tumors had few genetic alterations (median of 10.8). Nevertheless, clear examples of driver gene mutations were observed, including canonical mutations in TP53, PIK3CA, SETD2, AKT1, and subclonal mutation in FBXW7. Of particular interest were mutations in H3F3A, encoding the variant histone H3.3. Mutations in this gene have only been previously observed in gliomas. Loss of heterozygosity of exomic regions was extensive in osteosarcomas but rare in SYN and MLPS. These results provide intriguing nucleotide-level information on these relatively uncommon neoplasms and highlight pathways that help explain their pathogenesis.

SUBMITTER: Joseph CG

PROVIDER: S-EPMC4007004 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas.

Joseph Christine G CG Hwang Heejung H Jiao Yuchen Y Wood Laura D LD Kinde Isaac I Wu Jian J Mandahl Nils N Luo Jinyong J Hruban Ralph H RH Diaz Luis A LA He Tong-Chuan TC Vogelstein Bert B Kinzler Kenneth W KW Mertens Fredrik F Papadopoulos Nickolas N

Genes, chromosomes & cancer 20131105 1

Bone and soft tissue sarcomas are a group of histologically heterogeneous and relatively uncommon tumors. To explore their genetic origins, we sequenced the exomes of 13 osteosarcomas, eight myxoid liposarcomas (MLPS), and seven synovial sarcomas (SYN). These tumors had few genetic alterations (median of 10.8). Nevertheless, clear examples of driver gene mutations were observed, including canonical mutations in TP53, PIK3CA, SETD2, AKT1, and subclonal mutation in FBXW7. Of particular interest we ...[more]

PMID: 24190505

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Project description:Myxoid liposarcoma (LS), the most common subtype of LS, is known to be characterized by the specific t(12;16) resulting in a TLS-CHOP fusion in almost all cases. We wished to address the following questions: (i) Is this genetic hallmark also present in other types of LS with predominant myxoid change? (ii) What is the proportion of cases with the variant EWS-CHOP fusion? (iii) What is the optimal approach for Southern blot detection of TLS breakpoints? We identified 59 LS characterized histologically by >90% myxoid component, in which frozen tissue tumor was available for DNA extraction. These 59 LS with myxoid features were divided into 2 groups: 42 LS with classic myxoid/round cell appearance (myxoid LS) and 17 well-differentiated LS (WDLS) with a predominant (>90%) myxoid component. Within the myxoid LS group, 29 tumors were low grade and 13 high grade (>20% round cell component). Among the 17 predominantly myxoid WDLS, there were 15 low grade and 2 focally high grade tumors. In addition, we selected as control group, 20 LS of other histological types with minimal or no myxoid change (17 WDLS and 3 pleomorphic LS) and 13 myxofibrosarcomas. Southern blot analysis was performed in all cases using a CHOP cDNA probe, and in all CHOP rearranged cases using a TLS cDNA probe. Probe/enzyme combinations for Southern blot analysis were CHOP exon 3-4 cDNA probe with BamHI or SacI, TLS exon 3-6 cDNA probe with BclI. All 42 cases of myxoid LS showed a CHOP rearrangement and 38 of them also had a TLS rearrangement. Among the 4 myxoid LS without Southern blot evidence of TLS rearrangement, 1 showed an EWS-CHOP fusion by Southern blotting and reverse transcriptase-polymerase chain reaction and in another case, reverse transcriptase-polymerase chain reaction detected a TLS-CHOP fusion transcript. None of the predominantly myxoid WDLS and none of the tumors included in the control group showed rearranegements with CHOP probe. In addition, 12 predominantly myxoid WDLS, 10 other LS, and 5 myxofibrosarcoma from the control group were also tested for TLS rearrangement; all were negative. The TLS-CHOP fusion is highly sensitive and specific for the entity of classic myxoid/round cell LS. Other types of LS, even with a predominant myxoid component, lack the TLS-CHOP rearrangement, confirming that they represent a genetically distinct group of LS. The prevalence of the EWS-CHOP variant fusion was approximately 2% in this series. The optimal enzyme for TLS genomic breakpoint detection is BclI.

Project description:BackgroundRecently, recurrent point mutations in the telomerase reverse transcriptase (TERT) promoter region have been found in many human cancers, leading to a new transcription factor binding site, increased induction of TERT and subsequently to telomere maintenance. We determined the prevalence of TERT promoter mutations in soft tissue sarcomas of 341 patients comprising 16 entities and in 16 sarcoma cell lines covering 7 different soft tissue sarcoma types.MethodsThe sarcoma tissue samples were collected from the archives of the Institute of Pathology, University of Heidelberg and were composed of 39 myxoid liposarcomas (MLS), 61 dedifferentiated liposarcomas, 15 pleomorphic liposarcomas, 27 leiomyosarcomas, 25 synovial sarcomas (SS), 35 malignant peripheral nerve sheath tumors (MPNST), 40 undifferentiated pleomorphic sarcomas, 17 myxofibrosarcomas, 9 low grade fibromyxoid sarcomas, 10 cases of dermatofibrosarcoma protuberans, 31 solitary fibrous tumors (SFT), 8 extraskeletal myxoid chondrosarcomas, 9 angiosarcomas, 6 alveolar soft part sarcomas, 5 clear cell sarcomas and 4 epithelioid sarcomas. Sarcoma cell lines were obtained from the raising laboratories. A 193 bp fragment of the TERT promoter region covering the hot-spot mutations C228T and C250T was amplified, and direct sequencing of the PCR products was performed.ResultsTERT promoter mutations were detected in 36/341 sarcomas. They were highly recurrent in MLS (29/39; 74%) and were in the present MLS series not associated with the phenotype (myxoid vs. round cell variant), tumor grade, tumor site and patients' median age or gender. In the remaining cases, TERT promoter mutations were found only in 7/302 sarcoma samples and confined to SFTs (4/31; 13%), MPNSTs (2/35; 6%), and SSs (1/25; 4%). Within the collection of sarcoma cell lines examined, TERT promoter mutations were detected in two MLS and in one of three MPNST cell lines.ConclusionsTERT promoter mutations are frequent in MLSs including their round cell variants, representing the most prevalent mutation identified in this sarcoma entity to date, and in a minor fraction of SFTs, MPNSTs and SSs. The majority of sarcomas are devoid of TERT promoter hotspot mutations. These data suggest that telomere maintenance through increased expression of telomerase plays an important role in the pathogenesis especially of MLS.

Dataset Information

Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas.

Publications

Exomic analysis of myxoid liposarcomas, synovial sarcomas, and osteosarcomas.

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