Molecular spectrum of TP53 mutations in plasma cell dyscrasias by next generation sequencing: an Italian cohort study and overview of the literature

Abstract

The prevalence of TP53 mutations greatly varies between tumor types; in multiple myeloma (MM) they were rarely detected at presentation, while increased frequency was reported with disease progression. Using next-generation sequencing, we analyzed TP53 exons 4-9 in a large representative cohort comprising patients with MM at diagnosis and more aggressive forms of plasma cell (PC) dyscrasia, identifying mutations in 4/129 (3%) MM, 6/24 (25%) primary PC leukemia, and 2/10 (20%) secondary PC leukemia cases. A similar increase in prevalence associated with disease aggressiveness (5%, 29.2% and 44%, respectively) was observed for TP53 deletion. Interestingly, in five patients mutations were not concomitant with TP53 deletion. Furthermore, longitudinal analysis revealed the acquisition of TP53 mutations in three of nineteen cases analyzed at relapse. Identified variants were mostly missense mutations concentrated in the DNA binding domain, only partly reflecting the pattern globally observed in human cancers. Our data confirm that TP53 mutations are rare in MM at presentation and rather represent a marker of progression, similarly to del(17p); however, their occurrence even in absence of deletions supports the importance of their assessment in patients with PC dyscrasia, in terms of both risk stratification and therapeutic implications.

Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma

“…In MM, TP53 mutations are uncommon at diagnosis (~8%) [28,29,30], although the incidence increases in the advanced stages of the disease, suggesting its essential role in MM progression [31,32]. These findings have also been confirmed by using massively parallel sequencing [16,33]. Thus, only 8% of MM patients analyzed by Lohr et al showed missense TP53 mutations, two of which corresponded to hotspot residues R273 and R248 within the DNA-binding domain, and commonly mutated in other human tumors [33].…”

“…Thus, only 8% of MM patients analyzed by Lohr et al showed missense TP53 mutations, two of which corresponded to hotspot residues R273 and R248 within the DNA-binding domain, and commonly mutated in other human tumors [33]. In contrast, the frequency of TP53 mutations increases up to 25% in plasma cell leukemia [16]. Furthermore, longitudinal analysis of MM patients reveals that TP53 mutations are often acquired at relapse [16].…”

“…In contrast, the frequency of TP53 mutations increases up to 25% in plasma cell leukemia [16]. Furthermore, longitudinal analysis of MM patients reveals that TP53 mutations are often acquired at relapse [16]. …”

“…Interestingly, Lodé et al reported that TP53 mutations were exclusively associated with del(17p) [28]. Furthermore, it has been recently reported that biallelic inactivation of TP53 is more common in aggressive plasma cell neoplasms, and is frequently seen at relapse leading to rapid progression to plasma cell leukemia and/or extramedullary disease [16,49]. All these findings highlight the critical value of TP53 deletion and/or mutation in the pathogenesis of MM and reinforce the necessity of new therapeutic approaches for these high-risk patients.…”

“…In hematological malignancies, p53 mutations and deletions are uncommon events [12,13,14,15,16]. However, p53 may play a broader role in the pathogenesis or progression of these diseases than previously thought, since an imbalance in p53 activity can also be generated through post-transcriptional or post-translational mechanisms.…”