Tumor Protein 53 Mutations Research Articles

Analysis of circulating tumor DNA identifies distinct therapeutic response to intraperitoneal and intravenous paclitaxel plus S-1 in gastric cancer patients with peritoneal metastasis.

Circulating tumor DNA (ctDNA) is a promising technique for predicting curative effects and monitoring tumor recurrence. The utility of ctDNA for gastric cancer with peritoneal dissemination remains elusive. To assess the feasibility of ctDNA in predicting tumor response to chemotherapy in gastric cancer with peritoneal dissemination. This was a prospective study. We enrolled 30 patients with gastric cancer peritoneal metastasis, treated with intraperitoneal and intravenous paclitaxel plus S-1. Peripheral blood samples of patients were prospectively collected at baseline, after treatment initiation accompanied by computed tomography scan and disease progression. Mutational profiles from ctDNA were analyzed to evaluate its association with chemotherapeutic response. Tumor protein 53 (TP53) was the most frequently altered gene at baseline blood samples. Although baseline TP53 mutation was not related to therapeutic response, patients with TP53 mutation had worse progression-free survival (PFS) and overall survival (OS). Additionally, baseline ctDNA content fraction (CCF) was found to be significantly lower in responders than non-responders. Meanwhile, patients with high CCF had a trend of worse PFS and OS. Combining TP53 alteration and CCF, the prognosis of TP53-wt patients could be further stratified. Patients with CCF-low_TP53-wt had markedly longer survival than those with CCF-high_TP53-wt. Our study highlighted the significance of ctDNA in predicting potential clinical outcomes in gastric cancer patients during chemotherapy. ChiCTR-IIR-16009802 (Chinese Clinical Trial Registry).

Prospective clinical sequencing of 1016 Chinese prostate cancer patients: uncovering genomic characterization and race disparity.

Although there is a well-known disparity in prostate cancer (PC) incidence and mortality between Chinese and Western patients, the underlying genomic differences have been investigated only sparsely. This clinicogenomic study was conducted to reveal the genomic mutations contributing to the PC disparity across ethnicities and investigate the mutational profile of Chinese PC patients. A total of 1016 Chinese PC patients were prospectively enrolled and subjected to targeted sequencing, resulting in usable sequencing data for 41 genes from 859 patients. Genomic data retrieved from The Cancer Genome Atlas (TCGA; locoregional PC), Memorial Sloan Kettering Cancer Center [MSKCC; metastatic castration-sensitive PC (mCSPC)], and Stand Up To Cancer [SU2C; metastatic castration-resistant PC (mCRPC)] cohorts were used as comparators representing Western men. Genomic mutations were analyzed using an integrated bioinformatic strategy. A comparison of the disease stages revealed that mutations in tumor protein 53 (TP53), androgen receptor (AR), forkhead box A1 (FOXA1), and genes involved in the cell cycle pathway were enriched in mCRPC. Mutations in adenomatous polyposis coli (APC) gene were found to be more prevalent in patients with visceral metastasis. Genomic differences between Western and Chinese men were mainly observed in castration-sensitive PC, with tumors from Chinese men having more FOXA1 (11.4% vs. 4.2%) but fewer TP53 (4.8% vs. 13%) mutations in locoregional PC and harboring fewer TP53 (11% vs. 29.2%), phosphatase and tensin homolog (PTEN; 2.5% vs. 10.3%), and APC (1.7% vs. 7.4%) mutations in the mCSPC stage than those of Western men. Patients of both ethnicities with mCRPC had similar mutational spectra. Furthermore, FOXA1 class-2 was less common than FOXA1 class-1 and showed no enrichment in metastasis, contrary to the findings in the Western cohort. Our study provides a valuable resource for a better understanding of PC in China and reveals the genomic alterations associated with PC disparity across races.

CT-based radiomic phenotypes of lung adenocarcinoma: a preliminary comparative analysis with targeted next-generation sequencing.

This study aimed to explore the relationship between computed tomography (CT)-based radiomic phenotypes and genomic profiles, including expression of programmed cell death-ligand 1 (PD-L1) and the 10 major genes, such as epidermal growth factor receptor (EGFR), tumor protein 53 (TP53), and Kirsten rat sarcoma viral oncogene (KRAS), in patients with lung adenocarcinoma (LUAD). In total, 288 consecutive patients with pathologically confirmed LUAD were enrolled in this retrospective study. Radiomic features were extracted from preoperative CT images, and targeted genomic data were profiled through next-generation sequencing. PD-L1 expression was assessed by immunohistochemistry staining (chi-square test or Fisher's exact test for categorical data and the Kruskal-Wallis test for continuous data). A total of 1,013 radiomic features were obtained from each patient's CT images. Consensus clustering was used to cluster patients on the basis of radiomic features. The 288 patients were classified according to consensus clustering into four radiomic phenotypes: Cluster 1 (n = 11) involving mainly large solid masses with a maximum diameter of 5.1 ± 2.0 cm; Clusters 2 and 3 involving mainly part-solid and solid masses with maximum diameters of 2.1 ± 1.4 cm and 2.1 ± 0.9 cm, respectively; and Cluster 4 involving mostly small ground-glass opacity lesions with a maximum diameter of 1.0 ± 0.9 cm. Differences in maximum diameter, PD-L1 expression, and TP53, EGFR, BRAF, ROS1, and ERBB2 mutations among the four clusters were statistically significant. Regarding targeted therapy and immunotherapy, EGFR mutations were highest in Cluster 2 (73.1%); PD-L1 expression was highest in Cluster 1 (45.5%). Our findings provide evidence that CT-based radiomic phenotypes could non-invasively identify LUADs with different molecular characteristics, showing the potential to provide personalized treatment decision-making support for LUAD patients.

TP53 mutations in Romanian patients with colorectal cancer

BackgroundColorectal cancer (CRC) has been ranked as the second most deadly cancer and the third most diagnosed cancer cases for the year 2020. Specifically for Romania, the number of CRC-related deaths in 2019 was estimated at 6307 people, with a standardized mortality rate of 33.8 per 100,000 inhabitants. Although the tumor protein 53 (TP53) gene is intensively studied, there are few data on TP53 mutations in Romanian CRC. Furthermore, since genetic alterations may show geographical differences, our study aimed to analyze the clinical status and TP53 somatic variation in Romanian CRC patients.Subjects and methodsDNA from 40 randomly selected cases of CRC was extracted from formalin-fixed paraffin-embedded tissues and sequenced using direct Sanger sequencing techniques, and variants were annotated according to the recommendations of the Human Genome Variation Society. Novel variants were analyzed using MutationTaster2021 to predict their effects.ResultsThe mean age was 63.6 years (range 33–85 years) with a male to female ratio of 2.3. More than 45% (18/40) had an advanced cancer stage (≥ stage III). Mutations were found in 21/40 cases (52.5%), with one case having two mutations, giving a total of twenty-two mutations in the TP53 coding DNA. These mutations include 3 (13.6%) insertion-deletion mutations, two of which are novel frameshift mutations: c.165delT (in exon 4) and c.928_935dup (in exon 9), both of which are predicted to lead to nonsense-mediated mRNA decay and are classified as deleterious. The remaining 19 (86.36%) were substitution mutations: 1 nonsense and 18 (81.8%) missense mutations, with G > A (n = 7/19; 36.8%) and C > T (n = 6/19; 31.5%) transitions being the most common. The G > T transversion was found in 21.05% (4/19) of the substitution mutations.ConclusionWe have described two novel frameshift mutations in TP53. The discovery of novel mutations following the efforts of The Cancer Genome Atlas and other large-scale cancer genome sequencing projects may be further evidence of the heterogeneous nature of mutations in cancer and may indicate that the identification of carcinogenic mutations is not yet saturated. Further sequencing is therefore needed, especially in less studied populations. Importantly, consideration of their geographical environment will shed light on population-specific carcinogenesis.

“Paradoxical” p16 overexpression in cutaneous melanoma: Molecular and immunohistochemical analysis of a rare phenomenon with a focus on cell cycle regulatory molecules

BackgroundOne of the most relevant genetic alterations in cutaneous melanoma (CM) is the biallelic inactivation/loss-of-heterozygosis (LOH) of cyclin-dependent kinase inhibitor 2 A (CDKN2A), which results in the immunohistochemical loss of p16 frequently found in CM. However, we recently described a rare case of dermal/deep-seated melanoma arising in giant congenital nevus (DDM-GCN) with p16 overexpression combined with p53 loss and tumor protein 53 (TP53) mutation. Herein, we reported a case series of CM with p16 overexpression and analyzed their clinicopathologic features, immunohistochemical expression of the cell cycle regulatory molecules (CCRM: p53, p21, Cyclin D1, Rb), and mutational landscape. MethodsWe retrospectively tested for p16 all cases of CM diagnosed at our institution between January 1st 2019-April 1st 2022. In CM with p16 overexpression, we reported clinicopathologic features, immunohistochemical results for melanocytic markers and CCRM, and mutational landscape investigated with a next-generation sequencing (NGS) panel. In cases with zonal p16 overexpression, the immunohistochemical assessment for melanocytic markers and CCRM, as well as the NGS analysis have been performed in both components {with and without p16 overexpression [p16(+)c and p16(-)]}. ResultsOverexpression of p16 was found in 10/2879 (0.35%) CM [5/10 (50%) diffuse and 5/10 (50%) zonal]. We combined the immunohistochemical results for CCRM and molecular data to classify the cases as follows: a) Group 1 with altered expression of at least one CCRM but no TP53 mutations [3/10 (30%), all with Rb altered/lost]; b) Group 2 with altered expression of at least one CCRM and TP53 mutations [4/10 (40%), all with p53 altered]; c) Group 3 with normal expression of CCRM and no TP53 mutations [3/10 (30%), all with mutations in MAPK pathway genes (NRAS and BRAF)]. In CM with zonal p16 overexpression, the histologic appearance of p16(+)c was heterogeneous, whereas combining CCRM profiles and molecular data the cases could be categorized as follows: a) cases with the same CCRM and molecular profiles in both p16(+)c and p16(-)c; b) cases with p16(+)c showing additional genetic mutations and/or modifications of CCRM expression. Conclusionsp16 overexpression is a rare event, occurring in advanced-stage, clinically- and histologically-heterogeneous CM. These lesions may be classified into three different groups based on CCRM expression and mutational profiles (including TP53 mutation). The analysis of CM with zonal p16 overexpression suggests that, at least in a subset of cases, this phenomenon could represent a sign of “molecular progression” due to the acquisition of additional genetic mutations and/or modifications of the CCRM profile.

Heritable cancer predisposition testing in pediatric cancer patients excluding retinoblastoma in a middle-income country.

Resource-limited settings often have financial barriers to genetic testing for heritable cancer. This retrospective study investigated the pattern of heritable cancer predisposition testing in a middle-income country over the period 2014-2021, excluding retinoblastoma. After establishing a specific fund in 2019, rate of tests increased from 1.1% to 10.9% of new diagnoses. Most common testing was for constitutional mismatch repair deficiency (CMMRD), rhabdoid predisposition syndrome, TP53 (tumor protein 53) mutation, and hereditary cancer panel. Of 33 patients, 13 (39%) tested positive, 12 (36%) negative, and eight (24%) had variants of unknown significance. Positivity rate was 43% for a clinical phenotype and 44% for a tumor type indication.

TP53 Expression and Mutational Analysis in Hematological Malignancy in Jeddah, Saudi Arabia.

Background: Tumor protein 53 (TP53) is a tumor-suppressor gene and plays an essential role in apoptosis, cell cycle arrest, genomic stability, and DNA repair. Although it is the most often mutated gene in human cancer, it has respectively low frequency in hematological malignancy but is significantly linked with complex karyotype, poor prognosis, and chemotherapeutic response. Nevertheless, the prevalence and prognostic role of TP53 mutations in hematological malignancy in Saudi patients are not well reported. We, therefore, aim to assess the frequency of TP53 mutations in hematological malignancies in Saudi Arabia. Method: 20 different hematological malignancy samples were tested using fluorescence in situ hybridization (FISH) technique for TP53 deletion detection and next-generation sequencing (NGS) targeted panel was applied on 10 samples for mutations identification specifically TP53 mutation. Results: TP53 deletion was detected in 6 of 20 samples by FISH. Most of the 6 patients with TP53 deletion had acute lymphoblastic leukemia (ALL), and majority of them were child. NGS result revealed one heterozygous missense mutation in exon 5 of the TP53 gene (c. G9963A, p.H175R). Conclusion: To the best of our knowledge, the TP53 mutation is novel variant, and the first time we are reporting their association with myelodysplastic syndromic individual with complex karyotype. This study recommends further analysis of genomic mutations on bigger cohorts, utilizing high throughput technologies.

The Role of TP53 Mutations in EGFR-Mutated Non-Small-Cell Lung Cancer: Clinical Significance and Implications for Therapy.

Simple SummaryNon-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Patients carrying Epidermal Growth Factor Receptor (EGFR) mutations usually benefit from targeted therapy treatment. Nonetheless, primary or acquired resistance mechanisms lead to treatment discontinuation and disease progression. Tumor protein 53 (TP53) mutations are the most common mutations in NSCLC, and several reports highlighted a role for these mutations in influencing prognosis and responsiveness to EGFR targeted therapy. In this review, we discuss the emerging data about the role of TP53 in predicting EGFR mutated NSCLC patients’ prognosis and responsiveness to targeted therapy.Non-Small-Cell Lung Cancer (NSCLC) is the primary cause of cancer-related death worldwide. Oncogene-addicted patients usually benefit from targeted therapy, but primary and acquired resistance mechanisms inevitably occur. Tumor protein 53 (TP53) gene is the most frequently mutated gene in cancer, including NSCLC. TP53 mutations are able to induce carcinogenesis, tumor development and resistance to therapy, influencing patient prognosis and responsiveness to therapy. TP53 mutants present in different forms, suggesting that different gene alterations confer specific acquired protein functions. In recent years, many associations between different TP53 mutations and responses to Epidermal Growth Factor Receptor (EGFR) targeted therapy in NSCLC patients have been found. In this review, we discuss the current landscape concerning the role of TP53 mutants to guide primary and acquired resistance to Tyrosine-Kinase Inhibitors (TKIs) EGFR-directed, investigating the possible mechanisms of TP53 mutants within the cellular compartments. We also discuss the role of the TP53 mutations in predicting the response to targeted therapy with EGFR-TKIs, as a possible biomarker to guide patient stratification for treatment.

Potent, p53-independent induction of NOXA sensitizes MLL-rearranged B-cell acute lymphoblastic leukemia cells to venetoclax

The prognosis for B-cell precursor acute lymphoblastic leukemia patients with Mixed-Lineage Leukemia (MLL) gene rearrangements (MLLr BCP-ALL) is still extremely poor. Inhibition of anti-apoptotic protein BCL-2 with venetoclax emerged as a promising strategy for this subtype of BCP-ALL, however, lack of sufficient responses in preclinical models and the possibility of developing resistance exclude using venetoclax as monotherapy. Herein, we aimed to uncover potential mechanisms responsible for limited venetoclax activity in MLLr BCP-ALL and to identify drugs that could be used in combination therapy. Using RNA-seq, we observed that long-term exposure to venetoclax in vivo in a patient-derived xenograft model leads to downregulation of several tumor protein 53 (TP53)-related genes. Interestingly, auranofin, a thioredoxin reductase inhibitor, sensitized MLLr BCP-ALL to venetoclax in various in vitro and in vivo models, independently of the p53 pathway functionality. Synergistic activity of these drugs resulted from auranofin-mediated upregulation of NOXA pro-apoptotic protein and potent induction of apoptotic cell death. More specifically, we observed that auranofin orchestrates upregulation of the NOXA-encoding gene Phorbol-12-Myristate-13-Acetate-Induced Protein 1 (PMAIP1) associated with chromatin remodeling and increased transcriptional accessibility. Altogether, these results present an efficacious drug combination that could be considered for the treatment of MLLr BCP-ALL patients, including those with TP53 mutations.

The Role of Tissue and Liquid Biopsy in the Clinical Management of Adult Lung Cancer Patients in King Abdul-Aziz Medical City in Riyadh, Saudi Arabia.

BackgroundLung cancer is the most fatal malignancy worldwide, characterized by uncontrolled growth in the tissue of the lung(s). The diagnosis of lung cancer depends on the medical history of the patient, along with the physical examination, and various imaging studies. Furthermore, sputum cytology, thoracentesis, or a tissue and liquid biopsy can be examined. The TNM (tumor size, lymph nodes, and metastasis) system is used for staging and grading lung cancer. This study aimed to evaluate the role of tissue vs liquid biopsy in the clinical management of adenocarcinoma, at King Abdulaziz Medical City, Riyadh.MethodsIn this cross-sectional study, all adenocarcinoma patients treated between January 2016 to December 2018 were included using consecutive sampling. The participants were ≥ 18 years old patients with histologically confirmed adenocarcinoma (stage IIIb/IV) regardless of the mutation status. This data was collected through chart review. Data analysis was performed using the IBM Statistical Software for Social Sciences (SPSS) software, version 22 (IBM SPSS Statistics for Windows, Armonk, NY). ResultsA total of 58 participants were included in the analysis. All of them had undergone a tissue biopsy, while only 16 patients underwent liquid biopsy. Out of all patients, 26% of patients had tissue biopsy-related complications (TBRC), with pneumothorax being the most common complication. Single gene testing for epidermal growth factor receptor (EGFR) for patients who underwent tissue biopsy showed a 35% mutation rate. For the anaplastic lymphoma kinase (ALK) gene, 13% were found to be mutated; for the ROS proto-oncogene 1 (ROS1) gene, only 7% were seen to be mutated. For a panel of 12 genes, 25% had the tumor protein 53 (TP53) gene mutation and 39% had the gene Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. For patients who underwent a liquid biopsy, 20% had the TP53 mutation, 43% had the EGFR mutations on a single gene test and 42% on a panel test, and 10% had the KRAS mutation.ConclusionWe found that tissue and liquid biopsy showed genetic mutations, particularly with EGFR, TP53, and KRAS genes, among adenocarcinoma patients. Identifying genetic changes in adenocarcinoma patients is essential for charting a targeted therapy. Primary EGFR mutations and rearrangements of ALK or ROS1 are the only gene mutations that can be done with specific tyrosine kinase inhibitors available for clinical practice. Therefore, we recommend further studies to evaluate the role of tissue and liquid biopsy in clinical practice.

Integrated analysis of the genomic and transcriptional profile of gliomas with isocitrate dehydrogenase-1 and tumor protein 53 mutations.

Background: The gene mutation of isocitrate dehydrogenase-1 (IDH1) is commonly found in LGG and some GBM patients and usually carries tumor protein 53 (TP53) mutations. However, the underlying mechanisms on both mutations of glioma patients in IDH1 and TP53 are still unclear. Aim: To find the potential target markers in GBM and LGG patients with IDH1 and TP53 mutation.Method: A total of 1122 glioma patients from The Cancer Genome Atlas were enrolled and divided as wild-type (without IDH1 and TP53 mutations) or both mutant (both IDH1 and TP53 mutations). The data of clinicopathological characteristics, mRNA, mutations, and copy number alteration were analyzed. Results: IDH1 and TP53 mutations, not gene expression, affect the survival probability of GBM and LGG patients, which might be related to neuron function, immune function, tumor invasion, and metastasis. The effects of the selected gene (EMILIN3, SAA1, VSTM2A, HAMP, IFT80, and CHIC2) on glioma patients could be regulated by IDH1 and TP53 mutations and had a higher survival possibility in these patients. Conclusions: The selected genes in GBM and LGG patients with IDH1 and TP53 mutations could be a potential prognosis marker in the future.

TP53 mutations determined by targeted NGS in breast cancer: a case-control study.

Background: Tumor protein 53 (TP53) gene mutations are identified in up to 37% of breast tumors especially in HER-2 positive and basal-like subtype. Previous studies have indicated TP53 mutations as a prognostic biomarker in breast cancer. However, most of these studies performed immunohistochemistry (IHC) for the detection of TP53 mutations.Aim: The purpose of our study is to evaluate the role of TP53 somatic mutations detected via next-generation sequencing (NGS) as a potential prognostic marker in patients with breast cancer.Materials and Methods: 82 female patients with Stage I–III breast cancer underwent NGS in paraffin blocks and blood samples during the period 25/09/2019 through 25/05/2021. 23 cases of somatic TP53 mutations and 23 cases of healthy controls were matched on age at diagnosis, menopausal status, histological subtype, histological grade, ki67 expression and disease stage.Results: Mean age at diagnosis was 52.35 (SD; 11.47) years. The somatic TP53 mutation NM_000546.5:c.824G>A p.(Cys275Tyr) was most frequently detected. Co-existence of PIK3CA mutation was a common finding in somatic TP53-mutant tumors (4/23; 17.4%). Disease-free survival was shorter in TP53-mutated cases (16.3 months vs. 62.9 months). TP53 pathogenic somatic mutations were associated with a 8-fold risk of recurrence in the univariate Cox regression analysis (OR = 8.530, 95% CI: 1.81–40.117; p = 0.007).Conclusions: Our case-control study suggests that TP53 somatic mutations detected by next-generation sequencing (NGS) are associated with an adverse prognosis in breast cancer.

Curcumin Analogs, PGV-1 and CCA-1.1 Exhibit Anti-migratory Effects and Suppress MMP9 Expression on WiDr Cells

BACKGROUND: Colon cancer is still a crucial concern in the development of chemotherapeutic drugs due to the drug resistance phenomenon and various side effects to patients. One of the newest compound that show anticancer activities against several cancer cells, Chemoprevention Curcumin Analog 1 (CCA-1.1), has increasingly been explored to overcome the limitation of conventional drugs.METHODS: We evaluated the anti-migratory effect of CCA-1.1 and Pentagamavunone-1 (PGV-1) by using WiDr colon cancer cells. The expression profiles of Tumor Protein 53 (TP53) and Matrix Metalloproteinase-9 (MMP9) in colon cancer were obtained from the UALCAN database. Survival outcomes of TP53 and MMP9 in colon cancer patients were analyzed using the Kaplan-Meier method. We used 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), scratch wound healing, and gelatin zymography assays to observe the cytotoxic effect, anti-migratory activity, and MMP9 expression, respectively, in CCA-1.1 or PGV-1-treated cells.RESULTS: Level of MMP9 was found significantly overexpressed in the primary tumor and metastasis nodal, while TP53 mutation sample types were observed and influenced the survival outcome in colon cancer patients. CCA-1.1 and PGV-1 exhibited strong cytotoxic activity after 24 and 48 h treatment against WiDr cells. The migration assay demonstrated that PGV-1 and CCA-1.1 at 1 mM inhibited cell migration up to 40% after 48 h in single and combination with doxorubicin. The MMP9 expression was significantly inhibited by 0.5 mM CCA-1.1.CONCLUSION: This study emphasizes that the anti-migratory effect of CCA-1.1 is better than PGV-1 via MMP9 suppression on WiDr. Thus, CCA-1.1 is prominent to be developed as an anti-metastatic agent.KEYWORDS: chemopreventive curcumin analog 1.1 (CCA-1.1), PGV-1, WiDr cells, anti-migration, MMP9

Solitary Fibrous Tumor: Integration of Clinical, Morphologic, Immunohistochemical and Molecular Findings in Risk Stratification and Classification May Better Predict Patient outcome.

Although solitary fibrous tumors (SFTs) have an unpredictable evolution, some specific clinicopathologic factors have been associated with the final outcome. We retrieved clinical, pathological and molecular data of 97 patients with a histological diagnosis of SFT and Signal transducer and activator of transcription 6 (STAT6) positivity. We retrospectively studied the pathological factors predictive of recurrence/metastasis and compared them with the clinical outcome. A wide immunohistochemical study and molecular analysis to detect NAB2/STAT6 gene fusion, tumor protein-53 (TP53) and/or (telomerase reverse transcriptase) TERT promotor mutation were performed. The risk of metastasis was calculated using the Demicco risk stratification system (RSS). The results were combined and examined to assess the accuracy of risk stratification and classification. The most common location was in non-extremities; 66% were located in soft tissue or subcutaneous areas and 92.8% in deep locations. On microscopic analysis, 38.1% of tumors revealed hypercellularity with a predominant patternless and/or hemangiopericytic growth pattern; 13.4% had ≥4 mitoses/10HPF; 16.5% showed necrosis, and almost half the tumors showed at least focal myxoid areas. Dedifferentiation was observed in three tumors. Immunomarker expression in SFTs was as follows: CD34 92.9%, CD99 57.1%, Bcl2 67.9%, neuroendocrine markers (at least 1) 25.7%, Desmin 14.3%, CK(AE1/AE3) 3%, Apoptotic Protease Activating Factor (APAF-1) 87% and finally Ki-67 ≥ 10% in 14.4%. The NAB2/STAT6 gene fusion was detected in 50 tumors. After a median follow-up of 90 months, 9.3% recurred, 11.3% metastasized, 10.3% died of disease and 76.2% were free of disease. TERT mutations were detected in 40.6% of the SFTs; the TP53 mutation was detected in 17%, and only 9.3% showed both mutations. According to the Demicco RSS, 6.1%, 11.3% and 82.4% of the tumors were classified as high, intermediate or low-risk of metastasis, respectively. All high-risk tumors had ≥4 mitoses/10HPF, necrosis, Ki-67 ≥ 10, HTER and/or TP53 mutation and poor evolution. The intermediate risk SFTs with worse evolution displayed the HTER mutation. Almost all low-risk tumors had a favorable evolution, although four showed at least one adverse factor (Ki-67 ≥ 10, ≥4 mitoses/10HPF or high tumor size) and had a worse evolution. An integration of clinical, morphologic, immunohistochemical and molecular findings may improve risk stratification and classification and better predict patient outcome. The unfavorable course seems to be more frequent in high-risk SFTs, although it is not exceptional in low-risk SFTs either; hence, a long-term follow-up is required independently of the assigned risk stratification score. The inclusion of molecular findings in risk stratification systems could improve the precision in the classification of SFTs, especially those of intermediate risk. Future studies will be required to determine the most effective way to incorporate molecular analyses into RSS on SFTs. The coexistence of several adverse factors such as ≥4 mitoses/10HPF, necrosis, Ki-67 ≥ 10%, mutations in HTER and/or p53 may suggest a closer clinical follow-up regardless of the histological appearance of the tumor.

Transformation of non-small cell lung cancer into small cell lung cancer in a patient with advanced lung cancer: a case report

Targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often fails because of drug resistance. Here, we report a 57-year-old male patient with stage IV small cell lung cancer (SCLC) transformation during targeted therapy. Chest computerized tomography (CT), hematoxylin and eosin histological examination, immunohistochemistry, allele refractory mutation system‐based quantitative polymerase chain reaction analysis of EGFR point mutations, and next-generation sequencing were performed for diagnosis and therapeutic efficacy evaluation. A combination of chest CT, histological examination, and immunohistochemistry confirmed the initial NSCLC diagnosis. Next-generation sequencing detected only EGFR exon 19 deletion (ex19del) before treatment and later identified EGFR exon20p.T790M point mutation, EGFR amplification, myc proto-oncogene (MYC) amplification, retinoblastoma 1 (RB1) mutation, and tumor protein 53 (TP53) mutation. Histology and immunohistochemistry revealed transformation from NSCLC to SCLC during treatment, which eventually returned to NSCLC. Drug resistance to targeted therapy for patients with NSCLC frequently occurs because of EGFR exon20p.T790M point mutation, TP53 mutation, RB1 mutation, and MYC amplification. These mutations are also the major determining factors of NSCLC outcomes. Therefore, next-generation sequencing should be performed to confirm drug efficacy during targeted therapy for NSCLC.

The association between the expression of nuclear Yes-associated protein 1 (YAP1) and p53 protein expression profile in breast cancer patients.

BackgroundYes-associated protein 1 (YAP1) is a key effector molecule regulated by the Hippo pathway and described as a poor prognostic factor in breast cancer. Tumor protein 53 (TP53) mutation is well known as a biomarker related to poor survival outcomes. So far clinical characteristics and survival outcome according to YAP1 and TP53 mutation have been poorly identified in breast cancer.Patients and methodsRetrospectively, 533 breast tumor tissues were collected at the Seoul St Mary’s hospital and Gangnam Severance Hospital from 1992 to 2017. Immunohistochemistry with YAP1 and p53 specific antibodies were performed, and the clinical data were analyzed.ResultsMutant p53 pattern was associated with aggressive tumor features and advanced anatomical stage. Inferior overall survival (OS) and recurrence free survival (RFS) were related with mutant p53 pattern cases with low nuclear YAP1 expression (P = 0.0009 and P = 0.0011, respectively). Multivariate analysis showed that mutant p53 pattern was an independent prognostic marker for OS [hazard ratios (HR): 2.938, 95% confidence intervals (CIs): 1.028–8.395, P = 0.044] and RFS (HR: 1.842, 95% CIs: 1.026–3.304). However, in cases with high nuclear YAP1 expression, there were no significantly difference in OS and RFS according to p53 staining pattern.ConclusionWe found that mutant p53 pattern is a poor prognostic biomarker in breast tumor with low nuclear YAP1 expression. Our findings suggest that interaction between nuclear YAP1 and p53 expression pattern impact survival outcomes.

Simultaneous Identification of EGFR,KRAS,ERBB2, and TP53 Mutations in Patients with Non-Small Cell Lung Cancer by Machine Learning-Derived Three-Dimensional Radiomics.

Simple SummaryMultiple genetic mutations are associated with the outcomes of patients with non-small cell lung cancer (NSCLC) after using tyrosine kinase inhibitor, but the cost for detecting multiple genetic mutations is high. Few studies have investigated whether multiple genetic mutations can be simultaneously detected based on image features in patients with NSCLC. We developed a machine learning-derived radiomics approach that can simultaneously discriminate the presence of EGFR, KRAS, ERBB2, and TP53 mutations on CT images in patients with NSCLC. These findings suggest that machine learning-derived radiomics may become a noninvasive and low-cost method to screen for multiple genetic mutations in patients with NSCLC before using next-generation sequencing tests, which can help to improve individualized targeted therapies.Purpose: To develop a machine learning-derived radiomics approach to simultaneously discriminate epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene (KRAS), Erb-B2 receptor tyrosine kinase 2 (ERBB2), and tumor protein 53 (TP53) genetic mutations in patients with non-small cell lung cancer (NSCLC). Methods: This study included consecutive patients from April 2018 to June 2020 who had histologically confirmed NSCLC, and underwent pre-surgical contrast-enhanced CT and post-surgical next-generation sequencing (NGS) tests to determine the presence of EGFR, KRAS, ERBB2, and TP53 mutations. A dedicated radiomics analysis package extracted 1672 radiomic features in three dimensions. Discriminative models were established using the least absolute shrinkage and selection operator to determine the presence of EGFR, KRAS, ERBB2, and TP53 mutations, based on radiomic features and relevant clinical factors. Results: In 134 patients (63.6 ± 8.9 years), the 20 most relevant radiomic features (13 for KRAS) to mutations were selected to construct models. The areas under the curve (AUCs) of the combined model (radiomic features and relevant clinical factors) for discriminating EGFR, KRAS, ERBB2, and TP53 mutations were 0.78 (95% CI: 0.70–0.86), 0.81 (0.69–0.93), 0.87 (0.78–0.95), and 0.84 (0.78–0.91), respectively. In particular, the specificity to exclude EGFR mutations was 0.96 (0.87–0.99). The sensitivity to determine KRAS, ERBB2, and TP53 mutations ranged from 0.82 (0.69–90) to 0.92 (0.62–0.99). Conclusions: Machine learning-derived 3D radiomics can simultaneously discriminate the presence of EGFR, KRAS, ERBB2, and TP53 mutations in patients with NSCLC. This noninvasive and low-cost approach may be helpful in screening patients before invasive sampling and NGS testing.

Tumor protein 53 mutations in acute myeloid leukemia: conventional induction chemotherapy or novel therapeutics.

Tumor protein 53 (TP53) protein is involved in fundamental processes of cancer, aging, and DNA repair. Thus, TP53 dysfunction is implicated in malignant processes and remains the most commonly mutated gene in cancer but represents a relatively small proportion in acute myeloid leukemia (AML). Patients with TP53-mutated AML attain inferior responses to therapy resulting in poor overall outcomes. Traditional treatment approaches with conventional chemotherapy yields suboptimal responses for patients with TP53 mutant AML compared with wildtype TP53. In recent years, there is increasing interest in understanding the role and underlying biology of TP53 mutations in AML with efforts to harness the physiological tumor suppressive function of TP53 protein. Novel combination and targeted therapies may contribute to improved outcomes; however, responses to therapy may be short-lived and ongoing research is indicated to evaluate relapse-risk reduction strategies. These patients may benefit from consideration of enrollment in clinical trials or lower intensity therapy approaches in lieu of intensive chemotherapy. Pharmacological treatments targeting the TP53 pathway in addition to novel emerging therapeutics and immunotherapy-based approaches hold promise for treatment of TP53 mutant AML.

Implications of driver genes associated with a high tumor mutation burden identified using next‑generation sequencing on immunotherapy in hepatocellular carcinoma

Immune checkpoint blockade (ICB) therapy is a treatment strategy for hepatocellular carcinoma (HCC); however, its clinical efficacy is limited to a select subset of patients. Next-generation sequencing has identified the value of tumor mutation burden (TMB) as a predictor for ICB efficacy in multiple types of tumor, including HCC. Specific driver gene mutations may be indicative of a high TMB (TMB-H) and analysis of such mutations may provide novel insights into the underlying mechanisms of TMB-H and potential therapeutic strategies. In the present study, a hybridization-capture method was used to target 1.45 Mb of the genomic sequence (coding sequence, 1 Mb), analyzing the somatic mutation landscape of 81 HCC tumor samples. Mutations in five genes were significantly associated with TMB-H, including mutations in tumor protein 53 (TP53), Catenin®1 (CTNNB1), AT-rich interactive domain-containing protein 1A (ARID1A), myeloid/lymphoid or mixed-lineage leukemia (MLL) and nuclear receptor co-repressor 1 (NCOR1). Further analysis using The Cancer Genome Atlas Liver Hepatocellular Carcinoma database showed that TP53, CTNNB1 and MLL mutations were positively correlated with TMB-H. Meanwhile, mutations in ARID1A, TP53 and MLL were associated with poor overall survival of patients with HCC. Overall, TMB-H and associated driver gene mutations may have potential as predictive biomarkers of ICB therapy efficacy for treatment of patients with HCC.

Abstract C047: A phase Ia/Ib, dose-escalation/expansion study of BI 907828, an MDM2-p53 antagonist, in combination with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in patients with advanced solid tumors

Abstract The murine double minute 2 (MDM2) oncogene is the primary negative regulator of the tumor suppressor, tumor protein 53 (TP53). TP53 is either mutated or deleted in human cancers to ablate its pro-apoptotic functions, or its wild-type function is inhibited by high MDM2 levels, contributing to tumor cell proliferation and cancer growth. BI 907828 is a potent MDM2-p53 antagonist that has shown potent anti-tumor activity in preclinical studies. Increasing evidence suggests TP53 also plays a role in the regulation of immune responses. Preclinical data show that the combination of an MDM2-p53 antagonist with anti-PD-1 and anti-LAG3 antibodies produces a synergistic anti-tumor effect in multiple tumor types. This Phase Ia/Ib study aims to determine the safety, recommended phase 2 dose (RP2D), and preliminary anti-tumor activity of BI 907828 in combination with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in a variety of TP53 wild-type cancers. In the Phase Ia (dose escalation) part of the study, patients with a confirmed diagnosis of unresectable, advanced and/or metastatic solid tumors (of any type) irrespective of TP53 mutation status will be enrolled. Patients will receive one dose of BI 907828 every 21 days, at a starting dose of 10 mg orally, in combination with BI 754091 and BI 754111 (fixed doses of 240 mg and 600 mg respectively, intravenously) every 21 days. Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control. The primary endpoint is to determine the maximum-tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle. Secondary endpoints include pharmacokinetics and safety. Phase Ia will include approximately 30 evaluable patients. In the Phase Ib (dose expansion) part of the study, patients with previously treated, unresectable, advanced or metastatic tumors that are TP53 wild-type and have at least one measurable target lesion will be enrolled into four expansion cohorts (1: non-small cell lung cancer [NSCLC]; 2: melanoma; 3: well-differentiated/dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma; 4: hepatocellular carcinoma). The recommended dose for expansion (RDE; established in Phase Ia) of BI 907828 will be administered in combination with fixed doses of BI 754091 and BI 754111 every 21 days. In the NSCLC cohort only, patients will be randomized to one of three arms: RDE of BI 907828 in combination with 240 mg fixed dose BI 754091 and 600 mg fixed dose of BI 754111 every 21 days (arm A, 32 patients); 240 mg fixed dose of BI 754091 in combination with 600 mg fixed dose of BI 754111 every 21 days (arm B, 32 patients); RDE of BI 907828 in combination with 240 mg fixed dose of BI 754091 every 21 days (arm C, 16 patients). The primary endpoint is objective response (OR; investigator-assessed, per RECIST 1.1). Secondary endpoints include OR (per iRECIST), disease control (investigator assessed; per RECIST 1.1 and iRECIST), progression-free survival (PFS); PFS rate at 12 and 24 weeks (cohort 3 only) and safety. Phase Ib will include at least 140 evaluable patients (80 patients in cohort 1 and 20 patients each in cohorts 2, 3 and 4). Citation Format: Anthony Tolcher, Navid Hafez, Noboru Yamamoto, Jaehong Park, Rolf Grempler, Anthony Lucarelli, Markus P Vallaster, Bushi Wang, David Hyman. A phase Ia/Ib, dose-escalation/expansion study of BI 907828, an MDM2-p53 antagonist, in combination with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C047. doi:10.1158/1535-7163.TARG-19-C047