is a tumor-suppressor gene that functions as a regulator influencing cellular responses to DNA damage, and alterations are associated with pejorative outcome in most B-lymphoid disorders. Little is known regarding alteration in Waldenstrom's macroglobulinemia (WM). Here, we have explored the incidence of 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. Overall, we have identified alteration of locus including mutation, deletion, and copy-neutral LOH in 11.2% of WM. 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 mutations was observed. Patients with alteration had a greater number of genomic abnormalities. Importantly, WM with 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 may have to be studied. Nutlin-3a-targeted p53 signaling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, Prima, or CP31398 that bypass p53 pathway in WM, paving the path for future treatment-tailored options. Our results highlight the clinical significance of detection of 3 alteration in WM to determine the prognosis of WM and guide the treatment choice..

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