Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome

Abstract

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer disorder with highly variable clinical outcomes that results from germline mutations in the TP53 gene. Here we report that the quaternary structure of p53 is an important factor affecting cellular functions and the clinical outcomes of LFS patients (n = 87). Specifically, carriers of monomeric p53 mutants (n = 56) exhibited complete penetrance, with a 2.11-fold greater risk of cancer-related death (95% confidence interval [CI] = 1.07 to 4.30) and a statistically significantly lower median survival age as compared with carriers of multimeric (dimeric or tetrameric, n = 31) p53 mutants (33 years, 95% CI = 30 to 50, vs 51 years, 95% CI = 40 to NA, respectively, two-sided P = .03), who presented incomplete penetrance. Cellular functional assays using p53-null H1299 cells expressing clinically relevant p53 mutants confirmed that the cellular effects observed upon loss of p53 oligomerization are associated with clinical outcomes of LFS patients. The association between p53 oligomeric state and clinical phenotype suggests that TP53 mutations are not all equivalent and supports the implementation of new genotype-adapted guidelines for the management of LFS patients with TP53 mutations in the oligomerization domain.

Survival in males with glioma and gastric adenocarcinoma correlates with mutant p53 residual transcriptional activity

“…All data processing and statistical analyses were performed in the R statistical environment (v3.4.3), using R packages survival (v2.41-3), survminer (v0.4.1), cgdsr (v1.2.6), and miscTools (v0. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].…”

“…Increasing evidence suggests that not all mutations have equally deleterious effects on p53 activity, which has been previously described as the mutant p53 functional gradient effect (14)(15)(16)(17)(18). In vitro studies demonstrate a broad range of activities when comparing different p53 mutants, where some retain near WT transcriptional activity and others are inactive (15).…”

p53 tetramerization: at the center of the dominant-negative effect of mutant p53

“…While monomeric p53 TD mutants have a 100% cancer penetrance and yield a median survival time of ∼33 yr, multimeric p53 TD mutants (dimers or tetramers) exhibit a cancer penetrance of ∼80% and 51-yr median survival. Notably, monomeric mutants exhibit worse outcomes than hot spot p53 DBD mutants (penetrance: ∼90%; median survival: ∼47 yr) (Fischer et al 2018), highlighting the importance of the p53 TD in tumor suppression and the need to understand the mechanism of action of TD mutants in physiologically-relevant settings. The abnormally high cellular levels of cancer-prevalent p53 TD mutants (Rollenhagen and Chène 1998; Katz et al 2018;Park et al 2018) may confer additional activities that can contribute to disease severity and possibly explain disease outcomes.…”

Gain-of-function mutant p53: history and speculation

“…In collaboration with Jack Griffith, they found that human p53 C-terminal fragments interact with single stranded DNA and insertion/deletion mismatches (Lee et al, 1995). There are six critical lysines (6 K) in the C-terminal domain (CTD) of p53 (Laptenko et al, 2016) as well as critical residues for p53 function in the oligomerization domain (OD) (Fischer et al, 2016; Laptenko et al, 2016; Fischer et al, 2018). How these relate to the N-terminal region of p53 with its two transcription activation domains (AD1 and AD2) and the proline-rich (PR) region is well described (Laptenko et al, 2016) (see Figure 1, for a representation).…”