In this issue of Blood, Li et al report mutations in the 3′ untranslated region (3′UTR) of TP53 that modify the expression of p53 and thus its effect on response to therapy in diffuse large B-cell lymphoma (DLBCL) patients.1
Single nucleotide variations target the TP53 3′UTR and the CDS in DLBCL. Acquired somatic mutations (⋆) frequently target both the CDS and the 3′UTR of TP53 with a potential cooperative effect. Expression of TP53 is repressed by some miRNAs, including miR-125b, after binding to target sites located at 3′UTR of the mRNA. In the absence of 3′UTR mutations, wild-type (A) or mutated p53 protein (B) level remain under miRNA repression activity. In the case of mutations disrupting miRNA binding sites that reduce the efficiency of miRNA suppression, wild-type (C) or mutated (D) p53 protein expression is increased with potentially opposite prognostic effects.
Single nucleotide variations target the TP53 3′UTR and the CDS in DLBCL. Acquired somatic mutations (⋆) frequently target both the CDS and the 3′UTR of TP53 with a potential cooperative effect. Expression of TP53 is repressed by some miRNAs, including miR-125b, after binding to target sites located at 3′UTR of the mRNA. In the absence of 3′UTR mutations, wild-type (A) or mutated p53 protein (B) level remain under miRNA repression activity. In the case of mutations disrupting miRNA binding sites that reduce the efficiency of miRNA suppression, wild-type (C) or mutated (D) p53 protein expression is increased with potentially opposite prognostic effects.
p53, the first tumor suppressor identified, has a key role in maintaining genomic stability, particularly in inhibiting the damaging effect of oncogene activation. p53 modulates the transcription of genes that govern major defenses against tumor growth.2 p53 also interacts with numerous cellular proteins, particularly those controlling programmed cell death. These interactions with DNA and proteins explain its critical function against cancer. Mutation of TP53 has been associated with a wide range of cancers, particularly hematologic cancers and DLBCL.3 TP53 messenger RNA (mRNA) is composed of 4 regions: the 5′ untranslated region, which promotes translation and has a role in the stability of mRNA; a coding sequence (CDS); the 3′UTR, which contains regulatory sequences and binding sites for microRNA (miRNA); and a poly-A tail, which is important for the nuclear export, translation, and stability of mRNA. TP53 mutations associated with cancers are of 3 types: acquired tumor-associated mutations of the CDS, germline mutations found in Li-Fraumeni syndrome, and germline polymorphisms.2 Some of these single nucleotide polymorphisms have been related to cancer, like rs78378222 in basal cell carcinoma, but most are not.4 miRNAs act as gene regulators through a translational repression or mRNA degradation via binding to target sites in the 3′UTR of protein-coding transcripts. To date, 11 miRNAs are known to target the human TP53 gene, including miR-125b, miR-15a, and miR-16.
In this issue, Li et al1 present data regarding newly identified single nucleotide variants (nSNVs) targeting the TP53 3′UTR that alter the translation of TP53 in patients with DLBCL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus the monoclonal antibody rituximab regimen. They correlate these new genetic alterations with the outcome of the patients (see figure). To date, this is the first report of such TP53 mutation in cancer. The presence of these nSNVs disrupts the binding of miRNA to the 3′UTR decreasing the miRNA suppression effect and thus increasing the p53 protein expression. Compared with wild-type (WT) CDS, mutated p53 CDS is associated with a shorter survival.5,6 The influence of the nSNVs on the outcome of DLBCL patients depends on the status of TP53 CDS, WT or mutated. In the case of WT TP53 nSNVs, miRNA suppression is decreased and WT p53 expression increases, and outcome of patients improves compared with WT p53 without nSNVs. In the case of mutated TP53 and the presence of nSNVs, the expression of mutated p53 increases, leading to an increase in resistance to chemotherapy and the poorest outcome. Interestingly, the authors demonstrated that some nSNVs located within the seed match site in the TP53 3′UTR could significantly alter p53 protein levels in vitro. Approximately 50% of DLBCLs display 3′UTR alterations that are predicted to disrupt miRNA binding sites, a much higher frequency than observed within the CDS.
Thus, what is important to foresee for outcome after treatment is not the presence of mutated p53 but the existence of nSNVs and p53 status.
There are several genetic mechanisms associated with refractoriness to therapy in DLBCL patients, mutation of TP53 being one that is present in ∼20% of the patients. Genetic alterations of molecules upstream or downstream of the p53 pathway, such as MDM2, ATM, p21, CDKN2A, or p73, are also implicated in the refractoriness to therapy.2,6 Mutations or hyperexpression of c-MYC, hyperexpression of bcl-2, or survivin are other frequent alterations found in refractory patients, but not all genetic alterations are currently described. We know that patients who expressed these modifications at the time of DLBCL diagnosis are more prone not to respond well to monoclonal antibody rituximab, but it is not a clear-cut figure. To propose a different regimen for these patients is not possible currently because we do not have drugs/regimens allowing better response in these patients. Some small molecules targeting p53 are currently in development, but their exact activity is not known.7 According to the present work published in this issue of Blood, a complete and accurate knowledge of the genomic status of both TP 53 CDS and 3′UTR appears mandatory before their clinical usage.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
