UNASSIGNED: The discovery of driver genes such as EGFR, KRAS, and ALK, has dramatically shifted treatment patterns in patients harboring these oncogenes. However, dissemination into the central nervous system (CNS) is a severe complication. In addition, the particular anatomical structure of the CNS has made it difficult to obtain tissue specimens from brain metastases (BM) to generate a gene map, as such, potential predictive markers for survival in patients with non-small cell lung cancer (NSCLC) and BM (NSCLC-BM) remain unclear.
UNASSIGNED: Data from 28 patients diagnosed with NSCLC-BM between June 2019 and May 2021 at Guangdong Sanjiu Brain Hospital (Guangzhou, China), were reviewed. Targeted next-generation sequencing (NGS) of a 168 cancer-related gene panel was available for surgically resected brain tissues from all patients. In addition, molecular characteristics and overall survival (OS) were analyzed to determine potential predictive markers.
UNASSIGNED: Among patients with NSCLC-BM, NGS revealed that TP53 was the most frequent mutation (61 %), with a detection rate of 39 %, closely by EGFR amplification. Additionally, CDKN2A, MYC, LRP1B, and RNF43 were frequently observed (18 %). The median OS was significantly shorter in the TP53 mutation group than in the wildtype group (14 versus undefined months, p = 0.014). Similar results were also found in the genetic alteration of EGFR amplification, suggesting that EGFR amplification was associated with worse OS (14 vs. 24 months, p = 0.039). Interestingly, NGS revealed that gene alternations such as TP53, EGFR amplification, and CDKN2A, tended to coexist and such a co-alteration panel indicated worse clinical outcomes (median OS, 5 months). In addition, the detection rate of negative survival genes, including TP53 or EGFR amplification, was much higher in tumor tissues than in plasma samples, indicating the limited predictive value of matched PLA samples.
UNASSIGNED: Gene signatures, such as TP53 or EGFR amplification, were associated with worse survival in patients diagnosed with NSCLC-BM. These valuable findings may shed light on new strategies for the prognostic assessment of specific patient groups.

In 2022, the World Health Organization (WHO) and International Consensus Classification (ICC) recognized TP53 as an entity-defining alteration in myeloid neoplasms, yet with differing criteria that could lead to discrepant diagnoses and affect clinical trial eligibility. We studied 67 patients with TP53 mutant myeloid neoplasms, reclassifying them using both criteria. While most cases fulfill the criteria for TP53 mutant defined entities, most discrepancies were found in cases with ≥20% blasts. Patients were stratified into three groups based on blast count (<10%, 10-19%, and ≥20%) which revealed comparable clinicopathologic features, genetic characteristics, and outcomes. Notably, patients with ≥10% blasts had shorter overall survival compared to those with <10% blasts (8.1 vs. 12.4 months; p = 0.03). This study is among the few to examine TP53 mutant myeloid neoplasms as a single entity and suggests that the 10% blast count threshold could serve as a gateway to a more harmonized classification for these patients.

OBJECTIVE: This retrospective study was undertaken to assess the predictive efficacy of 18F-FDG PET/CT -derived radiomic features concerning the co-mutation status of epidermal growth factor receptor (EGFR) and TP53 in LUAD.
METHODS: A cohort of 150 LUAD patients underwent pretreatment 18F-FDG PET/CT scans with known mutation status of EGFR and TP53 were collected. The feature extraction based on their PET/CT images utilized the Pyradiomics package based on the 3D Slicer. The optimal radiomic features were selected through correlation analysis and the Gradient Boosting Decision Tree (GBDT) algorithm, followed by the construction of the radiomic model. The clinical model incorporated meaningful clinical variables, whereas the complex model integrated both the radiomic and clinical models. The area under the receiver operating characteristic curve (AUC) facilitated the comparison of prediction performance across the three models. The DCA gauged the clinical utility of these models.
RESULTS: The patient cohort was randomly allocated into a training set (n = 105) and a validation set (n = 45) in a 7:3 ratio. Eleven PET and eleven CT optimal radiomic features were selected to construct the radiomic model. The model showed a good ability to discriminate the co-occurrence of EGFR and TP53, with AUC equal to 0.850 in the training set, and 0.748 in the validation set, compared with 0.750 and 0.626 for the clinical model. The complex model exhibited the highest AUC values, with 0.880 and 0.794 in both sets, but there were no significant differences compared to the radiomic model. The DCA revealed favorable clinical value.
CONCLUSIONS:

In multiple myeloma (MM), while frequent mutations in driver genes are crucial for disease progression, they traditionally offer limited insights into patient prognosis. This study aims to enhance prognostic understanding in MM by analyzing pathway dysregulations in key cancer driver genes, thereby identifying actionable gene signatures. We conducted a detailed quantification of mutations and pathway dysregulations in 10 frequently mutated cancer driver genes in MM to characterize their comprehensive mutational impacts on the whole transcriptome. This was followed by a systematic survival analysis to identify significant gene signatures with enhanced prognostic value. Our systematic analysis highlighted 2 significant signatures, TP53 and LRP1B, which notably outperformed mere mutation status in prognostic predictions. These gene signatures remained prognostically valuable even when accounting for clinical factors, including cytogenetic abnormalities, the International Staging System (ISS), and its revised version (R-ISS). The LRP1B signature effectively distinguished high-risk patients within low/intermediate-risk categories and correlated with significant changes in the tumor immune microenvironment. Additionally, the LRP1B signature showed a strong association with proteasome inhibitor pathways, notably predicting patient responses to bortezomib and the progression from monoclonal gammopathy of unknown significance to MM. Through a rigorous analysis, this study underscores the potential of specific gene signatures in revolutionizing the prognostic landscape of MM, providing novel clinical insights that could influence future translational oncology research.

Accelerated chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL/SLL) is a histologically aggressive subtype of CLL/SLL that lies in between conventional CLL/SLL (C-CLL/SLL) and Richter transformation (RT) on the biological spectrum. Although the histologic criteria for A-CLL/SLL were defined 14 years ago, the clinical and genetic characteristics and survival outcomes of these patients have yet to be studied in the era of novel therapies. We retrospectively analyzed the clinicopathologic, genetic, and survival characteristics of 34 patients with confirmed tissue diagnosis of A-CLL/SLL and compared them with 120 patients with C-CLL/SLL. Patients with A-CLL/SLL had significantly higher frequencies of B-symptoms, anemia and thrombocytopenia, splenomegaly, higher LDH, and more advanced Rai stages. A-CLL/SLL showed a significantly higher frequency of TP53 mutations (55.0% vs. 11.5%;p < 0.0001) and deletions (38.2% vs. 8.3%;p < 0.0001), lower isolated del(13q) (5.8% vs. 27.5%;p < 0.0001), and increased incidence of RT (11.76% vs. 0.83%;p = 0.0025). The overall survival of patients with A-CLL/SLL was significantly lower than C-CLL/SLL (median survival: 6.17 years vs. not reached; 2 and 5-year survival rates: 75.5% vs. 94.7% and 53.3% vs. 93.7%, respectively; p < 0.0001); however, novel agents have improved the outcomes dramatically compared to the previously published data in the pre-BTKi era. Our results support the categorization of A-CLL/SLL as a distinct biologically aggressive subtype of CLL/SLL and highlight the need to revise the diagnostic criteria utilizing a multifaceted approach that integrates the overall pathobiological profile of the disease, in addition to the histology.

Rationale: PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. Methods: The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including TP53-mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P<0.001), a lower median PSA change (-55% vs. -75%, P=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P=0.003) compared to TP53-wildtype patients. Pathogenic alterations in AR, MYC, BRCA1, or BRCA2 as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside TP53-status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (P<0.05). Conclusion: TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.

The objective of the present study was to characterize the molecular features of endometrial carcinomas with ambiguous histology. Eighteen carcinomas that could not be conclusively typed based on morphology and immunohistochemistry underwent analysis of mismatch repair (MMR) status, microsatellite status, and whole-exome sequencing. None of the tumors had pathogenic POLE mutation. Twelve tumors (67%) were microsatellite stable, and 6 (33%) had microsatellite instability. Fourteen tumors (78%) harbored TP53 mutations, and 2 (11%) had mutations in MMR genes. Eleven carcinomas (61%) were classified as copy number high and 7 (39%) as MSI-hypermutated, the latter including 3 tumors with TP53 mutation who concomitantly had MSI or mutation in a MMR gene. Other mutations that were found in > 1 tumor affected MUC16 (7 tumors), PIK3CA (6 tumors), PPP2R1A (6 tumors), ARID1A (5 tumors), PTEN (5 tumors), FAT1 (4 tumors), FAT4 (3 tumors), BRCA2 (2 tumors), ERBB2 (2 tumors), FBXW7 (2 tumors), MET (2 tumors), MTOR (2 tumors), JAK1 (2 tumors), and CSMD3 (2 tumors). At the last follow-up (median = 68.6 months), 8 patients had no evidence of disease, 1 patient was alive with disease, 8 patients were dead of disease, and 1 patient died of other cause. In conclusion, based on this series, the molecular landscape of endometrial carcinomas with ambiguous histology is dominated by TP53 mutations and the absence of POLE mutations, with heterogeneous molecular profile with respect to other genes. A high proportion of these tumors is clinically aggressive.

Epidermal growth factor receptor (EGFR) mutations have emerged as the most well-studied oncogenic alterations in advanced non-small cell lung cancer. The presence of single common or rare EGFR mutations and extra complex EGFR mutations correlates with the response sensitivity to EGFR tyrosine kinase inhibitors. Therefore, given the lack of evidence for the emergence of rare EGFR mutation types, the pathogenic mechanisms of uncommon EGFR mutations and the optimal treatment strategies remain to be explored further. The present study describes the case of a patient diagnosed with lung adenocarcinoma (LUAD) carrying two rare EGFR exon 18 indel/G719C and exon 19 L747S mutations, in which persistent lesion shrinkage was exhibited within 16 months of osimertinib treatment. Given the paucity of clinical trials for the treatment of LUAD harboring complex EGER mutations, the present detailed case description may provide clinicians with effective clinical experience in treating patients.

UNASSIGNED: In the era of chemo-immunotherapy, high-risk factors unequivocally predicted inferior outcomes for patients with CLL. The widespread adoption of BTK inhibitors has challenged the practical implications of such testing, as many patients have improved outcomes despite the presence of high-risk features. The impact of adverse prognostic factors, such as unmutated IGHV, on survival has been ameliorated by continuous treatment with BTK inhibitors, but not by finite-duration therapy with venetoclax-based combinations. Furthermore, TP53 abnormalities continue to be associated with worse outcomes in the era of novel agents. New treatment modalities, such as pirtobrutinib, lisocabtagene maraleucel, and ongoing studies combining BTK inhibitors with venetoclax, raise new questions on the significance of prognostic factors of survival for patients with CLL.
UNASSIGNED: Herein, we summarized the available literature on patients with CLL harboring high-risk biomarkers, with a focus on data from key clinical trials.
UNASSIGNED: Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials.

BACKGROUND: High expression of ubiquitin ligase MDM2 is a primary cause of p53 inactivation in many tumors, making it a promising therapeutic target. However, MDM2 inhibitors have failed in clinical trials due to p53-induced feedback that enhances MDM2 expression. This underscores the urgent need to find an effective adaptive genotype or combination of targets.
METHODS: Kinome-wide CRISPR/Cas9 knockout screen was performed to identify genes that modulate the response to MDM2 inhibitor using TP53 wild type cancer cells and found ULK1 as a candidate. The MTT cell viability assay, flow cytometry and LDH assay were conducted to evaluate the activation of pyroptosis and the synthetic lethality effects of combining ULK1 depletion with p53 activation. Dual-luciferase reporter assay and ChIP-qPCR were performed to confirm that p53 directly mediates the transcription of GSDME and to identify the binding region of p53 in the promoter of GSDME. ULK1 knockout / overexpression cells were constructed to investigate the functional role of ULK1 both in vitro and in vivo. The mechanism of ULK1 depletion to activate GSMDE was mainly investigated by qPCR, western blot and ELISA.
RESULTS: By using high-throughput screening, we identified ULK1 as a synthetic lethal gene for the MDM2 inhibitor APG115. It was determined that deletion of ULK1 significantly increased the sensitivity, with cells undergoing typical pyroptosis. Mechanistically, p53 promote pyroptosis initiation by directly mediating GSDME transcription that induce basal-level pyroptosis. Moreover, ULK1 depletion reduces mitophagy, resulting in the accumulation of damaged mitochondria and subsequent increasing of reactive oxygen species (ROS). This in turn cleaves and activates GSDME via the NLRP3-Caspase inflammatory signaling axis. The molecular cascade makes ULK1 act as a crucial regulator of pyroptosis initiation mediated by p53 activation cells. Besides, mitophagy is enhanced in platinum-resistant tumors, and ULK1 depletion/p53 activation has a synergistic lethal effect on these tumors, inducing pyroptosis through GSDME directly.
CONCLUSIONS: Our research demonstrates that ULK1 deficiency can synergize with MDM2 inhibitors to induce pyroptosis. p53 plays a direct role in activating GSDME transcription, while ULK1 deficiency triggers upregulation of the ROS-NLRP3 signaling pathway, leading to GSDME cleavage and activation. These findings underscore the pivotal role of p53 in determining pyroptosis and provide new avenues for the clinical application of p53 restoration therapies, as well as suggesting potential combination strategies.