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A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma
Kenneth S Chen1, Woo Sun Kwon2, Jiwoong Kim3
1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;; Gill Center for Cancer and Blood Disorders, Children's Medical Center, Dallas, Texas 75235, USA;
Abstract:
Osteosarcoma is the most common primary bone cancer. It can be cured by aggressive surgery and chemotherapy, but outcomes for metastatic or chemoresistant disease remain dismal. Cancer sequencing studies have shown that the p53 pathway is dysregulated in nearly every case, often by translocation; however, no studies of osteosarcoma evolution or intratumor heterogeneity have been done to date. We studied a patient with chemoresistant, metastatic disease over the course of 3 years. We performed exome sequencing on germline DNA and DNA collected from tumor at three separate time points. We compared variant calls and variant allele frequencies between different samples. We identified subclonal mutations in several different genes in the primary tumor sample and found that one particular subclone dominated subsequent tumor samples at relapse. This clone was marked by a novel TP53-KPNA3 translocation and loss of the opposite-strand wild-type TP53 allele. Future research must focus on the functional significance of such clones and strategies to eliminate them.
Insights
Investigating osteosarcoma evolution revealed a dominant subclone with a TP53-KPNA3 translocation in a patient with metastatic, chemoresistant bone cancer. This finding highlights the need for targeted therapeutic strategies against specific cancer clones.
Area of Science:
- Oncology
- Genomics
- Cancer Evolution
Background:
- Osteosarcoma is the most common primary bone cancer, with poor outcomes for metastatic or chemoresistant cases.
- The p53 pathway is frequently dysregulated in osteosarcoma, but its role in tumor evolution and heterogeneity is understudied.
Purpose of the Study:
- To investigate the evolutionary trajectory and intratumor heterogeneity of osteosarcoma in a patient with chemoresistant, metastatic disease.
- To identify genetic alterations driving tumor progression and relapse.
Main Methods:
- Exome sequencing of germline DNA and tumor DNA from three distinct time points over 3 years.
- Comparative analysis of variant calls and variant allele frequencies to track subclonal evolution.
Main Results:
- Identification of subclonal mutations in the primary osteosarcoma sample.
- A specific subclone, characterized by a novel TP53-KPNA3 translocation and loss of wild-type TP53, became dominant in subsequent relapse samples.
- Demonstration of significant intratumor heterogeneity and clonal selection during disease progression.
Conclusions:
- Specific subclones with distinct genetic alterations, such as the TP53-KPNA3 translocation, can drive osteosarcoma progression and chemoresistance.
- Understanding clonal evolution is crucial for developing effective therapeutic strategies against aggressive osteosarcoma.
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