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

2012 ◽  
Vol 2012 ◽  
pp. 218-219
Author(s):  
R.J. Arceci
Keyword(s):  
Molecular Marker ◽  
Risk Stratification ◽  
Fusion Gene ◽  
Gene Status ◽  
Current Risk

Questionable Universal Validity of PAX3/FOXO1 Fusion Gene Status As Molecular Marker for Improvement of Risk Stratification in Rhabdomyosarcoma Therapy

2012 ◽  
Vol 30 (32) ◽  
pp. 4039-4040 ◽  
Author(s):  
Sabine Stegmaier ◽  
Stefan S. Bielack ◽  
Ivo Leuschner ◽  
Thomas Klingebiel ◽  
Ewa Koscielniak
Keyword(s):  
Molecular Marker ◽  
Risk Stratification ◽  
Fusion Gene ◽  
Gene Status

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.

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.

Impact of fusion gene status versus histology on risk-stratification for rhabdomyosarcoma: Retrospective analyses of patients on UK trials

2016 ◽  
Vol 64 (7) ◽  
pp. e26386 ◽  
Author(s):  
Joanna Selfe ◽  
David Olmos ◽  
Reem Al-Saadi ◽  
Khin Thway ◽  
Julia Chisholm ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Fusion Gene ◽  
Gene Status

Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma.

1997 ◽  
Vol 15 (5) ◽  
pp. 1831-1836 ◽  
Author(s):  
K M Kelly ◽  
R B Womer ◽  
P H Sorensen ◽  
Q B Xiong ◽  
F G Barr
Keyword(s):  
Metastatic Disease ◽  
Fusion Gene ◽  
Gene Fusions ◽  
Event Free Survival ◽  
Free Survival ◽  
Clinical Phenotypes ◽  
Significant Difference ◽  
The Common ◽  
Polymerase Chain ◽  
Gene Status

PURPOSE We evaluated the clinical features of the common PAX3-FKHR and variant PAX7-FKHR gene fusions observed in rhabdomyosarcoma. PATIENTS AND METHODS Reverse-transcriptase polymerase chain reaction (RT-PCR) assays were used to detect the gene fusions in 34 cases of rhabdomyosarcoma. Clinical data were obtained retrospectively and compared with the molecular results. RESULTS The PAX3-FKHR and PAX7-FKHR gene fusions were present in tumors from 18 and 16 patients, respectively. The group with a PAX7-FKHR fusion was younger (P = .01) and presented more often with an extremity lesion (82% v 22%; P = .001). PAX7-FKHR tumors were more often localized than PAX3-FKHR tumors (P = .03). In patients with metastatic disease at diagnosis, the patterns were different: PAX7-FKHR patients had metastatic disease that involved only bone (n = 2) and distant nodes (n = 2), while the PAX3-FKHR group had multiple sites involved, including bone (n = 7), marrow (n = 7), lungs (n = 3), distant nodes (n = 2), skin (n = 1), and brain (n = 1). No significant difference in relapse rate was observed. A trend toward improved overall survival in the PAX7-FKHR group was noted (P = .09). Event-free survival for this PAX7-FKHR group was significantly longer (P = .04). CONCLUSION Our results suggest that the common PAX3-FKHR and the variant PAX7-FKHR fusions are associated with distinct clinical phenotypes. Identification of fusion gene status may be a useful diagnostic tool in rhabdomyosarcoma.

scholarly journals Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia

2019 ◽  
Vol 20 (10) ◽  
pp. 2394 ◽  
Author(s):  
Minerva Mata-Rocha ◽  
Angelica Rangel-López ◽  
Elva Jiménez-Hernández ◽  
Blanca Angélica Morales-Castillo ◽  
Carolina González-Torres ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Fusion Genes ◽  
Cancer Etiology ◽  
Mexican Children ◽  
Genes Encoding ◽  
Identification And Characterization ◽  
Current Risk

Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified: CREBBP-SRGAP2B, DNAH14-IKZF1, ETV6-SNUPN, ETV6-NUFIP1. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as IKZF1, CREBBP, and ETV6. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets.

Absolute Lymphocyte Count Is a Novel Prognostic Indicator in Acute Leukemia: Implications for Risk Stratification and Future Studies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2276-2276
Author(s):  
Guillermo R. De Angulo ◽  
Carrie Yuen ◽  
Shana Palla ◽  
Peter M. Anderson ◽  
Patrick A. Zweidler-McKay
Keyword(s):  
Bone Marrow ◽  
Young Adults ◽  
Multivariate Analysis ◽  
Risk Stratification ◽  
Acute Leukemia ◽  
Induction Therapy ◽  
Age At Diagnosis ◽  
Acute Leukemias ◽  
Children And Young Adults ◽  
Current Risk

Abstract Background: Despite improving outcomes, 25–50% of children and young adults with acute leukemia still relapse and most salvage rates are discouraging. Additional prognostic factors, particularly those that represent host factors, may further stratify patients and decrease relapse rates. Purpose: To determine if absolute lymphocyte counts (ALC) during induction chemotherapy can improve current risk stratification and predict relapse-free survival (RFS) and overall survival (OS) in children and young adults with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Methods: We analyzed 160 consecutive cases of de novo ALL and AML patients 1–21 years of age, treated at the University of Texas M. D. Anderson Cancer Center from 1995–2005. Age at diagnosis, initial WBC, bone marrow blast % on days 0 and 7, were analyzed with ALC on days 0, 15, 21 and 28 of induction therapy. Results: ALC during induction therapy is a significant independent predictor of RFS and OS in young adults and children with either ALL or AML. Specifically, an ALC <350 cells/mcL on day 15 of induction therapy for ALL significantly predicts poor 6-year OS (52% vs. 87%, p=0.015; HR=4.2, Figure 1A) and RFS (46% vs. 80%, p=0.001; HR=4.8, Figure 1B). Similarly, an ALC of <350 cells/mcL on day 15 of induction therapy for AML predicts poor 6-year OS (35% vs. 86%, p=0.033; HR=4, Figure 1C). ALC-15 remains a significant predictor of OS and RFS after adjusting for age at diagnosis, initial WBC and bone marrow response on day 7 (p=0.013; HR=6.3, and p=0.003; HR=6.3, respectively) in multivariate analysis (Table 1). Importantly, ALC-15 defines a subgroup of half of our AML patients and predicts an excellent 5-year OS of 86% (p=0.033, Figure 1C). Conversely, prolonged lymphopenia predicts that 16% of young AML patients will have a dismal 5-year RFS of 14% (p=0.004, Figure 1D). Finally, ALC-15 <350 cells/mcL is able to predict 70% of relapses in both ALL and AML patients. One possible algorithm could identify half of AML patients with a predicted OS of 86% simply by measuring the ALC-15. Those patients with a low ALC on day 15 would be assessed at day 21 and 28 and those with persistent lymphopenia would be predicted to to have an RFS of 14% and would be stratified to receive intensified and/or experimental therapy. Conclusion: We demonstrate that ALC can identify patients at high and low risk for relapse early in the course of treatment for ALL or AML. Our data indicates that ALC is both independent of and a more powerful predictor than age at diagnosis, initial WBC and bone marrow response on day 7. This routine measurement could enhance current risk-stratification and lead to improved outcomes in young patients with acute leukemias. Figure 1 Figure 1. Table 1 Multivariate Analysis of ALC, Age, WBC, Bone marrow response and Survival

Current risk stratification for colorectal cancer screening using a blood-based RNA test.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e15090-e15090
Author(s):  
Choong-Chin Liew ◽  
Changming Cheng ◽  
Kris See ◽  
Shi Qian ◽  
Kee Liang Ong
Keyword(s):  
Colorectal Cancer ◽  
Cancer Screening ◽  
Risk Stratification ◽  
Colorectal Cancer Screening ◽  
Current Risk
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