TP53 R273C

This is the largest study to investigate the landscape of immunogenic neoantigens in BC and PC. The frequency of high-level binding affinity neoantigens was relatively low and associated with relatively lower TIS scores in MSS tumors, which may contribute to the immunogenic cold TME characterizing these tumor types.

Inhibition of mutant p53R248Q and miR-182-5p increased FOXF2-MTSS1 levels and decreased cell migration and invasion. In summary, our results suggest that p53 mutants increase the expression of miR-182-5p, and this miRNA is necessary for the p53R248Q mutant to induce cell migration and invasion in a cancer cell model.

Further, comparative analyses of large transcriptomics datasets on breast cancer cell lines and tumors suggest that dysregulation of the Hippo/YAP/TAZ pathway plays a key role in driving the cellular phenotypes towards basal-like in the presence of more aggressive p53 mutants. Overall, our study describes distinct gain-of-function impacts on protein functions, transcriptional profiles, and cellular behaviors of different p53 missense mutants, which contribute to clinical phenotypic heterogeneity of triple-negative breast tumors.

P2, N=60, Not yet recruiting, Sun Yat-sen University

NGS analysis of TETs revealed several somatic variants in genes related to the p53, AKT, MAPK, and K-Ras signalling pathways. TCs showed greater genetic dysregulation than TMs. KIT alterations in TCs have potential as therapeutic targets.

Material and Methods We analysed preoperative core biopsy samples of 20 patients with MRSTS who received 5×5 Gy radiotherapy combined with three cycles of doxorubicin-ifosfamide chemotherapy in a phase II clinical trial (NCTXXXXXXXX). D Undifferentiated pleomorphic sarcoma CDK4 Amplification - - D Dedifferentiated liposarcoma CDK4 Amplification - - E Undifferentiated pleomorphic sarcoma RB1 Nonsense mutation c.958C>T p.R320* D Myxofibrosarcoma AKT2 Amplification - - D Undifferentiated pleomorphic sarcoma PTEN Gene deletion - - D Undifferentiated pleomorphic sarcoma PTEN Gene deletion - - E Pleomorphic liposarcoma PTEN Gene deletion - - D Myxofibrosarcoma NF1 Nonsense mutation c.3520C>T p.Q1174* D Malignant peripheral nerve sheath tumor NF1 Nonsense mutation c.1278G>A p.W426* D Malignant peripheral nerve sheath tumor Conclusion The detection of known mutations in MRSTS suggests poor pathological response to neoadjuvant radiochemotherapy. Identified mutations may indicate new therapeutic targets in the treatment of MRSTS.

In CRC, non-GOF mTP53 was prevalent in more than half of all cases. Compared to GOF mTP53, predictive biomarkers of response to immune checkpoint inhibitors (TMB and MSI-H/dMMR) were higher in this cohort albeit still relatively rare. Otherwise, differences in molecular signatures between GOF and non-GOF mTP53 did not contain clinically meaningful differences.

These results confirm the non-equivalence of p53 mutations in the context of hepatocellular carcinoma and suggest the acquisition of a gain-of-function phenotype for certain mutants. Experiments are ongoing to validate this observation and identify the molecular mechanisms involved in this process.

To further evaluate for a time-dependent effect, 2 representative variants (R248Q and R273C) after 6 and 24 hours of incubation with 50μM APR-246 and 10μM of Nutlin-3. APR-246 demonstrated a negative, dose-dependent effect on cell viability in all EC cell lines. Our results demonstrate that APR-246's cytotoxic effects in EC seem to be p53-independent. Potential mechanisms for the anti-neoplastic effects of APR-246 include activity targeting antioxidant pathways demonstrated in other solid tumors and provides an area for further investigation in TP53mut EC.

The NGS panel could successfully detect actionable mutations in liquid biopsies with a high concordance rate and sensitivity. The detection of variants in cfDNA, but not in tDNA, suggests a greater representativeness of the mutational tumor spectrum in samples of liquid biopsies opening perspectives for employing this approach in the routing setting. The NGS assay for liquid biopsy may decrease tissue biopsies and turnaround time for report release, accelerating therapeutic strategies for NSCLC patients.

In this limited study, PRAME is expressed in 100% of PEComas demonstrating its utility as an additional IHC marker of melanocytic expression in this difficult tumor type. While PRAME expression was similar to HMB45 in most cases, it was stronger and more diffuse in two cases (33.3%). Additional testing to determine the expression of PRAME in tumors in the differential diagnosis with PEComas is underway.

FGFR3 :: TACC3 fusions may occur de-novo or as a secondary treatment resistance mechanism in NSCLC. These fusions appear to be enriched in smokers or former smokers and more frequently occur with squamous cell carcinoma histology and may demonstrate clear cell morphology by light microscopy. Identification of FGFR alterations is of particular importance given the lack of targeted therapeutic options for patients with squamous cell carcinoma.

Notably, AXT cells, which are cells derived from tumors originating from AX cells, lost wild-type p53 expression, were devoid of the intact transcription activation function, and were resistant to doxorubicin...Therefore, the therapeutic potency targeting R270C (equivalent to human R273C) mutant p53 is limited in osteosarcoma. However, considering the heterogeneous nature of osteosarcoma, it is important to further evaluate the biological and clinical significance of mutant p53 in various cases.

The germline and rare SNVs of uncertain clinical significance reported in this study add to the number of known genetic alterations in TETs, thus extending our molecular understanding of these neoplasms. Druggable KIT alterations in thymic carcinomas have potential as therapeutic targets.

Furthermore, we identified genes which could be associated with higher M2 macrophage infiltration and TMB in LGG patients with TP53 R273C mutation. The study indicates that TP53 R273C mutation is very likely oncogenic and may be used as an indicator of the prognosis of LGG.

Our findings suggest that compared to other TP53 mutations, IDHmut astrocytomas may select for TP53 mutations during tumorigenesis. The genotype, sex, and mutation-specific findings are clinically relevant and should prompt further investigation of TP53 .

Moreover, heterozygous modeling of R273C-p53 or R273H-p53 expression resulted in distinct phenotypic outcomes in vitro and in vivo. Thus, mutant p53 acts in a context-dependent manner to elicit pro-tumorigenic transcriptional profiles, providing critical insight into mutant p53-mediated prostate cancer progression.

We are currently validating the functional relevance of these findings in conjunction with the dysregulated pathways identified from RNA-Seq and ChIP-Seq analysis. Taken together, our integrated approach of utilizing phenotyping, multi-omics bioinformatics analysis, and screening has revealed the molecular mechanisms underlying phenotypic and molecular heterogeneity and potential molecular targets of TNBC.

We observed trans-species heterogeneity in as high as 75% of the identified proteins, indicating that the ambiguity of proteins should be addressed by specific strategies to avoid drawing false conclusions. The identification and characterization of gene mutation and expression heterogeneity across different ESCC datasets, including various novel TP53 mutations, ECM-receptor interaction, Focal adhesion, and Olfactory transduction pathways (CNGB1), provide researchers with evidence and implications for accurate research and precision therapeutic development.

Our results emphasized that liquid biopsy is applicable to analyze the drug resistance mechanisms of NSCLC patients treated with EGFR-TKIs. Moreover, we discovered two uncommon mutations, TP53 R273C and KRAS G12V, which attenuates the effectiveness of osimertinib.