Intratumoral Translocation Positive Heterogeneity in Pediatric Alveolar Rhabdomyosarcoma Tumors Correlates to Patient Survival Prognosis
Location
Medical Education Building, LSUHSC-NO
Presentation Date
10-10-2019 10:00 AM
End Date
10-10-2019 12:00 PM
Description
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma seen in children and accounts for 3% of all new childhood cancers diagnosed each year in the United States. The two most common subtypes of RMS are embryonal rhabdomyosarcoma (ERMS), comprising 60% of RMS cases, and alveolar rhabdomyosarcoma (ARMS), comprising 30% of RMS cases. Though ARMS is less common than ERMS, it exhibits a more aggressive clinical course with poorer patient prognosis. Sixty percent of ARMS cases are genetically characterized by the presence of a balanced translocation between chromosomes 2 and 13 at t(2;13)(p35;q14), resulting in the production of the PAX3-FOXO1 oncogenic fusion product, while 20% of ARMS cases are characterized by a translocation between chromosome 1 and 13 at t(1;13)(p36.q14), resulting in the formation of the PAX7-FOXO1 oncogenic fusion product. Though patient clinical data clearly illustrate that greater disease severity and mortality are associated with ARMS tumors exhibiting the t(2;13) translocation than tumors exhibiting the t(1;13) translocation, current diagnostic fluorescent in situ hybridization (FISH) probes fail to delineate between the two events. Our laboratory has developed FISH probes specific for PAX3, PAX7, and FOXO1 genes which are capable of simultaneously determining the presence of the t(2;13) or t(1;13) fusion products. Using these probes to analyze patient RMS tumor samples obtained from the Children’s Hospital of New Orleans, Louisiana (CHNOLA), intratumoral heterogeneity is seen in ARMS tumors with 3% - 98% of individual tumor cells containing a translocation event. Furthermore, our results demonstrate a significant inverse correlation (R2 = 0.66, p = 0.001) between the extent of intratumoral translocation heterogeneity and failure free survival of patients. Ultimately, these results provide a simple clinical assay allowing for the rapid and simultaneous determination of the status and extent of translocation heterogeneity seen in ARMS tumors. Ongoing studies involve the analysis of RNA derived from these tumor samples utilizing gene expression panels examining metabolic pathways, tumor microenvironment, and cancer immunity genes. Such insight could assist in a more accurate diagnosis and possibly offer a more precise treatment and management plan better fulfilling the needs of the patient.
Recommended Citation
Briscoe, James R., "Intratumoral Translocation Positive Heterogeneity in Pediatric Alveolar Rhabdomyosarcoma Tumors Correlates to Patient Survival Prognosis" (2019). Medical Student Research Poster Symposium. 4.
https://digitalscholar.lsuhsc.edu/sommrd/2019/posters/4
Intratumoral Translocation Positive Heterogeneity in Pediatric Alveolar Rhabdomyosarcoma Tumors Correlates to Patient Survival Prognosis
Medical Education Building, LSUHSC-NO
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma seen in children and accounts for 3% of all new childhood cancers diagnosed each year in the United States. The two most common subtypes of RMS are embryonal rhabdomyosarcoma (ERMS), comprising 60% of RMS cases, and alveolar rhabdomyosarcoma (ARMS), comprising 30% of RMS cases. Though ARMS is less common than ERMS, it exhibits a more aggressive clinical course with poorer patient prognosis. Sixty percent of ARMS cases are genetically characterized by the presence of a balanced translocation between chromosomes 2 and 13 at t(2;13)(p35;q14), resulting in the production of the PAX3-FOXO1 oncogenic fusion product, while 20% of ARMS cases are characterized by a translocation between chromosome 1 and 13 at t(1;13)(p36.q14), resulting in the formation of the PAX7-FOXO1 oncogenic fusion product. Though patient clinical data clearly illustrate that greater disease severity and mortality are associated with ARMS tumors exhibiting the t(2;13) translocation than tumors exhibiting the t(1;13) translocation, current diagnostic fluorescent in situ hybridization (FISH) probes fail to delineate between the two events. Our laboratory has developed FISH probes specific for PAX3, PAX7, and FOXO1 genes which are capable of simultaneously determining the presence of the t(2;13) or t(1;13) fusion products. Using these probes to analyze patient RMS tumor samples obtained from the Children’s Hospital of New Orleans, Louisiana (CHNOLA), intratumoral heterogeneity is seen in ARMS tumors with 3% - 98% of individual tumor cells containing a translocation event. Furthermore, our results demonstrate a significant inverse correlation (R2 = 0.66, p = 0.001) between the extent of intratumoral translocation heterogeneity and failure free survival of patients. Ultimately, these results provide a simple clinical assay allowing for the rapid and simultaneous determination of the status and extent of translocation heterogeneity seen in ARMS tumors. Ongoing studies involve the analysis of RNA derived from these tumor samples utilizing gene expression panels examining metabolic pathways, tumor microenvironment, and cancer immunity genes. Such insight could assist in a more accurate diagnosis and possibly offer a more precise treatment and management plan better fulfilling the needs of the patient.
Comments
Mentors: Fern Tsien, PhD and Andrew D. Hollenbach, PhD (Department of Genetics)