Tumour protein p53 (TP53) is a tumour suppressor gene that is frequently mutated in cancers. Traditional TP53 detection methods, such as polymerase chain reactions, are time-consuming and demand skilled laboratory personnel. As an alternative, in the current study, we have demonstrated a high resistivity silicon (HR-Si) based conductometric biosensor designed for the rapid and specific identification of TP53 point mutations directly at the point-of-need. This biosensor accurately detected R248Q and R248W point mutant single strand DNA (ssDNA) as models, in real-time. Both R248Q and R248W mutant ssDNA exhibited a limit of detection (LOD) of 0.5 ng/mL in human plasma. The selectivity studies revealed that both R248Q and R248W mutant ssDNA can be detected 10 × lower molar content against their wild-type ssDNA. Validation of the sensor using clinical samples harbouring known TP53 mutations demonstrated a sensitivity of 100%, a specificity of 100%, and a LOD of 2.5 ng/mL. This precision biosensing platform at the point-of-need has the potential to revolutionise cancer diagnostics.

Gastric cancer remains a leading cause of cancer-related mortality worldwide. The prognosis often depends on early detection and understanding the molecular mechanisms involved in its progression. Periodic tryptophan protein 1 (PWP1) has emerged as a novel diagnostic marker, potentially linked to gastric cancer progression. This study aims to elucidate the impact of PWP1 on gastric cancer development, focusing on apoptosis, cell cycle regulation, and the role of p53. This study utilized gastric cancer cell lines to investigate the expression and functional role of Pwp1. Quantitative PCR and Western blot analyses were conducted to measure PWP1 expression levels. Apoptosis was assessed by using flow cytometry and TUNEL assays, and cell cycle analysis was performed to evaluate the impact of PWP1 modulation. Additionally, animal experiments were conducted using mouse models injected with gastric cancer cells, with PWP1 knockdown or overexpression, to observe tumor growth and progression. Statistical significance was evaluated using t-tests and ANOVA where appropriate. Elevated PWP1 expression was observed in gastric cancer tissues compared to normal tissues. PWP1's knockdown resulted in increased apoptosis and cell cycle arrest at the G1 phase, suggesting its role in promoting invasion and proliferation. Furthermore, animal experiments demonstrated reduced tumor growth in mice with PWP1 knockdown. PWP1 was found to transcriptionally regulate p53, affecting its expression and thereby influencing apoptosis and cell cycle pathways in gastric cancer. Our study identifies PWP1 as a novel oncogene frequently overexpressed in gastric cancer (GC). Through transcriptional regulation of p53, PWP1 enhances cell growth by influencing apoptosis and inducing G1 phase cell cycle arrest. These findings underscore PWP1 as a promising therapeutic target for treating GC, suggesting its potential for future clinical applications.

Leukemia is a heterogeneous malignant tumor of the hematopoietic system and is characterized by the blockage of differentiation and uncontrolled proliferation of myeloid or lymphoid progenitor cells in the bone marrow and peripheral blood. Currently, intensified chemotherapy regimens and hematopoietic stem cell transplantation (HSCT) are the most common treatment methods for various types of leukemia. However, they are associated with severe side effects and multidrug resistance. Therefore, developing new treatment approaches with sufficient therapeutic effects to eliminate leukemia cells and improve leukemia outcomes selectively is essential. Traditional Chinese Medicine (TCM) has received widespread attention as an alternative treatment for acute myeloid leukemia (AML) because of its multi-component and multi-target characteristics. Increasing evidence suggests that TCM blocks AML progression by regulating various biological processes. Herein, we review the effects of TCM therapies for AML and its potential mechanisms and targets. Our findings will promote further research and improve the clinical application of TCM in treating AML.

TIP60 is a tumor suppressor with histone acetyltransferase (HAT) activity, playing a crucial role in regulating chromatin architecture by acetylating histones to enhance accessibility for other regulatory factors. Its function is vital for several key cellular processes, including DNA damage repair, apoptosis, and autophagy. While the downregulation of TIP60 has been associated with various cancers, the effects of naturally occurring mutations in TIP60 on its function in malignancies remain poorly understood. In this study, we explored how cancer-related mutations in TIP60 impact its structure and function. Several deleterious and destabilizing missense mutations were identified and analyzed for structural changes. Molecular dynamics simulations revealed alterations in protein conformational stability and radius of gyration due to these mutations, supported by significant changes in TIP60's solvent accessibility and intramolecular hydrogen bonding. Biochemical assays with recombinant proteins showed a loss of catalytic activity in the G400W mutant. Live cell imaging indicated abnormal localization of the G400W mutant within the nucleus. Additionally, we observed aberrant phase separation of TIP60 caused by the G400W mutation. Notably, the G400W mutation impairs TIP60's catalytic function, preventing effective DNA repair and leaving the genome vulnerable to further mutations. Our findings highlight cancer-associated mutations in TIP60 that may contribute to the molecular mechanisms underlying cancer initiation and progression.

Protein arginine methyl transferases (PRMTs) are generally upregulated in cancers. However, the mechanisms leading to this upregulation and its biological consequences are poorly understood. Here, we identify PRMT5, the main symmetric arginine methyltransferase, as a critical driver of chemoresistance in high-grade serous ovarian cancer (HGSOC). PRMT5 levels and its enzymatic activity are induced in a platinum-resistant (Pt-resistant) state at the protein level. To reveal potential regulators of high PRMT5 protein levels, we optimized intracellular immunostaining conditions and performed unbiased CRISPR screening. We identified Kelch-like ECH-associated protein 1 (KEAP1) as a top-scoring negative regulator of PRMT5. Our mechanistic studies show that KEAP1 directly interacted with PRMT5, leading to its ubiquitin-dependent degradation under normal physiological conditions. At the genomic level, ChIP studies showed that elevated PRMT5 directly interacted with the promoters of stress response genes and positively regulated their transcription. Combined PRMT5 inhibition with Pt resulted in synergistic cellular cytotoxicity in vitro and reduced tumor growth in vivo in Pt-resistant patient-derived xenograft tumors. Overall, the findings from this study identify PRMT5 as a critical therapeutic target in Pt-resistant HGSOC cells and reveal the molecular mechanisms that lead to high PRMT5 levels in Pt-treated and chemo-resistant tumors.

Next-generation sequencing has revealed TP53 alterations in localized prostate cancer (PCa), suggesting growing clinical potential for p53 immunohistochemistry (IHC). Prior research supports the use of IHC for the detection of p53 overexpression to predict the presence of TP53 alterations known to be associated with adverse outcomes. However, to reach a consensus definition of p53 overexpression in PCa, further insights are needed. This study aimed to compare two fundamental approaches of evaluating p53 expression across a variety of specimens regarding PCa progression.

This study included 84 patients (75% self-identified as African American) diagnosed with PCa between 1996 and 2021 at the DC VA Medical Center. Representative sections of core biopsies, radical prostatectomies, transurethral prostate resections, and metastatic deposits were examined. p53 nuclear expression was scored according to the highest intensity observed (0, 1+, 2+, 3+) and the percentage (0%, <1%, 1-5%, >5%) of tumor cells expressing any level of intensity in the aggregate tumor area. All slides were reviewed by two independent pathologists. Pertinent clinical data were collected.

A total of 34 patients (40%) exhibited p53 nuclear expression, of which 18 (21%) showed the maximum (3+) intensity. The presence of maximum intensity, regardless of percentage, was found to be associated with Grade Group (p < 0.001), higher PSA at biopsy (p < 0.001), BCR (p < 0.001) and metastasis (p < 0.001). Importantly, maximum p53 intensity was identified only in patients who developed metastatic disease.

Maximum (3+) p53 nuclear intensity of any percentage is highly associated with disease progression in PCa, suggesting that optimal determination of p53 overexpression should incorporate intensity.

This study aims to integrate multi-omic and clinical data concerning disulfidptosis-related genes (DRGs) to facilitate molecular typing and prognosis in colorectal cancer (CRC). Public databases provided CRC transcriptome and clinical data, enabling differential expression, genomic analyses, pathway enrichment, survival analysis, and subtyping based on the expression levels of 15 DRGs identified in published studies. Differentially expressed genes (DEGs) between subtypes were identified to create a disulfidptosis prognostic model using LASSO and Cox regression analyses. This model was evaluated by comparing risk scores, survival curves, cellular infiltration, and drug sensitivity between high- and low-risk groups. Analyses revealed differential expression, mutations, and copy number variations (CNV) in DRGs in CRC. Survival analysis demonstrated significant prognostic differences among DRG expression subtypes. GSVA and ssGSEA highlighted DRGs' regulatory roles in CRC. DEGs identified between DRG expression subtypes led to the classification into subtypes A and B. A disulfidptosis prognostic model, including genes VSIG4, SCG2, INHBB, DDC, CXCL13, KLK10, CXCL10, and CCL11A, was developed to stratify patients into high- and low-risk groups. This model displayed strong predictive capability (AUC = 0.700) and calibration. The risk score was also strongly associated with immune cell infiltration, stromal cell score, and stem cell index in the CRC tumor microenvironment. Drug sensitivity analysis indicated that high-risk samples were more responsive to most medications. We established a robust disulfidptosis prognostic model for CRC through comprehensive multi-omics analysis. Our findings provide valuable insights into the role of DRGs in CRC progression and disease management, presenting an important resource for further research.

Hepatocellular carcinoma (HCC) is a malignant disease with high incidence and mortality worldwide. This study focuses on the TP53 target protein to investigate the potential therapeutic effect of tetrahydrocurcumin (THC) on HCC and its mechanism of action. The research hypothesis is that THC can inhibit the proliferation, migration, and invasion of HCC cells, and promote their apoptosis by regulating the TP53 target protein.

To explore the mechanism by which THC inhibits HCC cell proliferation via the TP53 signaling pathway.

Potential targets of THC and HCC were identified from multiple databases. The core targets were subjected to analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, and visualization processing, using the online platform Metascape to identify the key molecules and signaling pathways involved in the action of THC against HCC. The molecular mechanisms of action of THC against TP53 in the inhibition of HCC cells were verified using cell counting kit-8, Transwell, apoptosis, and western blotting assays.

Molecular docking results showed that THC had a high score for the TP53 target protein. In vitro experiments indicated that THC effectively inhibited the proliferation and migration of HCC cells, and affected the expression levels of TP53, MDM2, cyclin B, Bax, Bcl-2, caspase-9, and caspase-3.

THC induces the apoptosis of HCC cells through the TP53 signaling pathway, thereby inhibiting their proliferation and migration.

Breast cancer is the second most common cancer in women worldwide. Treatments for this disease often result in side effects such as pain, fatigue, loss of muscle mass, and reduced quality of life. Physical exercise has been shown to effectively mitigate these side effects and improve the quality of life in patients with breast cancer.

This randomized clinical trial aims to evaluate the efficacy of a 12-week supervised exercise program on pain, physical function, and quality of life in female patients with cancer.

This randomized, double-blind clinical trial will recruit 325 participants, divided into an intervention group receiving the exercise program and a control group receiving standard care recommendations. Outcome measures, including pain (assessed via the Brief Pain Inventory), physical function (Disability of the Arm, Shoulder, and Hand Questionnaire), and quality of life (European Organization for Research and Treatment of Cancer QLQ-C30 and European Organization for Research and Treatment of Cancer QLQ-BR23), will be evaluated at baseline, immediately post intervention, and 12 weeks post intervention. Statistical analysis will involve repeated measures of ANOVA and MANOVA to determine the significance of the intervention's effects across time points.

Recruitment and data collection will commence in February of 2025, and data analysis is scheduled for completion at the end of 2025. No results are currently available.

Physical exercise is anticipated to play a significant role in alleviating pain, enhancing physical function, and improving the quality of life in female patients with cancer. This study will provide robust evidence to support the integration of supervised exercise into standard care protocols for this population.

ClinicalTrials.gov NCT06618690; https://clinicaltrials.gov/ct2/show/NCT06618690.

PRR1-10.2196/63891.

The tumor suppressor p53 (Trp53), also known as p53, is the most commonly mutated gene in cancer. Canonical p53 DNA damage response pathways are well characterized and classically thought to underlie the tumor suppressive effect of p53. Challenging this dogma, mouse models have revealed that p53-driven apoptosis and cell cycle arrest are dispensable for tumor suppression. Here, we investigated the inverse context of a p53 mutation predicted to drive the expression of canonical targets but is detected in human cancer.

We established a novel mouse model with a single base pair mutation (GAG>GAT, p53E221D) in the DNA-Binding domain that has wild-type function in screening assays, but is paradoxically found in human cancer in Li-Fraumeni syndrome. Using mouse p53E221D and the analogous human p53E224D mutants, we evaluated expression, transcriptional activation, and tumor suppression in vitro and in vivo.

Expression of human p53E224D from cDNA translated to a fully functional p53 protein. However, p53E221D/E221D RNA transcribed from the endogenous locus is mis-spliced resulting in nonsense-mediated decay. Moreover, fibroblasts derived from p53E221D/E221D mice do not express a detectable protein product. Mice homozygous for p53E221D exhibited increased tumor penetrance and decreased life expectancy compared to p53WT/WT animals.

Mouse p53E221D and human p53E224D mutations lead to splice variation and a biologically relevant p53 loss of function in vitro and in vivo.

Around 10% to 15% of prostate cancers harbor recurrent aberrations in the Forkhead Box A1 gene, FOXA1, whereby the alteration type and the effect on the forkhead (FKH) domain affect protein function. We developed a FOXA1 classification system to inform clinical management.

A total of 5,014 prostate cancer samples were examined using whole-exome and -transcriptome sequencing from the Caris Life Sciences database. We denoted class 1 FOXA1 alterations as missense and in-frame insertions/deletions with subclasses oriented with respect to the FKH domain. These were in the first part of the FKH domain [class 1A: amino acids (AA) 168-246], within the Wing2 region of FKH (class 1B: AA 247-269), or outside FKH (class 1C: AA 1-167, 270+). Two hotspot missense mutations at R219 were denoted class 2. Class 3 included predicted truncating mutations with subclasses partitioned based on the FKH domain (class 3A: AA 1-269 and class 3B: AA 270+). Class 4 represented FOXA1 amplifications. Real-world overall survival and therapy outcomes were determined from insurance claims.

FOXA1 alterations did not influence survival when considered in aggregate but had distinct prognostic effects when stratified by class. In primary prostate samples, class 1A alterations were associated with overall improved survival (HR, 0.57; P = 0.03); a similar trend was seen in metastatic biopsies with class 1B (HR, 0.84; P = 0.09). Conversely, in primary specimens, class 1C exhibited worse survival upon second-generation androgen receptor signaling inhibitor treatment (HR, 1.93; P < 0.001). Class 2 mutations (R219C/S) were enriched in neuroendocrine prostate cancers and were associated with overall poor survival (HR, 2.05; P < 0.001) and worse outcomes to first-line androgen-deprivation therapies (HR, 2.5; P < 0.001). Class 3A alterations indicated improved survival (HR, 0.70; P = 0.01), whereas class 3B alterations portended poor outcomes (HR, 1.50; P < 0.001). Amplifications (class 4) indicated poor outcomes in metastatic samples (HR, 1.48; P = 0.02). Molecularly, different FOXA1 alteration classes harbored distinct mutational and immunologic features as well as unique transcriptional programs. Finally, relative to European Americans, African Americans had increased class 1C alterations, whereas Asian/Pacific Islander patients had increased class 1B alterations.

FOXA1 alterations should not be interpreted in aggregate, as different classes are associated with divergent molecular features and clinical outcomes. Our revised classification schema facilitates clinical decision-making for patients with prostate cancer and uncovers important racial differences.

Homeobox A5 (HOXA5) has been identified as a tumor suppressor gene in breast cancers, but its role in oral squamous cell carcinoma (OSCC) has not been confirmed. The Illumina GoldenGate Assay for methylation identified that DNA methylation patterns differ between tumorous and normal tissues in the oral cavity and that HOXA5 is one of the genes that are hypermethylated in oral tumor tissues. The present study obtained more‑complete information on the methylation status of HOXA5 by using the Illumina Infinium MethylationEPIC BeadChip and bisulfite sequencing assays. The results indicated that HOXA5 hypermethylation has great potential as a biomarker for detecting OSCC. Comparing HOXA5 RNA expression between normal oral tissue and OSCC tissue samples indicated that its median level was 2.06‑fold higher in normal tissues that in OSCC tissues. Moreover, treatment using the demethylating agent 5‑aza‑2'‑deoxycytidine can upregulate HOXA5 expression in OSCC cell lines, verifying that the silencing of HOXA5 is primarily regulated by its hypermethylation. It was also found that upregulation of HOXA5 expression can not only increase OSCC cell death but that it can also enhance the therapeutic effect of cisplatin both in vitro and in vivo, suggesting that HOXA5 is an epigenetically downregulated proapoptotic gene in OSCC.

TP53 mutations are associated with poor prognosis in myelodysplastic neoplasm (MDS) and AML. The updated 5th WHO classification and International Consensus Classification (ICC) categorize TP53-mutated MDS and AML as unique entities. We conducted a multicenter study in Korea to investigate the characteristics of TP53-mutated MDS and AML, focusing on diagnostic aspects based on updated classifications.

This study included patients aged ≥ 18 yrs who were diagnosed as having MDS (N=1,244) or AML (N=2,115) at six institutions. The results of bone marrow examination, cytogenetic studies, and targeted next-generation sequencing, including TP53, were collected and analyzed.

TP53 mutations were detected in 9.3% and 9.2% of patients with MDS and AML, respectively. Missense mutation was the most common, with hotspot codons R248/R273/G245/Y220/R175/C238 accounting for 25.4% of TP53 mutations. Ten percent of patients had multiple TP53 mutations, and 78.4% had a complex karyotype. The median variant allele frequency (VAF) of TP53 mutations was 41.5%, with a notable difference according to the presence of a complex karyotype. According to the 5th WHO classification and ICC, the multi-hit TP53 mutation criteria were met in 58.6% and 75% of MDS patients, respectively, and the primary determinants were a TP53 VAF >50% for the 5th WHO classification and the presence of a complex karyotype for the ICC.

Collectively, we elucidated the molecular genetic characteristics of patients with TP53-mutated MDS and AML, highlighting key factors in applying TP53 mutation-related criteria in updated classifications, which will aid in establishing diagnostic strategies.

Leukemia is a type of blood cancer characterized by the uncontrolled growth of abnormal cells in the bone marrow, which replace normal blood cells and disrupt normal blood cell function. Timely and personalized interventions are crucial for disease management and improving survival rates. However, many patients experience relapse following conventional chemotherapy, and increasing treatment intensity often fails to improve outcomes due to mutated gene-induced drug resistance in leukemia cells. This article analyzes the association of gene mutations and drug resistance in leukemia. It explores genetic abnormalities in leukemia, highlighting recently identified mutations affecting signaling pathways, cell apoptosis, epigenetic regulation, histone modification, and splicing mechanisms. Additionally, the article discusses therapeutic strategies such as molecular targeting of gene mutations, alternative pathway targeting, and immunotherapy in leukemia. These approaches aim to combat specific drug-resistant mutations, providing potential avenues to mitigate leukemia relapse. Future research with these strategies holds promise for advancing leukemia treatment and addressing the challenges of drug-resistant mutations to improve patient outcomes.

To directly examine the interplay between mutant p53 or Mdm2 and wild type p53 in gene occupancy and expression, an integrated RNA-seq and ChIP-seq analysis was performed in vivo using isogenically matched mouse strains. Response to radiation was used as an endpoint to place findings in a biologically relevant context. Unexpectedly, mutant p53 and Mdm2 only inhibit a subset of wild type p53-mediated gene expression. In contrast to a dominant-negative or inhibitory role, the presence of either mutant p53 or Mdm2 actually enhances the occupancy of wild type p53 on many canonical targets. The C-terminal 19 amino acids of wild type p53 suppress the p53 response allowing for survival at sublethal doses of radiation. Further, the p53 mutant 172H is shown to occupy genes and regulate their expression via non-canonical means that are shared with wild type p53. This results in the heterozygous 172H/+ genotype having an expanded transcriptome compared to wild type p53 + /+.

The widespread implementation of cancer genomic profiling (CGP) has led to an increase in the detection of germline TP53 pathogenic variants (gTP53v) in patients who do not meet the classical Li-Fraumeni syndrome (LFS) criteria. The present study aimed to characterize the clinical features and treatment outcomes of gTP53v cases identified through routine CGP testing.

We conducted a retrospective analysis of 43 patients with gTP53v identified through CGP testing between June 2019 and August 2024. Clinical characteristics, molecular features, and treatment outcomes were analyzed and compared with TP53 wild-type cases from the same database (n=6,515).

The median age at diagnosis was 38 years (range=1-83 years), with 58.1% of cases presenting with non-core LFS tumors. A genomic analysis revealed diverse variant types (missense: 32, frameshift: 8, and nonsense: 3) with variant allele frequencies ranging between 0.10 and 0.696. Among 37 patients who received first-line chemotherapy, the objective response rate was 62%, which was significantly higher than in TP53 wild-type cases (32%, p=0.02). Complete responses were observed in six patients and partial responses in 14.

The present results suggest that gTP53v carriers identified through CGP represent a broader clinical spectrum than classical LFS, while demonstrating potentially favorable treatment outcomes. These results challenge traditional paradigms and emphasize the need for individualized approaches to patient care, particularly in cases with atypical presentations requiring the careful interpretation of mosaicism, de novo mutations, and clonal hematopoiesis.

Head and neck squamous cell carcinoma (HNSCC) cells have a high p53 mutation rate, but there were rare reported about the p53 gain of function through the prion-like aggregated form in p53 mutated HNSCC cells. Thioflavin T (ThT) is used to stain prion-like proteins in cells. Previously, we found that ThT and p53 staining were co-localized in HNSCC cells (Detroit 562 cells) with homozygous p53 R175H mutation. NAMPT inhibitor can repress ThT staining in Detroit 562 cells. In our previous study, co-treatment with p73 activator NSC59984 and NAMPT inhibitor FK886 synergistically repressed Detroit 562 cell proliferation. In this study, we found that two heterozygous p53-R280T mutation HNSCC cell lines, TW01 and HONE-1, also have the ThT staining signal. Treatment with chlorophyllides and p73 activator or NAMPT inhibitor did not synergistically repress cell proliferation in either Detroit 562 or HONE-1 cells. Chlorophyllides reduced the ThT aggregation signal in both Detroit 562 and HONE-1 cells. Chlorophyllides also induced p73 and caspase 3/7 expression and repressed NAMPT expression in both Detroit 562 and HONE-1 cells. Chlorophyllides reduced tumor size in vivo in Detroit 562 cells injected into a xenograft nude mice model, but this in vivo tumor repression effect was not found in p73 knockdown Detroit 562 cells. Moreover, NAMPT was repressed by chlorophyllides independent of p73 status in vivo. We thus concluded that chlorophyllides have a dual anticancer function when applied to HNSCC cells with p53 gain-of-function mutation, via activation of p73 and repression of p53 aggregation.

We present one of the largest cohorts of TP53 -pathogenic germline variants (PGVs) associated with patients with Li-Fraumeni syndrome (n = 82) with breast tumors (19 to 76 y; median age: 35). Most had missense variants (77%), followed by large gene rearrangements (LGRs; 12%), truncating (6%), and splice-site (5%) variants. Twenty-one unique germline missense variants were found, with hotspots at codons 175, 181, 245, 248, 273, 334, and 337. Of 100 total breast tumors, 63% were invasive (mostly ductal), 30% pure ductal carcinoma in situ, 4% fibroepithelial lesions, and 3% with unknown histology. Unlike BRCA -associated tumors, approximately half of the breast cancers exhibited HER2 -positivity, of which ~50% showed estrogen receptor coexpression. Pathology slides were available for review for 61 tumors (44 patients), and no significant correlation between the type of TP53 PGVs and histologic features was noted. High p53 immunohistochemistry expression (>50%) was seen in 67% of tumors tested (mostly missense variant). Null pattern (<1% cells) was seen in 2 (LGR and splicing variants carriers). Surprisingly, 2 tumors from patients with an LGR and 1 tumor from a patient with a truncating variant showed p53 overexpression (>50%). The subset of patients with the Brazilian p.R337H variant presented at a higher age than those with non-p.R337H variant (46 vs 35 y) though statistically insignificant ( P = 0.071) due to an imbalance in the sample size, and were uniquely negative for HER2 -overexpressing tumors. To conclude, breast cancer in carriers of TP53 PGVs has some unique clinicopathological features that suggest differential mechanisms of tumor formation. p53 immunohistochemistry cannot be used as a surrogate marker to identify germline TP53 -mutated breast cancers.

Primary sarcomas of the bladder and prostate are exceedingly rare, often highly aggressive and account for less than 1 % of all malignant tumors of these organs. In this landscape study, we searched for genomic biomarkers that could aid in either treatment selection or further classification of these tumors. 18 (0.2 %) bladder sarcomas were identified from 11,193 bladder cancers and 11 (0.6 %) prostate sarcomas were identified from 19,057 prostate cancers that underwent hybrid capture-based comprehensive genomic profiling (CGP) to assess all classes of genomic alterations (GA). The bladder sarcomas included 12 leiomyosarcomas, 3 rhabdomyosarcomas and 3 high-grade undifferentiated sarcomas. The sarcomas of the prostate featured 9 primary prostatic stromal sarcomas, 1 leiomyosarcoma and 1 rhabdomyosarcoma. The most frequent gene alterations were in TP53, RB1 and ATRX. Bladder sarcomas were also found to have more than 2-fold more genetic alterations than compared to prostatic sarcomas.

Cutaneous angiosarcoma is a rare and highly aggressive skin malignancy. The aim of this study is to explore the alteration of serum-derived extracellular vesicle (EV) in angiosarcoma patients and to evaluate its clinical utility as a novel circulating biomarker. In a microarray analysis to examine the differential expression of specific EV-associated microRNAs in sera between cutaneous angiosarcoma patients and healthy controls, 73 microRNAs with significant upregulation and 100 microRNAs with significant downregulation, respectively, were identified in patients with angio-sarcoma. Among them, quantitative PCR confirmed that miR-184, miR-3925-5p, miR-3926, and miR-5703 were upregulated in sera of cutaneous angiosarcoma patients compared with those of healthy controls and melanoma patients. Additionally, these 4 microRNAs were expressed more highly in angiosarcoma cell lines compared with normal human endothelial cell lines and were prone to elevate along with disease progression. Furthermore, a gene analysis predicted that the target gene set of microRNAs might affect the regulation of TP53 via the epigenetic regulation of MECP2. Taken together, these 4 extracellular vesicle-associated microRNAs in circulation serve as a promising liquid biomarker to identify angiosarcoma patients and trace disease progression.

Breast cancer, a highly heterogeneous and complex disease, remains the leading cause of cancer-related death among women worldwide. Despite advances in treatment modalities, effective prognostic models and therapeutic strategies are still urgently needed.

We retrospectively analyzed 15 independent breast cancer cohorts to explore the role of RNA modifications in the prognosis of patients with breast cancer. By integrating nine types of RNA modifications, we developed a comprehensive machine learning-based RNA modification signature (CMRS). Furthermore, single-cell RNA sequencing data were analyzed to understand the biological mechanisms underlying CMRS. In addition, immune infiltration levels were evaluated via six different algorithms, and immune checkpoint inhibitor responsiveness was predicted. Moreover, the response of high-CMIS patients to chemotherapy was predicted via multiple datasets. Finally, immunohistochemistry was performed on tissue samples from breast cancer patients to validate protein expression levels.

Our analysis revealed five key RNA modification-related genes (ENO1, ARAF, WT1, GADD45A, and BIRC3) associated with breast cancer prognosis. The CMRS model demonstrated high predictive accuracy across multiple cohorts and was significantly correlated with patient survival outcomes. Multiomics analysis revealed that high CMRS was associated with increased tumor mutational burden and distinct mutational signatures, particularly in pathways related to TP53, MYC, and cell proliferation. Single-cell analysis highlighted the involvement of epithelial cells and MYC signaling in high CMRS activity. Cell‒cell communication analysis revealed reduced interaction strength in hig CMRS patients, indicating poor prognosis. Furthermore, low CMRS patients presented increased immune cell infiltration and improved responsiveness to immune checkpoint inhibitors, whereas high CMRS patients were identified as potential candidates for treatment with panobinostat and vincristine.

Our study elucidates the significant role of RNA modifications in breast cancer prognosis and treatment. The CMRS model serves as a sensitive biomarker for predicting patient survival and treatment responsiveness, offering a new avenue for personalized therapy in patients with breast cancer.

The P53 protein, a cancer-associated transcriptional factor and tumor suppressor, houses a Zn2+ ion in its DNA-binding domain (DBD), essential for sequence-specific DNA binding. However, common mutations at position 273, specifically from Arginine to Histidine and Cysteine, lead to a loss of function as a tumor suppressor, also called DNA contact mutations. The mutant (MT) P53 structure cannot stabilize DNA due to inadequate interaction. To investigate the conformational changes, we performed a comparative molecular dynamic simulation (MDS) to study the effect of the P53-Wildtype (P53-WT) and the DNA contact mutations (R273H and R273C) on the DBD. Our research indicated that the DNA binding bases lose Hydrogen bonds (H bonds) when mutated to P53-R273H and P53-R273C during the simulation. We employed tools, such as PDIviz to highlight the contacts with DNA bases and backbone, major and minor grooves, and various pharmacophore forms of atoms. The contact maps for R273H and R273C were generated using the COZOID tool, which displayed changes in the frequency of the amino acids and DNA bases interaction in the DNA binding domain. These residues have diminished interactions, and the zinc-binding domain shows significant movements by Zn2+ ion binding to the phosphate group of the DNA, moving away from its binding sites. In conclusion, our research suggests that R273H and R273C each have unique stability and self-assembly properties. This understanding might assist researchers in better comprehending the function of the p53 protein and its importance in cancer.Communicated by Ramaswamy H. Sarma.

APG-115 is a novel small-molecule selective inhibitor that destabilizes the p53-MDM2 complex and activates p53-mediated apoptosis in tumor cells. Anlotinib inhibits tumor angiogenesis and promotes apoptosis. In this study, we investigated the apoptotic effect and potential mechanism of APG-115 and anlotinib combination on AML cell lines with different p53 backgrounds.

The IC50 values ​of APG-115 and anlotinib were detected by CCK-8 assay. The apoptosis rate of AML cells was evaluated by Annexin-V and PI double staining. Transcriptome sequencing was performed on the MOLM16 cell line treated with APG-115 and anlotinib, and differential analysis and enrichment analysis were performed. Real-time quantitative PCR and Western blot were used to detect the changes in cell cycle and pathway-related genes and proteins in AML cell lines after drug treatment. In vivo experiments, the anti-leukemia effects of APG-115 and anlotinib on AML xenograft mouse models were evaluated.

APG-115 and anlotinib could independently promote AML cell apoptosis, and the combination of the two drugs could produce a synergistic effect. Transcriptome sequencing showed that compared with the APG-115 monotherapy group, the differentially expressed genes were mainly enriched in the MDM2-p53 and PI3K/AKT pathways. In vivo experiments showed that compared with AML xenograft mice treated with either drug alone, AML progression was slowed in AML xenograft mice treated with APG-115 and anlotinib.

In vivo and in vitro experimental have shown that APG-115 combined with anlotinib can promote AML cells apoptosis and inhibit the progression of disease is independent of the p53 status.

Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from the nasopharynx epithelial cells and has been linked with Epstein-Barr virus (EBV) infection, dietary habits, environmental and genetic factors. It is a common malignancy in Southeast Asia, especially with gender preference among men. Due to its non-specific symptoms, NPC is often diagnosed at a late stage. Thus, the molecular diagnosis of NPC plays a crucial role in early detection, treatment selection, disease monitoring, and prognosis prediction. This review aims to provide a summary of the current state and the latest emerging molecular diagnostic techniques for NPC, including EBV-related biomarkers, gene mutations, liquid biopsy, and DNA methylation. Challenges and potential future directions of NPC molecular diagnosis will be discussed.

Li-Fraumeni Syndrome (LFS) is a predisposition associated with early onset malignant tumors caused by germline pathogenic variants in the TP53 gene. Although rare worldwide, LFS is prevalent in Southern Brazil due to the founder pathogenic variant R337H. Here, we assessed tumor patterns and temporal trends, cancer risk, and sex differences of adult R337H carriers and carriers of other LFS-associated variants.

We retrospectively analyzed 708 adults, combining data from two sources: the Brazilian Li-Fraumeni Syndrome Study cohort and the NCI TP53 database. We assessed the clinical characteristics of 303 adults with R337H and compared them with those associated with 405 carriers of other TP53 variants.

R337H carriers, compared to adult carriers of other TP53 variants typical of LFS, had a lower cumulative risk of developing cancer (54% vs 78%). Female R337H carriers were at a higher risk than males (65% vs 30%) and had a higher risk of developing a second primary cancer, underscoring a strong sex bias not observed in carriers of other variants. The most common cancers were breast cancer and soft tissue sarcoma in females, and soft tissue sarcoma and prostate cancer in males. Common second malignancies were breast cancer in females and lung cancer in males.

This study shows that R337H is associated with a lifetime risk of multiple LFS-spectrum cancers but with incomplete penetrance, particularly in males. Our findings suggest that R337H carriers would benefit from tailored surveillance and risk reduction strategies.

São Paulo Research Foundation, Conselho Nacional de Pesquisa, and Hospital Sírio-Libanês.

Androgen deprivation therapy intensification (ADTi) with androgen receptor pathway inhibitors (ARPI), docetaxel or both has been shown to improve survival outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Currently, baseline tumor genomic markers have no role in clinical decision-making in patients with mHSPC.

In this IRB-approved retrospective study, patients diagnosed with mHSPC who underwent comprehensive genomic profiling from primary tissue or metastatic sites and treated with ADTi were included. Genomic alterations with an incidence ≥5% were included in the analysis.

A total of 276 patients were eligible and included in the study. In the multivariable analysis, TP53 (HR 1.71, 95% CI 1.17-2.49, p = 0.006), RB1 (HR 2.32, 95% CI 1.28-4.18, p = 0.006), PTEN (HR 1.74, 95% CI 1.12-2.7, p = 0.014), and BRCA2 (HR 2.64, 95% CI 1.42-4.92, p = 0.003) were associated with significantly shorter PFS, while TP53 (HR 1.63, 95% CI 1.00-2.64, p = 0.049), RB1 (HR 4.5, 95% CI 2.32-8.70, p < 0.001), and PTEN (HR 2.4, 95% CI 1.38-4.2, p = 0.003) were associated with significantly worse OS.

This is one of the largest studies to show the association of baseline tumor genomic markers with survival in patients with mHSPC treated with ADTi. Upon external validation, these results may aid in developing a clinical-genomic risk stratification model, patient counseling, and prognostication.

Objective: To investigate the preclinical efficacy and identify predictive biomarkers of polo-like kinase 1 (PLK1) inhibitors in small cell lung cancer (SCLC) models. Methods: We tested the cytotoxicity of selective PLK1 inhibitors (rigosertib, volasertib, and onvansertib) in a panel of SCLC cell lines. We confirmed the therapeutic efficacy of subcutaneous xenografts of representative cell lines and in four patient-derived xenograft models generated from patients with platinum-sensitive and platinum-resistant SCLC. We employed an integrated analysis of genomic and transcriptomic sequencing data to identify potential biomarkers of the activity and mechanisms of resistance in laboratory-derived resistance models. Results: Volasertib, rigosertib, and onvansertib showed strong in vitro cytotoxicity at nanomolar concentrations in human SCLC cell lines. Rigosertib, volasertib, and onvansertib showed equivalent efficacy to that of standard care agents (irinotecan and cisplatin) in vivo with significant growth inhibition superior to cisplatin in PDX models of platinum-sensitive and platinum-resistant SCLC. There was an association between YAP1 expression and disruptive or inactivation TP53 gene mutations, with greater efficacy of PLK1 inhibitors. Comparison of lab-derived onvansertib-resistant H526 cells to parental cells revealed differential gene expression with upregulation of NAP1L3, CYP7B1, AKAP7, and FOXG1 and downregulation of RPS4Y1, KDM5D, USP9Y, and EIF1AY highlighting the potential mechanisms of resistance in the clinical setting. Conclusions: We established the efficacy of PLK1 inhibitors in vitro and in vivo using PDX models of platinum-sensitive and resistant relapsed SCLC. An ongoing phase II trial is currently testing the efficacy of onvansertib in patients with SCLC (NCT05450965).

TP53 mutations are recognized to correlate with a worse prognosis in individuals with non-small cell lung cancer (NSCLC). There exists an immediate necessity to pinpoint selective treatment for patients carrying TP53 mutations. Potential drugs were identified by comparing drug sensitivity differences, represented by the half-maximal inhibitory concentration (IC50), between TP53 mutant and wild-type NSCLC cell lines using database analysis. In addition, clinical data from NSCLC patients were collected to evaluate both their TP53 status and their response to gemcitabine, thereby facilitating further validation. Subsequently, NSCLC cell lines with different TP53 status (A549 and H1299) were subjected to gemcitabine treatment to investigate the association between TP53 mutations and gemcitabine response. According to the dataset, NSCLC cell lines carrying TP53 mutations displayed heightened sensitivity to gemcitabine. From a clinical standpoint, patients exhibiting TP53 hotspot mutations demonstrated prolonged overall survival upon gemcitabine treatment. In vitro, overexpressing various hotspot TP53 mutations significantly sensitized H1299 cells to gemcitabine. Moreover, the knockdown of TP53 in A549 cells notably augmented sensitivity to gemcitabine treatment, as evidenced by cell viability and reproductive cell death assays. Conversely, the overexpression of wild-type TP53 in H1299 cells led to an increased resistance against gemcitabine. Gemcitabine is a treatment option for patients with non-small cell lung cancer (NSCLC) who carry TP53 hotspot mutations. This potential effectiveness might arise from its ability to disrupt DNA damage repair processes, leading to G2/M phase cell cycle arrest or an augmentation of mitotic abnormalities, eventually cause cell death. As a result, when planning treatment strategies for NSCLC patients possessing TP53 hotspot mutations, gemcitabine should be considered to incorporate into the indication.

Next-generation sequencing has revolutionized genome science over the last two decades. Indeed, the wealth of sequence information on our genome has deepened our understanding on cancer. Cancer is a genetic disease caused by genetic or epigenetic alternations that affect the expression of genes that control cell functions, particularly cell growth and division. Utilization of next-generation sequencing in cancer gene panels has enabled the identification of actionable gene alterations in cancer patients to guide personalized precision medicine.

The aim is to provide information that can identify actionable gene alterations, enabling personalized precision medicine for cancer patients.

Equipped with next-generation sequencing techniques, international collaboration programs on cancer genomics have identified numerous mutations, gene fusions, microsatellite variations, copy number variations, and epigenetics changes that promote the transformation of normal cells into tumors. Cancer classification has traditionally been based on cell type or tissue-of-origin and the morphological characteristics of the cancer. However, interactive genomic analyses have currently reclassified cancers based on systemic molecular-based taxonomy. Although all cancer-causing genes and mechanisms have yet to be completely understood or identified, personalized or precision medicine is now currently possible for some forms of cancer. Unlike the "one-size-fits-all" approach of traditional medicine, precision medicine allows for customized or personalized treatment based on genomic information.

Despite the availability of numerous cancer gene panels, technological innovation in genomics and expansion of knowledge on the cancer genome will allow precision oncology to manage even more types of cancers.

Genetic studies have associated thousands of enhancers with breast cancer (BC). However, the vast majority have not been functionally characterized. Thus, it remains unclear how BC-associated enhancers contribute to cancer.

Here, we perform single-cell CRISPRi screens of 3513 regulatory elements associated with breast cancer to measure the impact of these regions on transcriptional phenotypes. Analysis of > 500,000 single-cell transcriptomes in two breast cancer cell lines shows that perturbation of BC-associated enhancers disrupts breast cancer gene programs. We observe BC-associated enhancers that directly or indirectly regulate the expression of cancer genes. We also find one-to-multiple and multiple-to-one network motifs where enhancers indirectly regulate cancer genes. Notably, multiple BC-associated enhancers indirectly regulate TP53. Comparative studies illustrate subtype specific functions between enhancers in ER + and ER - cells. Finally, we develop the pySpade package to facilitate analysis of single-cell enhancer screens.

Overall, we demonstrate that enhancers form regulatory networks that link cancer genes in the genome, providing a more comprehensive understanding of the contribution of enhancers to breast cancer development.

Hereditary predisposition to breast and ovarian cancer syndrome (HBOC) is a pathological condition with increased cancer risk, including breast (BC), ovarian cancer (OC), and others. HBOC pathogenesis is caused mainly by germline pathogenic variants (GPV) in BRCA1 and BRCA2 genes. However, other relevant genes are related to this syndrome diagnosis, prognosis, and treatment, including TP53, PALB2, CHEK2, ATM, etc. This study aimed to identify the prevalence of non-BRCA genes in HBOC patients of Northeast Mexico.

This multicentric study included 1285 patients with HBOC diagnosis from four oncologic centers in northeast Mexico from 2016 to 2023. Genomic and clinical data were analyzed based on multi-gene panel results and electronic records of the medical geneticist consultation. For the data analysis of qualitative and quantitative variants, JASP statistical software (version 0.18.1) was used, taking p < 0.05 as a significant result.

We found that 32.7% of the patients had at least one GPV in non-BRCA genes. The five most frequent non-BRCA genes were CHEK2, PALB2, MUTYH, CDKN2A, and ATM. Among the group of non-BRCA genes, six are involved in the homologous repair pathway (HR), and three are related to DNA damage repair (DDR) pathways. In analyzing GPVs in molecular pathways, both have similar frequencies with no statistical difference for BC.

Multi-gene testing implementation improves the detection of often overlooked genes related to HBOC pathogenesis and treatment. Non-BRCA GPVs in Northern Mexico correspond to one-third of the HBOC cases, including HR and DDR pathways genes that would be misdiagnosed if not tested. HR patient carriers are potential targets of iPARP therapies. The optimal approach to cancer treatment for non-BRCA mutation carriers warrants further investigation to develop newer therapies.

Amyloidosis is a condition marked by misfolded proteins that build up in tissues and eventually destroy organs. It has been connected to a number of fatal illnesses, including non-neuropathic and neurodegenerative conditions, which in turn have a significant influence on the worldwide health sector. The inability to identify the underlying etiology of amyloidosis has hampered efforts to find a treatment for the condition. Despite the identification of a multitude of putative pathogenic variables that may operate independently or in combination, the molecular mechanisms responsible for the development and progression of the disease remain unclear. A thorough investigation into protein aggregation and the impacts of toxic aggregated species will help to clarify the cytotoxicity of aggregation-mediated cellular apoptosis and lay the groundwork for future studies aimed at creating effective treatments and medications. This review article provides a thorough summary of the combination of various experimental and computational approaches to modulate amyloid aggregation. Further, an overview of the latest developments of novel therapeutic agents is given, along with a discussion of the possible obstacles and viewpoints on this developing field. We believe that the information provided by this review will help scientists create innovative treatment strategies that affect the way proteins aggregate.

Rationale: The tumor suppressor p53 safeguards against cellular transformation, with its expression regulated by diverse post-translational modifications (PTMs). While polyubiquitination by Mdm2 principally drives its proteasomal degradation, the identity of p53 deubiquitinases (DUBs) remains less well defined. This study investigates the role of the deubiquitinase enzyme OTUD7B in hepatocellular carcinoma (HCC), where it is notably downregulated and proposed to function as a tumor suppressor. Methods: Mass spectrometry screening of immunoprecipitates from HCC cells was used to identify OTUD7B-binding proteins. Co-immunoprecipitation assays with endogenous, ectopic, and mutant forms of OTUD7B and p53 assessed binding interactions and p53 polyubiquitination levels, respectively. Regulatory mechanisms were explored via luciferase reporter and chromatin immunoprecipitation (ChIP) assays. OTUD7B function was evaluated in vitro and in xenograft models using shRNA knockdown, overexpression, and CRISPR-Cas9 knockout. OTUD7B expression in normal and HCC tissues was analyzed by immunohistochemistry and immunoblotting. Results: We identified p53 as a binding partner of OTUD7B, confirming interactions with both wild-type and mutant p53 in HCC cells. OTUD7B was shown to remove lysine-linked polyubiquitin chains in p53, including those mediated by Mdm2, thereby stabilizing p53 by inhibiting its proteasomal degradation. Overexpression of OTUD7B suppressed growth in HCC cultures and xenografts through p53-dependent mitochondrial apoptosis, marked by PUMA and BAX induction. Conversely, OTUD7B knockdown promoted tumor growth. These effects were absent in p53-null or CRISPR-knockout cells, underscoring p53 as a key OTUD7B substrate. Additionally, OTUD7B expression was found to be transcriptionally repressed via p53-dependent mechanisms. Bioinformatics and ex vivo analysis revealed a positive correlation between OTUD7B and p53 protein levels in HCC tissues. Conclusion: OTUD7B plays a critical role in stabilizing both wild-type and mutant p53 in HCC cells, with its expression regulated through a mutual feedback loop involving p53. By inhibiting cell growth, OTUD7B exhibits tumor-suppressive properties, underscored by its atypical downregulation in patient tissues and its positive correlation with p53 expression. These findings highlight the clinical significance of OTUD7B and position it as a promising therapeutic target for modulating the p53 pathway in HCC.

Globally, breast and ovarian cancers are major health concerns in women and account for significantly high cancer-related mortality rates. Dysregulations and mutations in genes like TP53, BRCA1/2, KRAS and PTEN increase susceptibility towards cancer. Here, we discuss the impact of mutations in the key regulatory gene, TP53 and polymorphisms in its negative regulator MDM2 which are reported to accelerate cancer progression. Missense mutations, null mutations, transversions, transitions, and point mutations occurring in the TP53 gene can cause an increase in metastatic activity. This review discusses mutations occurring in exon regions of TP53, polymorphisms in MDM2 and their interaction with large ribosomal subunit protein (RPL) leading to cancer development. We also highlight the potential of small molecules e.g. p53 activators like XI-011, Tenovin-1, and Nutlin-3a for the treatment of breast and ovarian cancers. The therapeutic efficacy of natural compounds in amelioration of these two types of cancers is also discussed.

Clinically, hepatoma patients are more frequently encountered in the intermediate and advanced stages. Consequently, the majority of patients miss out on the chance to undergo liver transplantation or radical surgery. Radiotherapy and chemotherapy often fall short of delivering satisfactory outcomes. The incidence and mortality rates for liver cancer approach nearly 100%. In recent years, both exosomes (Exos) and natural chemical compounds have demonstrated robust anti-cancer properties; however, the synergistic effect of their combination remains unexplored.

Exos were extracted from human umbilical cord mesenchymal stem cells (hUC-MSCs). The impact of gallic acid (GA), hUC-MSCs-Exos, and their combined administration on the proliferation inhibition rate and apoptosis of SMMC-7721 hepatoma cells was assessed to ascertain the efficacy differences before and after the combined treatment. A combination of cells metabolomics and network pharmacology techniques was employed to investigate the underlying mechanisms of action. The pivotal targets associated with glycolysis, inflammation, and oxidative stress pathways were confirmed through ELISA assays.

The findings elucidate that GA profoundly impedes the proliferation of SMMC-7721 hepatoma cells and instigates apoptotic processes therein. While the impact of hUC-MSCs-Exos alone was inconspicuous, a notable augmentation in effect ensued upon their combined application. Concomitantly, a marked reduction was observed in the expressionlevels of key enzymes including HK, PFK, PK, LDH, TNF-α, IL-1β, CAT, SOD and GSH-Px in the malignant hepatocytes, while IL-6 and MDA exhibited heightened expression. Pathway enrichment analysis underscored selenocompound metabolism and cysteine and methionine metabolism as pivotal pathways.

The potentiated efficacy of GA conjunction with hUC-MSCs-Exos may be attributed to their synergistic modulation of anti-inflammatory, antioxidant, and glycolytic functions, thereby influencing selenocompound metabolism and cysteine and methionine metabolism. This study reveals the efficacy and mechanism of Exos and GA combined therapy for hepatoma, providing new methods and ideas for the clinical treatment of hepatoma.

The study was designed to evaluate molecular alterations, relevant to the prognosis and personalized therapy of salivary gland cancers (SGCs).

DNA was extracted from archival tissue of 40 patients with various SGCs subtypes. A targeted next-generation sequencing (NGS) panel was used for the identification of small-scale mutations, focal and chromosomal arm-level copy number changes. The final analysis included selected genes with potential actionable aberrations for targeted therapies and outcome predictions in 37 tumours' samples.

The follow-up of the SGCs study cohort revealed disease recurrence or metastasis in 19 patients and indicated poor individual outcomes. The mean disease-free survival (DFS) within the poor outcome group was 2.4 years, and the overall survival (OS) was 5.4 years. The DFS and OS of the remaining 18 patients with favourable outcomes were 8.3 years. The genes most frequently affected with aberrations were NF1 (n = 9, 24%) and TP53 (n = 8, 22%), with increased occurrence observed in the poor outcome group: NF1 (n = 6, 32%) and TP53 (n = 6, 32%). CDKN2A biallelic deletion was the most common copy number variation (n = 5), and was detected in 4 cases with identified disease relapse. TERT promoter mutation and amplification were found in myoepithelial carcinoma. A p.Ile35Thr mutation was discovered in CTNNB1 in two cases of adenoid cystic carcinoma. ERBB2 alterations were remarkable for SDC ex PA. Furthermore, TP53 mutation was established as a relevant negative prognostic factor for overall survival (p = 0,04). The analysis revealed potentially actionable genes in detected alterations in: MECA 100% (1/1), SDC 100% (7/7), AD 92% (11/12), Ca ex PA 82% (18/22), MECA 65% (20/31), AdCC 64% (9/14) and AcCC 0% (0/1).

SGCs are a heterogeneous group of malignancies with distinct molecular landscape that characterized by poor prognosis and inadequate treatment options. Nonstandard strategies might be beneficial for patients who suffer from salivary gland cancers. Wider utilization of NGS analysis may increase the opportunity for patients with those rare cancers to receive more precise, personalized therapy.

Although lung cancer is one of the most common malignancies, the underlying genetics regarding susceptibility remain poorly understood. We characterized the spectrum of pathogenic/likely pathogenic (P/LP) germline variants within DNA damage response (DDR) genes among lung cancer cases and controls in non-Hispanic Whites (NHWs) and African Americans (AAs).

Rare, germline variants in 67 DDR genes with evidence of pathogenicity were identified using the ClinVar database. These P/LP variants were genotyped in a sample of 3,040 lung cancer cases and controls from the Inflammation, Health, Ancestry, and Lung Epidemiology study (NHW: n = 1,915; AA: n = 1,125) and were tested for their association with lung cancer using multivariate logistic regression adjusting for age, sex, pack-years, and race.

We identified 49 unique rare P/LP variants in 21 genes among 156 carriers. Approximately 5.9% of lung cancer cases and 4.2% of controls carried at least one P/LP variant. P/LP variants in DDR genes were more common in lung cancer cases, particularly those diagnosed with adenocarcinoma (odds ratio [OR], 1.46 [95% CI, 1.00 to 2.14]). MUTYH variants were associated with lung cancer overall (OR, 1.82 [95% CI, 1.10 to 3.12]), with the strongest associations among never smokers (OR, 3.37 [95% CI, 1.08 to 10.26]), and in individuals who do not meet current USPSTF screening criteria (OR, 2.85 [95% CI, 1.20 to 7.53]).

Germline variants in DDR genes appear to be associated with lung cancer, particularly when examined by gene subtype and morphologic subtype. MUTYH, a gene historically associated with colorectal and other GI malignancies, emerged as a candidate gene that should be examined in individuals who do not have a significant smoking history.