Abstract

<div>Abstract<p><b>Purpose:</b> <i>TP53</i> is a tumor-suppressor gene that functions as a regulator influencing cellular responses to DNA damage, and <i>TP53</i> alterations are associated with pejorative outcome in most B-lymphoid disorders. Little is known regarding <i>TP53</i> alteration in Waldenstrom's macroglobulinemia (WM).</p><p><b>Experimental Design:</b> Here, we have explored the incidence of <i>TP53</i> alteration using Sanger sequencing and ultradeep-targeted sequencing in 125 WM and 10 immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS), along with the clinical features and the associated genomic landscape using single-nucleotide polymorphism array and mutational landscape in an integrative study.</p><p><b>Results:</b> Overall, we have identified alteration of <i>TP53</i> locus including mutation, deletion, and copy-neutral LOH in 11.2% of WM. <i>TP53</i> mutation was acquired in 7.3% of patients with WM at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with <i>CXCR4</i> mutations was observed. Patients with <i>TP53</i> alteration had a greater number of genomic abnormalities. Importantly, WM with <i>TP53</i> alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of the international prognostic scoring system for Waldenstrom macroglobulinemia (IPSSWM) score. Specific treatment for WM with <i>TP53</i> may have to be studied. Nutlin-3a–targeted p53 signaling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, Prima<sup>Met</sup>, or CP31398 that bypass p53 pathway in WM, paving the path for future treatment-tailored options.</p><p><b>Conclusions:</b> Our results highlight the clinical significance of detection of <i>TP5</i>3 alteration in WM to determine the prognosis of WM and guide the treatment choice. <i>Clin Cancer Res; 23(20); 6325–35. ©2017 AACR</i>.</p></div>

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