Development of prognostic molecular markers in pediatric rhabdomyosarcoma based on gene expression and copy number variations.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9510-9510
Author(s):  
Edoardo Missiaglia ◽  
Dan Williamson ◽  
Julia C. Chisholm ◽  
Pratyaksha Wirapati ◽  
Gaëlle Pierron ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Stratification ◽  
Copy Number ◽  
Fusion Gene ◽  
Gene Expression Signature ◽  
Copy Number Variations ◽  
Biological Data ◽  
Prognostic Information ◽  
Prognostic Gene ◽  
Gene Status

9510 Background: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and comprises two major histological subtypes: alveolar and embryonal. The majority of alveolar tumors harbor PAX/FOXO1 fusion genes. Current patient risk stratification, unlike other pediatric embryonal tumors, does not utilize any molecular data. Therefore, we aimed to improve the risk stratification of RMS patients through the use of molecular biological data. Methods: Two independent data sets of gene expression profiling for 124 and 101 RMS were used to derive prognostic gene signatures by meta-analysis. Genomic array CGH data for 109 RMS was also evaluated to develop a prognostic marker based on copy number variations (CNVs). The performance and usefulness of these derived metagenes and CNVs as well as a previously published metagene signature were evaluated using rigorous leave-one-out cross-validation analyses. Results: The new prognostic gene expression signature, MG15, and one previously published (MG34) (Davicioni. JCO. 2010) performed well with reproducible and significant effects (HR 3.2 [1.7-5.9] p < 0.001 and HR 2.5 [1.5-4.3] p < 0.001, respectively). However, they did not significantly add new prognostic information over the fusion gene status (PAX3/FOXO1, PAX7/FOXO1 and Negative). Similarly, a prognostic CNV marker, although showing HR 2.9 [1.5-5.6] p < 0.01, was also not improving models with fusion gene status. Within fusion negative RMS, the analysis identified prognostic markers based on either gene expression or CNVs and showed significant association with patients outcome (HR 6.3 [1.5-26.3] p ≤ 0.016 and HR 11.2 [2.5-50.7] p < 0.010, respectively). Moreover, these were able to identify distinct risk groups within the COG (Children's Oncology Group) risk categories, which is currently used to guide treatment. Conclusions: Molecular signatures derived using all RMS effectively stratify patients by their risk, but most of their prognostic information is contained in the PAX/FOXO1 fusion gene status which is simpler to assay. New markers developed within the fusion negative population seem improving current RMS risk classifier and should be tested in follow-up studies.

PAX3/FOXO1 Fusion Gene Status Is the Key Prognostic Molecular Marker in Rhabdomyosarcoma and Significantly Improves Current Risk Stratification

2012 ◽  
Vol 30 (14) ◽  
pp. 1670-1677 ◽  
Author(s):  
Edoardo Missiaglia ◽  
Dan Williamson ◽  
Julia Chisholm ◽  
Pratyaksha Wirapati ◽  
Gaëlle Pierron ◽  
...  
Keyword(s):  
Gene Expression ◽  
Risk Stratification ◽  
Risk Score ◽  
Fusion Gene ◽  
Gene Expression Signature ◽  
Independent Data ◽  
Gene Signatures ◽  
Prognostic Gene ◽  
Gene Status ◽  
Current Risk

Purpose To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. Patients and Methods Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. Results We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. Conclusion Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.

scholarly journals Clinical Application of Prognostic Gene Expression Signature in Fusion Gene–Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group

2015 ◽  
Vol 21 (20) ◽  
pp. 4733-4739 ◽  
Author(s):  
Pooja Hingorani ◽  
Edoardo Missiaglia ◽  
Janet Shipley ◽  
James R. Anderson ◽  
Timothy J. Triche ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Application ◽  
Fusion Gene ◽  
Gene Expression Signature ◽  
Oncology Group ◽  
Expression Signature ◽  
Prognostic Gene

Clinical application of prognostic gene expression signature in fusion gene-negative rhabdomyosarcoma: A report from the Children’s Oncology Group.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 10510-10510
Author(s):  
Pooja Hingorani ◽  
Edoardo Missiaglia ◽  
Janet Shipley ◽  
James Robert Anderson ◽  
Timothy J. Triche ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Application ◽  
Fusion Gene ◽  
Gene Expression Signature ◽  
Oncology Group ◽  
Expression Signature ◽  
Prognostic Gene

scholarly journals Gliosarcoma Is Driven by Alterations in PI3K/Akt, RAS/MAPK Pathways and Characterized by Collagen Gene Expression Signature

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 284 ◽  
Author(s):  
Bartosz Wojtas ◽  
Bartlomiej Gielniewski ◽  
Kamil Wojnicki ◽  
Marta Maleszewska ◽  
Shamba Mondal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
Somatic Mutations ◽  
Complex Analysis ◽  
Expression Patterns ◽  
Gene Expression Signature ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Gene Expression Patterns ◽  
Sequencing Analysis

Gliosarcoma is a very rare brain tumor reported to be a variant of glioblastoma (GBM), IDH-wildtype. While differences in molecular and histological features between gliosarcoma and GBM were reported, detailed information on the genetic background of this tumor is lacking. We intend to fill in this knowledge gap by the complex analysis of somatic mutations, indels, copy number variations, translocations and gene expression patterns in gliosarcomas. Using next generation sequencing, we determined somatic mutations, copy number variations (CNVs) and translocations in 10 gliosarcomas. Six tumors have been further subjected to RNA sequencing analysis and gene expression patterns have been compared to those of GBMs. We demonstrate that gliosarcoma bears somatic alterations in gene coding for PI3K/Akt (PTEN, PI3K) and RAS/MAPK (NF1, BRAF) signaling pathways that are crucial for tumor growth. Interestingly, the frequency of PTEN alterations in gliosarcomas was much higher than in GBMs. Aberrations of PTEN were the most frequent and occurred in 70% of samples. We identified genes differentially expressed in gliosarcoma compared to GBM (including collagen signature) and confirmed a difference in the protein level by immunohistochemistry. We found several novel translocations (including translocations in the RABGEF1 gene) creating potentially unfavorable combinations. Collected results on genetic alterations and transcriptomic profiles offer new insights into gliosarcoma pathobiology, highlight differences in gliosarcoma and GBM genetic backgrounds and point out to distinct molecular cues for targeted treatment.

scholarly journals Prognostic gene expression signature for high-grade serous ovarian cancer

2020 ◽  
Vol 31 (9) ◽  
pp. 1240-1250 ◽  
Author(s):  
J. Millstein ◽  
T. Budden ◽  
E.L. Goode ◽  
M.S. Anglesio ◽  
A. Talhouk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Gene Expression Signature ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Expression Signature ◽  
Prognostic Gene

The stem cell-associated gene expression signature allows risk stratification in pediatric acute myeloid leukemia

Leukemia ◽  
2018 ◽  
Vol 33 (2) ◽  
pp. 348-357 ◽  
Author(s):  
Nicolas Duployez ◽  
Alice Marceau-Renaut ◽  
Céline Villenet ◽  
Arnaud Petit ◽  
Alexandra Rousseau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Gene Expression Signature ◽  
Pediatric Acute Myeloid Leukemia ◽  
Expression Signature ◽  
Acute Myeloid

Impact of MYC and BCL2 structural variants in tumors of DLBCL morphology and mechanisms of false-negative MYC IHC

Blood ◽  
2020 ◽  
Author(s):  
Brett J Collinge ◽  
Susana Ben-Neriah ◽  
Lauren C. Chong ◽  
Merrill Boyle ◽  
Aixiang Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
De Novo ◽  
Cell Lymphoma ◽  
False Negative ◽  
Gene Expression Signature ◽  
B Cell Lymphoma ◽  
Copy Number Variations ◽  
Similar Gene Expression Profile ◽  
Double Hit

When the WHO defined high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) as a clinical category, rearrangements were the only structural variant (SV) incorporated. An "atypical double-hit" entity has been proposed, encompassing tumors with concurrent MYC and BCL2 SVs other than co-occurring translocations - i.e. copy number variations (CNVs). While the identification of a gene expression signature (DHITsig) shared among tumors harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2) has confirmed a shared underlying biology, the biological implication of MYC and BCL2 CNVs requires further elucidation. We performed a comprehensive analysis of MYC and BCL2 SVs, as determined by fluorescent in situ hybridization (FISH), in a cohort of 802 de novo tumors with diffuse large B-cell lymphoma (DLBCL) morphology. While BCL2 CNVs were associated with increased expression, MYC CNVs were not. Furthermore, MYC and BCL2 CNVs, in the context of atypical double-hit, did not confer a similar gene expression profile as HGBL-DH/TH-BCL2. Finally, while MYC IHC has been proposed as a screening tool for FISH testing, two mechanisms were observed that uncoupled MYC rearrangement from IHC positivity. 1) low MYC mRNA expression and 2) false-negative immunohistochemistry (IHC) staining mediated by a single nucleotide polymorphism resulting in an asparagine to serine substitution at the 11th amino acid residue of MYC (MYC-N11S). Taken together, these results support the current exclusion of MYC and BCL2 CNVs from HGBL-DH/TH and highlight the ability of a molecular based classification system to identify tumors with shared biology that FISH and IHC fail to fully capture.

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