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Molecular Biology of Sarcoma

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Molecular Biology of Sarcoma REVIEW ARTICLE Michał Fiedorowicz1, Ewa Bartnik2, 3, Paweł Sobczuk4, 5, Paweł Teterycz4, Anna M. Czarnecka1, 4 1Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland 2Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Poland 3Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland 4Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute — Oncology Centre, Warsaw, Poland 5Department of Experimental and Clinical Physiology, Warsaw Medical University, Warsaw, Poland Molecular biology of sarcoma Address for correspondence: ABSTRACT Anna M. Czarnecka, MD, PhD Soft tissue sarcomas are a large group of heterogenous neoplasms, many of them are highly aggressive. Most of Klinika Nowotworów Tkanek Miękkich, the cases are sporadic, without any well-defined pathogenetic factor. Potential risk factors are ionizing radiation, Kości i Czerniaków lymphatic oedema (secondary angiosarcoma of the breast), viral infections (HHV8 and Kaposi sarcoma), exposure Centrum Onkologii — Instytut to chemical factors (vinyl chloride and hepatic angiosarcoma). Genetic susceptibility plays a role in a minority of im. Marii Skłodowskiej-Curie cases. However, mutations in TP53, ATM and ATR genes are associated with enhanced susceptibility to radiation. ul. Roentgena 5, 02–781 Warszawa Li-Fraumeni syndrome (autosomal dominant TP53 mutation) predisposes to development of malignancies, one Phone: +48 22 546 20 27 third of them are sarcomas. Genetic alterations observed in sarcomas could be divided into three major groups Fax: +48 22 643 93 75 characterized by: (1) chromosome translocations; (2) simple karyotype and mutations; (3) variably complex e-mail: [email protected] karyotypes. A large part of sarcomas belong to the first group and the specific chromosal translocations could Oncology in Clinical Practice be utilized in the diagnostic process. A smaller number of sarcomas could be assigned to the second group, 2018, Vol. 14, No. 6, 307–330 e.g. desmoid fibromatosis (CTNNB1 or APC mutations) and GIST (KIT, PDGFRA, or less frequently BRAF, SDH, DOI: 10.5603/OCP.2018.0045 NF1). A large number of sarcomas are characterized by complex and variable karyotypes. Gene copy number Translation: dr n. med. Dariusz Stencel alterations are frequent in this group, e.g. in well-differentiated liposarcoma there is an amplification of MDM2, Copyright © 2018 Via Medica CDK4 and HMGA2 genes or sarcoma-specific chromosomal break regions present in theCHOP gene in myxoid ISSN 2450–1654 liposarcoma and FKHR in alveolar rhabdomyosarcoma. Key words: sarcoma, genetics, STS Oncol Clin Pract 2018; 14, 6: 307–330 Soft tissue sarcomas account for a large group of Mutations in genes TP53, ATM, and ATR are associ- heterogeneous mesenchymal tumours, which constitute ated with increased sensitivity to ionising radiation and about 1% of solid tumours in adults. Many of them subsequent development of sarcomas [3]. In 10% of are very aggressive, so they are responsible for dispro- patients with type 1 neurofibromatosis (NF1, mutation portionately more malignancy-related deaths in young in the gene encoding neurofibromin 1) gastrointestinal adults than cancers. Their typical classification is based stromal tumours (GIST) as well as malignant peripheral on the similarity to healthy mesenchymal tissues to which nerve sheath tumours (MPNST) develop. Li-Fraumeni the type of specific sarcoma is the closest. The term soft syndrome (autosomal dominant mutation in the tissue sarcoma includes more than 70 types, and primary TP53 gene encoding p53 tumour suppressor protein) sarcoma consists of 12 basic types, which differ in terms predisposes to the development of malignant tumours, of pathological and clinical features [1, 2]. one third of them are sarcomas. Other syndromes that In the vast majority of cases, sarcomas occur sporadi- predispose to the development of sarcomas are Gardner cally, without a clearly defined factor underlying tumori- syndrome (desmoid tumour), Werner syndrome (soft genesis. Possible risk factors include exposure to ionising tissue sarcomas), Bloom’s syndrome (osteosarcoma), radiation, lymphoedema (breast angiosarcoma), viral Beckwith-Wiedemann syndrome (rhabdomyosarcoma), infections (HHV8 — Kaposi sarcoma), or exposure to and Costello syndrome (rhabdomyosarcoma). Some of chemical agents (vinyl chloride — liver angiosarcoma) [2]. the spindle cell sarcomas (SCSs) are present during the 307 ONCOLOGY IN CLINICAL PRACTICE 2018, Vol. 14, No. 6 course of other diseases, for example osteosarcomas dur- Recently published genomic research of the Can- ing Paget’s disease or chondrosarcomas during multiple cer Genome Atlas Research Network (https://can- cartilage-capped bony excrescences [2, 4–6]. cergenome.nih.gov/) [8] included a genetic analysis of Recent studies on a group of 1162 patients with sar- 206 tumours of six major types of adult sarcomas. There comas suggest other genetic risk factors, such as BRCA2, were five tumours with complex karyotype: (1) dedif- ATM, ATR, and ERCC2 gene damage [3]. The early ferentiated liposarcoma (DDLPS ), (2) leiomyosarcoma phase research centre MD Anderson Cancer Centre (LMS), (3) undifferentiated pleomorphic sarcoma carried out an analysis of potential mutations in patients (UPS), (4) myxofibrosarcoma (MFS), (5) malignant with soft tissue sarcomas, i.e. 102 consecutive patients peripheral nerve sheath tumour and sarcoma with directed to this centre were tested using the Foundation a relatively simple karyotype, and (6) synovial sarcoma, Medicine (FoundationOne) test based on next-genera- in which a single chromosomal translocation t(X;18) tion sequencing (NGS). The study included a panel of (p11;q11) is typically observed. In contrast to tumours 315 genes for which targeted drugs are established. Most of epithelial origin, the examined sarcomas (with the commonly the mutations were found in TP53 (31.4% of exception of synovial sarcoma) are characterised pri- patients), CDK4 (23.5%), MDM2 (21.6%), RB1 (18.6%), marily by changes in the number of gene copies, with and CDKN2A/B (13.7%) genes. Interestingly, 50% of a small overall number of point mutations (insertions, patients receiving treatment based on the result of the test deletions, missense mutations). A high number of mu- (16%) achieved stable disease (SD). Of the 102 patients tations occur in only a few genes (TP53, ATRX, RB1), in the examined cohort, 40 (39%) were characterised by which are “repeated” in many types of sarcomas. For either no known mutation (7%) or no mutation currently example, while MDM2 amplification was present in all recognised as the target of the available drug (32%). The DDLPS, deletions in TP53 were found in 9% of LMS, remaining 62 (61%) patients had mutations potentially 16% of UPS, and 12% of MFS. In RB path, RB1 dele- allowing the use of targeted therapy. Fourteen (14%) tions were detected in 14% of LMS, 16% of UPS, and patients had lesions that could be used for treatment 24% of MFS; and CDKN2A deletions (p16) in 8% of with the medicinal products registered for sarcoma treat- LMS, 20% of UPS, and 18% of MFS. The disturbances ment. There were cases of treatment with pazopanib or of the RB pathway also included CDK4 amplification in imatinib, which included five patients with the PDGFR 86% and CDKN2A deletions in 2% of DDLPS. Gener- mutation (1 GIST), four with the FGFR mutation, three ally, it has been shown that the total number of somatic with the KIT mutation (2 GIST), and two with the KDR mutations in the aforementioned types of sarcomas are gene aberrations [7]. Due to the high heterogeneity of relatively low (1.06 per Mb); however, 67% of tumours sarcomas one should expect a very wide spectrum of carried mutations previously known as potentially on- genome damage but also numerous epigenetic changes. cogenic. The highest mutation burden was identified Generally, the genetic changes observed in sarcomas in DDLPS and MPNST, mostly C>T mutations in the can be divided into three groups: CpG islands. Only 12% of the tumours had elongated — chromosomal translocations; telomeres. A significant role in tumour progression — point mutations without changing the karyotype; of sarcomas may be played by specific changes in the — the presence of a variable and complex karyotype; DNA methylation pattern and regulation via miRNA. The sarcomas characterised by the presence of In these studies, JUN gene amplification was identified the first group of lesions (translocations) include as a potential marker for shorter survival and a puta- a significant proportion of sarcomas. Occurrence of tive therapeutic target in the subgroup of DDLPS sar- translocations is used for diagnostic purposes (Tables comas. Although it has been found that uterine LMS 1, 2). A smaller number of cases could be included in (ULMS) and soft tissue LMS (STLMS) are molecularly the group of the second type of defects (point muta- distinct, inhibitors of the PI3K-AKT-mTOR signalling tions), for example desmoid tumour (CTNNB1 or APC pathway may have potential application in the treatment gene mutations) or GIST (KIT or PDGFRA mutations, of both sarcoma groups. STLMS were characterised by significantly less BRAF, SDH, NF1). Finally, a large the activation of the HIF1a and IGF1R pathway, cell cy- proportion of sarcomas are classified as the third type cle (CCNE2 — G1/S-Specific Cyclin-E2), DNA replica- of lesion, which are characterised by a complex
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