TP53 mutation and its prognostic significance in Waldenstrom's Macroglobulinemia

Purpose: TP53 is a tumor suppressor gene that functions as regulator influencing cellular responses to DNA damage, and TP53 alteration are associated to pejorative outcome in most of B lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's Macroglobulinemia (WM). <p>Experimental design: Here we have explored the incidence of TP53 alteration using sanger sequencing and ultra-deep targeted sequencing in 125 WM and 10 IgM MGUS, along with the clinical features and the associated genomic landscape using SNP array and mutational landscape in an integrative study.</p> <p>Results: Overall, we have identified alteration of TP53 locus including mutation, deletion and copy neutral loss of heterozygosity in 11,2% of WM. TP53 mutation was acquired in 7,3% of WM patients at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with CXCR4 mutations was observed. Patients with TP53 alteration had a greater number of genomic abnormalities. Importantly, WM with TP53 alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of IPSSWM score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a-targeted p53 signalling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, Prima^Met or CP31398 that bypass p53 pathway in WM, paving the path for future treatment tailored options.</p> <p>Conclusion: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice.

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