Molecular biology of sarcoma (original) (raw)
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Molecular pathology of sarcomas: concepts and clinical implications
Virchows Archiv, 2010
The molecular genetic changes that have been described in sarcomas over the past era have aided our understanding of their pathogenesis. The majority of sarcomas carry nonspecific genetic changes within a background of a complex karyotype. These constitute the challenges in sarcoma research for unraveling a putative multistep genetic model, such as for chondrosarcoma, and finding targets for therapeutic strategies. Approximately 15-20% of mesenchymal tumors carry a specific translocation within a relatively simple karyotype. The resulting fusion products act either as transcription factors upregulating genes responsible for tumor growth, as for instance in Ewing sarcoma, or translocate a highly active promoter in front of an oncogene driving tumor formation, as for instance in aneurysmal bone cyst. In addition, a small subset of mesenchymal tumors have specific somatic mutations driving oncogenesis. The specific genetic changes unraveled so far had great impact on the classification of bone and soft tissue tumors. In addition, these changes can assist the pathologist in the differential diagnosis of some of these entities, especially within the groups of small blue round cell tumors and spindle cell tumors, if performed in specialized centers. While a putative association between certain fusion products and outcome is still under debate, the role of predicting response of targeted therapy has been well established for KIT and PDGFRA mutations in gastrointestinal stromal tumors.
REVIEW AND PERSPECTIVE Molecular pathology of sarcomas: concepts and clinical implications
2013
The molecular genetic changes that have been described in sarcomas over the past era have aided our understanding of their pathogenesis. The majority of sarcomas carry nonspecific genetic changes within a background of a complex karyotype. These constitute the challenges in sarcoma research for unraveling a putative multistep genetic model, such as for chondrosarcoma, and finding targets for therapeutic strategies. Approximately 15–20 % of mesenchymal tumors carry a specific translocation within a relatively simple karyotype. The resulting fusion products act either as transcription factors upregulating genes responsible for tumor growth, as for instance in Ewing sarcoma, or translocate a highly active promoter in front of an oncogene driving tumor formation, as for instance in aneurysmal bone cyst. In addition, a small subset of mesenchymal tumors have specific somatic mutations driving oncogenesis. The specific genetic changes unraveled so far had great impact on the classificatio...
The Clinical Relevance of Molecular Genetics in Soft Tissue Sarcomas
Advances in Anatomic Pathology, 2010
Bone and soft tissue sarcomas are an infrequent and heterogeneous group of mesenchymal tumors including more than a hundred different entities attending to histologic patterns. Research into the molecular aspects of sarcomas has increased greatly in the last few years. This enormous amount of knowledge has allowed, for instance, to refine the classification of sarcomas, improve the diagnosis, and increase the number of therapeutical targets available, most of them under preclinical evaluation. However, other important key issues, such as sarcomagenesis and the cell of origin of sarcomas, remain unresolved. From a molecular point of view, these neoplasias are grouped into 2 main types: (a) sarcomas showing relatively simple karyotypes and translocations, which originate gene fusions (eg, EWS-FLI1 in Ewing sarcoma) or point mutations (eg, c-kit in the gastrointestinal tumors) and (b) sarcomas showing unspecific gene alterations, very complex karyotypes, and no translocations. The discovery of the early mechanisms involved in the genesis of sarcomas, the more relevant signaling pathways, and the development of genetically engineered mouse models could also provide a new individualized therapeutic strategy against these tumors. This review describes the clinical application of some of the molecular alterations found in sarcomas, some advances in the field of sarcomagenesis, and the development of animal models.
Laboratory Investigation, 2005
Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma. Nevertheless, the validity of this heterogeneous pathological entity has been recurrently questioned by pathologists. Recently, analyses by comparative genomic hybridization (CGH) of a large series of MFHs suggested that MFHs consist of morphologic modulation of other poorly differentiated sarcomas like leiomyosarcomas (LMS) or dedifferentiated liposarcomas (DLPS). We report here an analysis by CGH of 22 myxoid MFHs (mMFH), one of the five histological subtypes of MFH, and of nine pleomorphic liposarcomas (pLPS), a rare poorly differentiated LPS. The chromosome imbalances encountered in the series of mMFH were very similar to those observed in the series of pLPS studied in the laboratory and in the series of 14 pLPS published in the literature. The most frequent gains involved chromosome subregions: pericentromeric regions of 1, 5p, 19p, 19q and 20q. Losses found in the chromosomal arms 1q, 2q, 3p, 4q, 10q, 11q and 13q were also recurrent. The use of a clustering software did not separate the two pathological groups (mMFH and pLPS) on the basis of genomic data. Moreover, pLPS-mMFH represented, according to the clustering software results, an entity clearly distinguished from other soft tissue sarcomas, LMS in particular, with which they share common genetic aberrations. Additional studies are needed to identify genes targeted by these genomic aberrations, and implicated in the oncogenesis of these tumor subtypes. The characterization of common gene alterations in both tumor groups would suggest a closer relationship between these two types of soft tissue sarcomas.
Chromosome-12 copy number alterations and MDM2, CDK4 and TP53 expression in soft tissue liposarcoma
Anticancer research
Liposarcoma is a heterogeneous group of soft tissue sarcomas in which definitive prognostic parameters need to be identified. The series included 33 consecutive soft tissue (well-differentiated, WDLPS, n=19; and dedifferentiated, DDLPS, n=14) liposarcoma. Clinicopathological variables included age, gender, body location, degree of dedifferentiation and mitotic count. The rrolecular analysis included MDM2, CDK4 and TP53 expressions and chromosome-12 copy number alterations. Centrally located (retroperitoneal, abdominal cavity or groin region) WDLPS had more dedifferentiation (p=0.001). Patients with DDLPS and a high mitotic rate died (p=0.070) or experienced recurrencies (p=0.029) more frequently. Co-expression of MDM2/CDK4 (p=0.001) and TP53 accumulation (p=0.017) related to dedifferentiation but not to recurrence or death, both in WDLPS and DDLPS. DDLPS had higher centromeric chromosome-12 copy number than WDLPS (p=0.013), but this was unrelated to recurrence or death. Central loca...
Molecular classification of soft tissue sarcomas and its clinical applications
International journal of clinical and experimental pathology, 2010
Sarcomas are a heterogeneous group of tumors that are traditionally classified according to the morphology and type of tissue that they resemble, such as rhabdomyosarcoma, which resembles skeletal muscle. However, the cell of origin is unclear in numerous sarcomas. Molecular genetics analyses have not only assisted in understanding the molecular mechanism in sarcoma pathogenesis but also demonstrated new relationships within different types of sarcomas leading to a more proper classification of sarcomas. Molecular classification based on the genetic alteration divides sarcomas into two main categories: (i) sarcomas with specific genetic alterations; which can further be subclassified based on a) reciprocal translocations resulting in oncogenic fusion transcripts (e.g. EWSR1-FLI1 in Ewing sarcoma) and b) specific oncogenic mutations (e.g. KIT and PDGFRA mutations in gastrointestinal stromal tumors) and (ii) sarcomas displaying multiple, complex karyotypic abnormalities with no specif...
The Journal of Pathology, 2009
which limited genetic information, including a t(1;10)(p22;q24) and amplification of chromosome 3 material, is available. To further characterize these aberrations, we have investigated eight soft tissue sarcomas diagnosed as MIFS, haemosiderotic fibrolipomatous tumour (HFT), myxoid spindle cell/pleomorphic sarcoma with MIFS features, and inflammatory malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma with prominent inflammation (IMFH) harbouring a t(1;10) or variants thereof and/or ring chromosomes with possible involvement of chromosome 3. Using chromosome banding, fluorescence in situ hybridization, array-based comparative genomic hybridization, global gene expression, and real-time quantitative PCR analyses, we identified the breakpoint regions on chromosomes 1 and 10, demonstrated and delineated the commonly amplified region on chromosome 3, and assessed the consequences of these alterations for gene expression. The breakpoints in the t(1;10) mapped to TGFBR3 in 1p22 and in or near MGEA5 in 10q24, resulting in transcriptional up-regulation of NPM3 and particularly FGF8, two consecutive genes located close to MGEA5. The ring chromosomes contained a commonly amplified 1.44 Mb region in 3p11-12, which was associated with increased expression of VGLL3 and CHMP2B. The identified genetic aberrations were not confined to MIFS; an identical t(1;10) was also found in a case of HFT and the amplicon in 3p was seen in an IMFH.
Modern Pathology, 2003
Few studies have investigated the loss of heterozygosity and microsatellite instability in soft tissue sarcomas. Therefore, we analyzed samples of human soft tissue sarcomas to determine the status of the chromosomal region 12q14 -15, which contains the MDM2 gene encoding the well-known counterpart of the tumor suppressor p53. In addition, we determined whether an amplified MDM2 gene was present in the samples. Of the 88 soft tissue sarcoma samples, 24 (27%) showed evidence of loss of heterozygosity of markers representing 12q14 -15, and 12 (14%) showed evidence of microsatellite instability. Of the 72 samples analyzed by semiquantitative polymerase chain reaction, 15 (21%) possessed an amplified MDM2 gene. Loss of heterozygosity (P ؍ .008) and microsatellite instability (P ؍ .035) were significantly more common in Stage I tumors than in higher stage tumors. This result indicated that these alterations occur early in soft tissue sarcoma progression and possibly define a subgroup of soft tissue sarcoma. Surprisingly, MDM2 amplification in soft tissue sarcoma patients was associated with a prognosis better than that of patients without the amplification; however, this difference was not statistically significant (P ؍ .6). Furthermore, of the tumors with an MDM2 amplification, 40% (6/15) also experienced loss of heterozygosity at 12q14 -15; in contrast, only 16% of tumors without an MDM2 amplification (9/57) underwent a loss of heterozygosity. A concomitant occurrence of deletions and amplifications resulting from deficiencies in the nonhomologous end-joining pathway could in part explain this finding.
Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas
Cancer research, 1994
Genetic alterations in the p53 and mdm2 genes have been reported to occur in soft tissue sarcomas. This study was designed to determine the prevalence and potential clinical value of detected molecular abnormalities and altered patterns of expression of mdm2 and p53 genes in adult soft tissue sarcomas. A cohort of 211 soft tissue sarcomas from adults that were both clinically and pathologically well characterized was analyzed. Monoclonal antibodies directed against mdm2 and p53 proteins were used to measure overexpression of these proteins in the nuclei of cells from sections of these tumors. Seventy-six of 207 tumors had abnormally high levels of mdm2 proteins and 56 of 211 tumors overexpressed p53 protein. Twenty-two cases had abnormally high levels of both mdm2 and p53 proteins based upon immunoreactivity with these antibodies. There was a striking statistically significant correlation between the overexpression of p53 and mdm2 proteins in the same tumor and poor survival (P <...
Human Pathology, 2009
Since the first description of sclerosing rhabdomyosarcoma in 2000, 19 pediatric cases have been reported in the literature. However, it is debated whether sclerosing rhabdomyosarcoma represents a specific rhabdomyosarcoma entity or a variant of embryonal or alveolar rhabdomyosarcoma. To date, 6 sclerosing rhabdomyosarcoma karyotypes and 1 sclerosing rhabdomyosarcoma comparative genomic hybridization profile have been reported. We present the first whole-genome tumoral genotyping of a sclerosing rhabdomyosarcoma by high-density single nucleotide polymorphism array. The single nucleotide polymorphism genotyping revealed a complex pattern including gains and losses of whole chromosomes and an amplification of the 12q13-15 region. Amplification of the 12q13-q15 region containing SAS, GLI, CDK4, and MDM2 has been observed in rhabdomyosarcoma. In the present case, the 2 amplified target genes were MDM2 and HMGA2, excluding CDK4. The identification of a specific MDM2-HGMA2 amplicon excluding CDK4 has only been described so far in well-differentiated and dedifferentiated liposarcoma. Further studies are needed to assess if this anomaly is a specific marker of sclerosing rhabdomyosarcoma.