Whole exome sequencing of a single osteosarcoma case¿integrative analysis with whole transcriptome RNA-seq data

Reimann, Ene; Kõks, Sulev; Ho, Xuan; Maasalu, Katre; Märtson, Aare

doi:10.1186/preaccept-1873296159134645

Cited by 17 publications

(22 citation statements)

References 36 publications

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“…To identify driver mutations conferring clonal advantage and the processes by which somatic mutations are generated, several groups have performed whole genome sequencing (WGS) of 47 OS samples with paired normal controls, whole exome sequencing (WES) of 111 samples with paired normal controls, and whole transcriptome sequencing of 36 samples [28-33]. These studies detected distinct classes of DNA mutations such as somatic point mutations, which include single base substitutions, and indels, which are insertions or deletions of small segments of DNA.…”

Section: The Genomic Landscape Of Osteosarcomamentioning

confidence: 99%

“…These 14 genes include: TP53 , RB1 , BRCA2 , BAP1 , RET , MUTYH , ATM , PTEN , WRN , RECQL4 , ATRX , FANCA , NUMA1 , and MDC1 , the majority of which are either well-known cancer drivers or have been reported in the context of cancer susceptibility. Additionally, most of them have been identified as somatically mutated genes by several groups [28, 29, 31-33]. However, the roles of several genes are unknown in the context of OS, such as FANCA , NUMA1 , and MDC1 [30].…”

Section: The Genomic Landscape Of Osteosarcomamentioning

confidence: 99%

“…OS mountain driver genes including p53 , Rb , CDKN2A and PTEN have been identified by prior targeted investigations, as well as through current unbiased GWS [28-33, 47-50]. The genes listed in Table 2 are good candidates for mountain or hill drivers.…”

Section: The Genomic Landscape Of Osteosarcomamentioning

confidence: 99%

“…Before these GEMMs were generated, somatic driver mutations for these genes in human OS had not been reported, however, most of them are consensus genes in other common forms of human cancer. For example, somatic mutations in components of the Notch signaling pathway had not been discovered in any mesenchyme-derived rare cancers such as OS, until recent GWS and forward genetic screens in mice identified mutations in FBXW7 , MAML2 , Notch1 , Notch 2 , Notch3 and Notch4 [19, 28-33]. Tao et al generated a mouse model of OS (cNICD mice), and found that expression of an activating truncated form of the Notch1 receptor in osteoblasts was sufficient to drive OS development [73].…”

Section: Understanding the Role Of Driver Gene Mutations In The Dementioning

confidence: 99%

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Molecular genetics of osteosarcoma

Rickel

Fang

Tao

2017

Bone

206

179

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Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogues of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma. One of the lessons learned here is that the extent of somatic mutations and complexity of the osteosarcoma genome are similar to that of common forms of adult cancer. Thus, a much higher number of samples than those currently obtained are needed to complete the catalogue of driver mutations in human osteosarcoma. In parallel, genetic studies in other species have revealed candidate driver genes and their roles in the genesis of osteosarcoma. This review also summarizes newly identified drivers in genetically engineered mouse models (GEMMs) and discusses our understanding of the impact of nature and number of drivers on tumor latency, subtypes, and metastatic potentials of osteosarcoma. It is becoming apparent that a synergistic team composed of three drivers (one ‘first driver’ and two ‘synergistic drivers’) may be required to generate an animal model that recapitulates aggressive osteosarcoma with a short latency. Finally, new cancer therapies are urgently needed to improve survival rate and quality of life for osteosarcoma patients. Several vulnerabilities in osteosarcoma are illustrated in this review to exemplify the opportunities for next generation molecularly targeted therapies. However, much work remains in order to complete our understanding of the somatic mutation basis of osteosarcoma, to develop reliable animal models of human disease, and to apply this information to guide new therapeutic approaches for reducing morbidity and mortality of this rare disease.

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Section: The Genomic Landscape Of Osteosarcomamentioning

confidence: 99%

Section: The Genomic Landscape Of Osteosarcomamentioning

confidence: 99%

Section: The Genomic Landscape Of Osteosarcomamentioning

confidence: 99%

Section: Understanding the Role Of Driver Gene Mutations In The Dementioning

confidence: 99%

See 2 more Smart Citations

Molecular genetics of osteosarcoma

Rickel

Fang

Tao

2017

Bone

206

179

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“…These two domains have been reported to serve a role as chromatin remodelers (5). A third domain, predicted as a coiled coil structure, has been demonstrated to interact particularly with EZH2, a protein belonging to the polycomb multigenic family that is involved in histone methylation and deacetylation (6 identified in recent whole genome and/or whole exome genomic studies in sarcomas, particularly osteosarcoma (7)(8)(9)(10). Telomeres, the short, non-protein coding repeated hexameric TTAGGG sequences at each end of a chromosome, are involved in the control of genome integrity and chromosomal stability, and the development of cancer cells (11).…”

Section: Introductionmentioning

confidence: 99%

Alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas (Review)

Ren

Tang

et al. 2018

Oncol Lett

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Abstract. Sarcoma is a rare and heterogeneous type of cancer with an early mean onset age and a poor prognosis. However, its genetic basis remains unclear. A series of recent genomic studies in sarcomas have identified the occurrence of mutations in the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene. The ATRX protein belongs to the SWI/SNF family of chromatin remodeling proteins, which are frequently associated with α-thalassemia syndrome. Cancer cells depend on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative programmed mortality. Loss of ATRX is associated with ALT in sarcoma. In the present review, recent whole genome and/or whole exome genomic studies are summarized. In addition ATRX immunohistochemistry and ALT fluorescence in situ hybridization in sarcomas of various subtypes and at diverse sites, including osteosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma and chondrosarcoma are evaluated. The present review involves certain studies associated with the molecular mechanisms underlying the loss of ATRX controlling the activation of ALT in sarcomas. Identification of the loss of ATRX and ALT in sarcomas may provide novel methods for the treatment of aggressive sarcomas.

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The molecular landscape of extraskeletal osteosarcoma: A clinicopathological and molecular biomarker study

Jour

Wang

Middha

et al. 2015

The Journal of Pathology CR

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Extraskeletal osteosarcoma (ESOSA) is a rare soft tissue neoplasm representing <5% of osteosarcomas and <1% of all soft‐tissue sarcomas. Herein, we investigate the clinicopathological and molecular features of ESOSA and explore potential parameters that may affect outcome. Thirty‐two cases were retrieved and histomorphology was reviewed. Clinical history and follow‐up were obtained through electronic record review. DNA from formalin‐fixed paraffin‐embedded (FFPE) tissue was extracted and processed from 27 cases. Genome‐wide DNA copy number (CN) alterations and allelic imbalances were analyzed by single nucleotide polymorphism array using Affymetrix OncoScan FFPE Assay. Massive high‐throughput deep parallel sequencing was performed using a customized panel targeting 410 cancer genes. Log rank, Fisher's exact test and Cox proportional hazards were used for statistical analysis. In this series of 32 patients (male n = 12, female n = 20), the average age was 66 years (19–93) and median follow up was 24 months (range 6–120 months). Frequent genomic alterations included CN losses in tumour suppressor genes including CDKN2A (70%), TP53 (56%) and RB1 (49%). Mutations affecting methylation/demethylation, chromatin remodeling and WNT/SHH pathways were identified in 40%, 27%, and 27%, respectively. PIK3CA and TERT promoter variant mutations were identified in 11% of the cases. Cases harbouring simultaneous TP53 and RB1 biallelic CN losses were associated with worse overall survival and local recurrence (p = 0.04, p = 0.02, respectively). CDKN2A losses and positive margins were also associated with worse overall survival (p = 0.002; p = 0.03, respectively). Our findings suggest that age above 60, positive margin status, simultaneous biallelic TP53 and RB1 losses and CDKN2A loss are associated with a worse outcome in ESOSA. Comparison between conventional paediatric osteosarcoma and ESOSA shows that, while both share genetic similarities, there are notable dissimilarities and mechanistic differences in the molecular pathways involved in ESOSA.

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Whole exome sequencing of a single osteosarcoma case¿integrative analysis with whole transcriptome RNA-seq data

Cited by 17 publications

References 36 publications

Molecular genetics of osteosarcoma

Molecular genetics of osteosarcoma

Alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas (Review)

The molecular landscape of extraskeletal osteosarcoma: A clinicopathological and molecular biomarker study

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