TP53 G245S

Our findings indicate a high frequency of TP53 variants in CRC patients from Rwanda. Importantly, these variants are enriched in the CMS2 subtype. This study, representing the second investigation into molecular alterations in patients with CRC from Rwanda and the first to explore TP53 mutations and CMS classification, provides valuable insights into the molecular landscape of CRC in this understudied population.

Yet, to our knowledge, we present herein the first case of ALK + NSCLC rapidly progressing on 1 st line Brigatinib treatment due to de novo MET- amplification. The recognition of this mechanism of ALK-TKI resistance by FISH, especially in NGS-negative cases, should be considered before initiating 1 st line treatment. This is of clinical importance, as effective combined therapy with ALK-TKI and MET-inhibitor is feasible.

Hazard ratios and p-values were computed via Cox regression when comparing OS relative to date of advanced diagnosis and PFS on subsets who received 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA)... TP53 mutations correlated with worse prognosis in advanced PDAC. Potential predictive associations favoring FFX over GA in the TP53 LOF subgroup (but not in GOF or WT subgroups) warrant further exploration. >

STR profiling indicated no evidence of cross-contamination. In conclusion, SCEACono2 could serves as a promising and robust research resource of EACSCC in vitro and in vivo.

Developing an effective treatment strategy for TP53-mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated TP53 holds promise as an approach to combating TP53-mutated AML, and recent developments in immunologic agents for AML offer hope in this field.

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.

The TP53 R249M mutation was also significantly (p < 0.0001) associated with smoking habits (OR, 11.77; 95% CI, 3.219-36.20), but not the same for the TP53 R249S mutation. Screening of ctDNA TP53 and CTNNB1 gene mutations by ddPCR may be helpful for early detection and identifying the risk of HCC progression.

Results The NGS analysis showed similar results for melanoma cell lines A375 and A2058, with SNV genomic alteration of BRAF (V600E) as relevant biomarker targeted by kinase inhibitors (binimetinib + encorafenib; cobimetinib + vemurafenib; dabrafenib; dabrafenib + trametinib), but also indicator of checkpoint inhibitors uses (atezolizumab; ipilimumab + nivolumab) in combinatorial therapies. Nevertheless, SK-MEL-2 cell line had similar immunophenotypic profile, although the genomic alterations were totally different. Discussion For establishing the appropriate therapeutic approach in melanoma cases, the personalized treatment should be envisioned, based on both next generation sequencing, surface markers expression, as well as microenvironment assessment.

Results The NGS analysis showed similar results for melanoma cell lines A375 and A2058, with SNV genomic alteration of BRAF (V600E) as relevant biomarker targeted by kinase inhibitors (binimetinib + encorafenib; cobimetinib + vemurafenib; dabrafenib; dabrafenib + trametinib), but also indicator of checkpoint inhibitors uses (atezolizumab; ipilimumab + nivolumab) in combinatorial therapies. Nevertheless, SK-MEL-2 cell line had similar immunophenotypic profile, although the genomic alterations were totally different. Discussion For establishing the appropriate therapeutic approach in melanoma cases, the personalized treatment should be envisioned, based on both next generation sequencing, surface markers expression, as well as microenvironment assessment.

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.

Furthermore, we explored the combination of the HSP90 inhibitor HSP90i and the AGAP1 inhibitor QS11 could inhibit ESCC cell proliferation and metastasis. Thus, the p53-G245S/hnRNPA2B1/AGAP1 axis promotes ESCC progression by enhancing exosome formation, and the combination of an HSP90 inhibitor and an AGAP1 inhibitor may serve as a potential therapeutic strategy.

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.

Further, comprehensive analysis of gene expression and exome sequencing of MYCN-induced clones indicated osteosarcoma-specific molecular features, such as the activation of TGF-β signaling and DNA copy number amplification of GLI1. The model of MYCN-expressing chondroblastic osteosarcoma was developed from hiPSC-derived neural crest cells, providing a useful tool for the development of new tumor models using hiPSC-derived progenitor cells with gene modifications and in vitro transformation.

Survival analysis indicated that the probability of short-term recurrence-free survival was significantly different among different TP53 p.G245S mutation frequency, MTM, PVTT, and AFP risk groups (p < 0.05). The mutation frequency of the p.G245S site was a novel prognostic risk factor for the short-term recurrence of HCC.