Despite the great diversity of genes involved in oncogenesis, the transcription factor TP53 remains a key tumor suppressor and a master regulator of various signaling pathways involved in this process[22]. It is considered a powerful tumor suppressor regarding its various roles including the ability to induce cell cycle arrest, DNA repair, senescence, and apoptosis, to name only a few. Furthermor, TP53 mutations were reported to occur in almost every type of cancer at rates varying between 10% (e.g., in hematopoietic malignancies)[23]and close to 100% (e.g., in high-grade serous carcinoma of the ovary)[24].
Germline mutation of TP53 are also asossiated with cancer predisposition emphasized notably by Li-Fraumeni syndrome (LFS) characterized by a wide spectrum of tumor types occurring over a wide age range, starting at a young age[25].
Here, we identified in moroccan prostate cancer patients 22 variants in the DNA-binding domain of TP53 that has been reported in previous study. The mutation c.423C > G (p.Cyst141Trp) is one of the highly frequent variant recorded in 9 patients (18%). This mutant was reported in breast cancer and Li-Fraumeni syndrome[26].The mutant c.392A > T detected in 5 patients, result into deletrious substitution of asparginine in position 131 by isoleucine, this variant was identified first in a familly with a history of multiple malignancies[27]. Another missense variant identified at the same frequency is c.523C > G mutant and affect the arginine in position 175, considered one of the hot spot residu. This alteration was identified in a French family meeting Li-Fraumeni syndrome criteria[28], beside, another alteration at this same amino acid position (p.R175H) is a well characterized TP53 hotspot mutation[29]. The nonsense variant c.430C > T identified in one case, generates a premature translational stop signal (p.Gln144*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. This mutant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome[30]. Within the known mutations identified the intronic variant c.559 + 31G > A was the most frequent recorded in 26 patients (54%).
Considering previous reports on TP53 gene, the majority of mutations reported are missense mutations[31]. Indeed, among the mutants identified in our study, missense variants were very frequent and has been recorded in 27 cases. Furthermore, 79% of the population studied was found to carry germline mutation all localized at the DNA-Bainding site, according to previous studies this site hosts 90% of the mutations between residues 110 and 290, and this could therefore lead to the inhibition of its transcriptional activity [32]. Although few data are available on the association of PC with germline TP53 mutations [33, 34], but a large study by Maxwell et al identified germline TP53 mutations in 38 PC patients (0.55% prevalence) with a relative risk of having gTP53 significantly elevated at 9.1 (95% CI 6.2–14, p < 0.0001) compared with the noncancer population database. In the same study the incidence of PC in LFS was assessed, and PC was identified in 31 cases of 163(19%).
Our study identified high frequency of new germlines mutations affecting the TP53 gene and which not appear to be associated with Li-Fraumeni syndrome, a similar finding was reported by the maxwell study, revelead that over half of the gTP53 variants identified in PC patients are considered attenuated or hypomorphic variants and not typically associated with classic LFS. The actual effects of these variants on the TP53 protein are unknown. But, the two prediction tools SIFT and Polyphene.2 emplyed to asseess the impact of the missense variants, revealed that more than half of this missense mutants predict to alter the function of the TP53 protein. Hense leading to a defects in protein pathway as tumor suppressor gene. The variants predicted as the most deleterious by both SIFT and Polyphene.2 tools namely : p.Ala138Gly, p.Tyr126Arg, p.Val143Ala, p.Val143Glu, p.Gln144Pro, p.Gln144His, p.Pro152Thr, p.Gly154Asp, p.Ala159Asp, p.Lys164Gln, p.His168Asn, p.Asp184His. Indeed, the codon at position 143 could be considered as a critical residue, a study by Dridi W et al aimed to determine the dominant-negative effect of different p53 mutations in the near-diploid LoVo colon carcinoma cell line in response to mitotic spindle inhibitors, demonstrated that the TP53-175H and p53-143A mutant clones re-enter S phase with no apparent arrest unlike the wild type showing a tetraploid G1 cell arrest[35]. Regarding functionnal significance of TP53 mutations, missense mutation can have dominant negative effects on transactivation of other genes containing p53-specific responsive elements. According to Forrester et al. generally minimal dominant negative effects can be attributed only to codons 143ala-, 175his-, 248trp-, 249ser-, 273his-mutations in PCa cell line PC-3, lacking one basepair in codon 138 [36].
Despite the absence of correlation between the clinicopathological features and mutational status, we noticed a significant frequency of mutations in patients at localized stages of PC T1(29%) and T2(50%) (Fig. 1). Indeed, although alterations of this gene have been mainly associated with advanced stages of PC and constitute a late event of carcinogenesis[37, 38], but substancials aberrations in TP53 have previously been reported not only in advanced prostate cancer but also in primary prostate cancer and were associated with a poor patient outcome[14, 39–41]. Taken together, our results suggest that some patients may harbor germline genetic alterations of the TP53 gene likely to be involved in the initiation or progression of the disease, such is the case of the BRCA1/2 genes whose germline mutations have been associated with PC and are a part of the gene panels used for patient stratification in the context of PARP inhibition that doasn’t includ TP53[42].