It is demonstrated that oncogenesis in LFS can be driven by partial impairment of functional p53, rather than dominant-negative or gain-of-function mutations alone.
Abstract
Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in the
TP53
tumour suppressor gene, which encodes the multifunctional transcription factor p53. p53 is the most commonly mutated protein in human cancer, with the majority occurring within the DNA-binding domain, often disrupting transcriptional activity and resulting in a loss-of-function. Here, we characterise the novel p53
N263Tfs*7
truncated mutant, identified as a germline mutation from a patient with LFS who developed breast cancer. Functional assays revealed a partial loss-of-function across key cellular processes, including proliferation, cell death, cell motility, and transcriptional transactivation. This mutant lacked a dominant-negative effect, distinguishing it from common DNA-binding domain missense mutations. Our findings demonstrate that oncogenesis in LFS can be driven by partial impairment of functional p53, rather than dominant-negative or gain-of-function mutations alone. This underscores the clinical significance of recognising subtle
TP53
variants for the refined molecular classification and clinical prediction of cancer risk in
TP53
mutation carriers.
The role of the PI3K/AKT pathway in the PIK3CA-related overgrowth is clarified, with one pediatric patient carrying a novel mosaic de novo in-frame deletion mutation in the PIK3CA gene identified.
Jing-Heng Wu, Shan-Lin Chen, Yunhao Xue et al.· Yi chuan = Hereditas· 0 citations
Functional evidence is provided to fine-tune the classification of these SAMD9L variants and significantly advance the understanding of the molecular mechanisms by which SAMD9L variants drive inherited myeloid neoplasms.
E. Vuelta, A. Liquori, M. Morín et al.· British Journal of Haematolo...· 0 citations
Background/Objectives: Müllerian duct anomalies (MDAs) are congenital structural abnormalities of the female reproductive tract with heterogeneous and incompletely defined genetic contributions. PAX8 is a developmental transcription factor implicated in thyroid and urogenital development. This study assessed the functional consequences of a rare PAX8 variant identified by whole-exome sequencing (WES) in an MDA cohort, without presuming a causal relationship. Methods: WES was performed in 150 patients with MDAs. The PAX8 c.791T>C (p.Leu264Pro) variant was evaluated using computational predictions, cellular assays, and RNA sequencing in a 293FT transient-overexpression model. Results: The heterozygous p.Leu264Pro variant was identified in one patient with a complex septate uterine, cervical, and vaginal anomaly and was absent from 120 controls. Parental samples were unavailable. No statistically significant difference in construct-derived PAX8 mRNA abundance was detected between PAX8-WT and PAX8-L264P, and both proteins showed predominantly nuclear localization. In the direct PAX8-WT-versus-L264P RNA-seq comparison, 76 transcripts had nominal p values below 0.05, but none remained significant after Benjamini–Hochberg correction, and no gene met the prespecified differential-expression criteria. AK5, RCBTB2, and IFT88 were identified as candidate PAX8-responsive genes in this experimental system. Conclusions: No major functional difference was detected between PAX8-WT and L264P under the tested conditions; however, these findings do not establish functional equivalence or exclude smaller, tissue-specific, or developmental-stage-specific effects. The p.Leu264Pro variant remains a variant of uncertain significance with respect to MDAs, and the functional results were not used as benign evidence under ACMG/AMP criterion BS3.
Lin He, Liang-Zhe Li, Yuxiao Li et al.· Genes· 0 citations
ASXL3 patient truncations in neurodevelopmental condition Bainbridge-Ropers syndrome are shown to mediates gain-of-function (GOF) by escaping nonsense-mediated decay and Cullin 4-dependent degradation, resulting in aberrant protein accumulation, widespread transcriptional dysregulation, and altered chromatin accessibility.
Y. Nakamura, T. Nguyen, N. Mor et al.· medRxiv· 0 citations
The DICER1 gene is mutated in cancer, including in DICER1-related tumour predisposition. Cancer-associated hotspot mutations have been reported in both catalytic domains of DICER and are predicted to disrupt miRNA biogenesis. To understand how these hotspot mutations contribute to cancer development, we generate cell lines harbouring single amino acid substitutions within the catalytic RNase IIIa (S1344L) or RNase IIIb (D1709N) domains of the endogenous DICER1 gene. Here we show that both mutations result in a widespread loss of 5p miRNAs, and an increase in 3p passenger strands loading into AGO2. The shared similarities between both mutants can be attributed to the structural proximity of the S1344 residue to the RNase IIIb catalytic centre. Functionally, we find that changes in the repertoire of miRNAs loaded into AGO2 result in altered gene expression, impacting critical pathways for cancer development. Additionally, our results indicate that inactivating the processing activity of DICER does not result in genomic instability. Instead, mutations cause upregulation of transposable elements, including the human endogenous retrovirus H through miRNA-independent mechanisms. This suggests that both canonical and non-canonical DICER functions are important to understand DICER1-related tumour predisposition. DICER1 is often mutated in cancer, including in DICER1-related tumour predisposition. Here, the authors show that cancer-associated DICER1 mutations shift microRNA processing and reactivate HERVH endogenous retroviruses.
K. Gordon, N. Bellora, Jeroen Witteveldt et al.· Nature Communications· 0 citations
Abstract Tumor Protein p53 (TP53) is the most frequently altered gene in human cancer, yet mutant p53 has long been considered undruggable. The Y220C mutation is exceptional because it both destabilizes the p53 DNA-binding domain (DBD) and creates a unique surface pocket absent in wild-type protein. Availability of structural information enabled structure-based development of rezatapopt (PC14586), which binds this neo-pocket, stabilizes mutant p53, and restores transcriptional tumor suppressor activity. Early clinical studies in the PYNNACLE trial provide proof-of-concept efficacy and reveal emerging on-target resistance. This success supports a broader paradigm in which oncogenic missense mutations can generate druggable neo-pockets, exemplified by KRAS G12C inhibitors such as sotorasib. While most p53 hotspot mutations lack such features, computational pocket detection and structure-guided design may expand targetability across the mutational landscape. Complementary strategies, including covalent stabilization and targeted degradation, further extend this framework, establishing mutation-encoded structural vulnerabilities as actionable therapeutic opportunities.
Lin-Wan Song, Hua Wang· Medical Review· 0 citations
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