Abstract
Purpose:TP53 is a tumor-suppressor gene that functions as a regulator influencing cellular responses to DNA damage, and TP53 alterations are associated with pejorative outcome in most B-lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's macroglobulinemia (WM).Experimental Design: Here, we have explored the incidence of TP53 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.Results: Overall, we have identified alteration of TP53 locus including mutation, deletion, and copy-neutral LOH in 11.2% of WM. TP53 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 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 the international prognostic scoring system for Waldenstrom macroglobulinemia (IPSSWM) score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a-targeted p53 signaling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, PrimaMet, or CP31398 that bypass p53 pathway in WM, paving the path for future treatment-tailored options.Conclusions: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice. Clin Cancer Res; 23(20); 6325-35. ©2017 AACR.
Highlights
TP53, that encodes for a tumor-suppressor protein, p53, is mapped at the chromosome 17p13 locus and has proved to play a key role in cancer physiopathology. p53 is a transcription factor and acts as a critical regulator of cellular proliferation, cell-cycle checkpoint, DNA repair, and apoptosis [1, 2]
Frequency of TP53 mutation in Waldenstrom's macroglobulinemia (WM) at diagnosis No mutation of TP53 was observed in the monoclonal gammopathy of undetermined significance (MGUS) immunoglobulin M (IgM) group (n 1⁄4 10)
We observed that TP53 mutation was present in the dominant clone as defined by more than 40% of VAF, and subclonal in two cases in WM (Fig. 1B)
Summary
TP53, that encodes for a tumor-suppressor protein, p53, is mapped at the chromosome 17p13 locus and has proved to play a key role in cancer physiopathology. p53 is a transcription factor and acts as a critical regulator of cellular proliferation, cell-cycle checkpoint, DNA repair, and apoptosis [1, 2]. The deletion of the short arm of chromosome 17 (Del17p) that contains the TP53 gene is often monoallelic, and mutations may occur on the remaining allele of TP53 [5,6,7]. The prevalence of TP53 alterations, either mutation or deletion, differs considerably between tumor types and stages of lymphoid disorders; p53 inactivation is often associated with cancer progression and drug resistance [1, 6, 8, 9]. The mutations of TP53, especially when located in the DNA-binding domain, are associated with a greater risk of more aggressive disease, poorer responses to conventional chemoimmunotherapy, and short survival in numerous lymphoid disorders, including chronic lymphocytic leukemia (CLL) and marginal zone lymphoma [6, 10,11,12]. An alternative strategy could be to target the overexpressed p53-mutant protein by directly modifying its conformation to restore its proapoptotic transcriptional function [1,2,3]
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