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Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma
- Source :
- Experimental Hematology & Oncology
- Publisher :
- Springer Nature
-
Abstract
- none 12 no Therapeutic implications of intra-tumor heterogeneity are still undefined. In this study we report a genetic and functional analysis aimed at defining the mechanisms of chemoresistance in a 43-year old woman affected by stage IVB Burkitt lymphoma with bulky abdominal masses and peritoneal effusion. The patient, despite a transient initial response to chemotherapy with reduction of the bulky masses, rapidly progressed and died of her disease. Targeted TP53 sequencing found that the bulky mass was wild-type whereas peritoneal fluid cells harbored a R282W mutation. Functional studies on TP53 mutant cells demonstrated an impaired p53-mediated response, resistance to ex vivo doxorubicin administration, overexpression of DNA damage response (DDR) activation markers and high sensitivity to pharmacologic DDR inhibition. These findings suggest that intra-tumor heterogeneity for TP53 mutational status may occur in MYC-driven cancers, and that DDR inhibitors could be effective in targeting hidden TP53 mutant clones in tumors characterized by genomic instability and prone to intra-tumor heterogeneity. none Derenzini, Enrico; Iacobucci, Ilaria; Agostinelli, Claudio; Imbrogno, Enrica; Storlazzi, Clelia Tiziana; L`abbate, Alberto; Casadei, Beatrice; Ferrari, Anna; Ghelli Luserna Di Rorà, Andrea; Martinelli, Giovanni; Pileri, Stefano; Zinzani, Pier Luigi Derenzini, Enrico; Iacobucci, Ilaria; Agostinelli, Claudio; Imbrogno, Enrica; Storlazzi, Clelia Tiziana; L`abbate, Alberto; Casadei, Beatrice; Ferrari, Anna; Ghelli Luserna Di Rorà, Andrea; Martinelli, Giovanni; Pileri, Stefano; Zinzani, Pier Luigi
- Subjects :
- Genomic instability
Genome instability
Cancer Research
medicine.medical_specialty
Pathology
DNA damage
CHK1
medicine.medical_treatment
Intra-tumor heterogeneity
Case Report
MYC
medicine.disease_cause
Internal medicine
medicine
Doxorubicin
Chemotherapy
Mutation
Hematology
business.industry
Burkitt lymphoma
medicine.disease
3. Good health
Lymphoma
γ-H2AX
Oncology
Cancer research
business
Ex vivo
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 21623619
- Volume :
- 4
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Experimental Hematology & Oncology
- Accession number :
- edsair.doi.dedup.....ffdb847d395e242ff766fc3518784bd2
- Full Text :
- https://doi.org/10.1186/s40164-015-0019-9