Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma

• Published in: Experimental hematology & oncology Vol. 4; no. 1; p. 24
• Main Authors: Derenzini, Enrico, Iacobucci, Ilaria, Agostinelli, Claudio, Imbrogno, Enrica, Storlazzi, Clelia Tiziana, L Abbate, Alberto, Casadei, Beatrice, Ferrari, Anna, Di Rora, Andrea Ghelli Luserna, Martinelli, Giovanni, Pileri, Stefano, Zinzani, Pier Luigi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.08.2015; BioMed Central
• Subjects: Abdomen; Analysis; Anthracyclines; Biopsy; Burkitt's lymphoma; Cancer; Cancer therapies; Care and treatment; Case Report; Cell cycle; Chemotherapy; Deoxyribonucleic acid; Development and progression; DNA; DNA damage; DNA repair; Genetic aspects; Health aspects; Hematology; Kinases; Leukemia; Lymphoma; Mutation; Non-Hodgkin's lymphomas; Studies; Tumor proteins; Tumors; Italy; γ-H2AX; CHK1; MYC; Burkitt lymphoma; Genomic instability; Intra-tumor heterogeneity
• ISSN: 2162-3619; 2162-3619
• DOI: 10.1186/s40164-015-0019-9

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.