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2.
Zhonghua Bing Li Xue Za Zhi ; 53(6): 585-591, 2024 Jun 08.
Article in Chinese | MEDLINE | ID: mdl-38825904

ABSTRACT

Objective: To investigate the clinical, radiological, and pathological features of anaplastic gangliogliomas (AGGs) and to determine whether these tumors represent a distinct entity. Methods: Consecutive 667 cases of ganglioglioma (GG) diagnosed at the Xuanwu Hospital, Capital Medical University, Beijing, China between January 2015 and July 2023 were screened. Among these cases, 9 pathologically confirmed AGG cases were identified. Their clinical, radiological, treatment, and outcome data were analyzed retrospectively. Most of the tumor samples were subject to next-generation sequencing, while a subset of them were subject to DNA methylation profiling. Results: Among the 9 patients, there were five males and four females, with a median age of 8 years. Epileptic seizures (5/9) were the most frequently presented symptom. Radiological examinations showed three types of radiological manifestations: four cases showed abnormal MRI signals with no significant mass effects and mild enhancement; two cases demonstrated a mixed solid-cystic density lesion with peritumoral edema, which showed significant heterogeneous enhancement and obvious mass effects, and one case displayed cystic cavity formation with nodules on MRI, which showed evident enhancements. All cases exhibited mutations that were predicted to activate the MAP kinase signaling pathway, including seven with BRAF p.V600E mutation and two with NF1 mutation. Five AGGs with mutations involving the MAP kinase signaling pathway also had concurrent mutations, including three with CDKN2A homozygous deletion, one with a TERT promoter mutation, one with a H3F3A mutation, and one with a PTEN mutation. Conclusions: AGG exhibits a distinct spectrum of pathology, genetic mutations and clinical behaviors, differing from GG. Given these characteristics suggest that AGG may be a distinct tumor type, further expansion of the case series is needed. Therefore, a comprehensive integration of clinical, histological, and molecular analyses is required to correctly diagnose AGG. It will also help guide treatments and prognostication.


Subject(s)
Brain Neoplasms , DNA Methylation , Ganglioglioma , Magnetic Resonance Imaging , Mutation , PTEN Phosphohydrolase , Proto-Oncogene Proteins B-raf , Humans , Ganglioglioma/pathology , Ganglioglioma/genetics , Male , Female , Child , Retrospective Studies , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/diagnostic imaging , Proto-Oncogene Proteins B-raf/genetics , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Telomerase/genetics , Histones/genetics , Histones/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Epilepsy/pathology , Epilepsy/genetics
3.
Hum Genomics ; 18(1): 55, 2024 May 31.
Article in English | MEDLINE | ID: mdl-38822443

ABSTRACT

BACKGROUND: Although CDKN2A alteration has been explored as a favorable factor for tumorigenesis in pan-cancers, the association between CDKN2A point mutation (MUT) and intragenic deletion (DEL) and response to immune checkpoint inhibitors (ICIs) is still disputed. This study aims to determine the associations of CDKN2A MUT and DEL with overall survival (OS) and response to immune checkpoint inhibitors treatment (ICIs) among pan-cancers and the clinical features of CDKN2A-altered gastric cancer. METHODS: This study included 45,000 tumor patients that underwent tumor sequencing across 33 cancer types from four cohorts, the MSK-MetTropism, MSK-IMPACT, OrigiMed2020 and TCGA cohorts. Clinical outcomes and genomic factors associated with response to ICIs, including tumor mutational burden, copy number alteration, neoantigen load, microsatellite instability, tumor immune microenvironment and immune-related gene signatures, were collected in pan-cancer. Clinicopathologic features and outcomes were assessed in gastric cancer. Patients were grouped based on the presence of CDKN2A wild type (WT), CDKN2A MUT, CDKN2A DEL and CDKN2A other alteration (ALT). RESULTS: Our research showed that CDKN2A-MUT patients had shorter survival times than CDKN2A-WT patients in the MSK MetTropism and TCGA cohorts, but longer OS in the MSK-IMPACT cohort with ICIs treatment, particularly in patients having metastatic disease. Similar results were observed among pan-cancer patients with CDKN2A DEL and other ALT. Notably, CDKN2A ALT frequency was positively related to tumor-specific objective response rates to ICIs in MSK MetTropism and OrigiMed 2020. Additionally, individuals with esophageal carcinoma or stomach adenocarcinoma who had CDKN2A MUT had poorer OS than patients from the MSK-IMPACT group, but not those with adenocarcinoma. We also found reduced levels of activated NK cells, T cells CD8 and M2 macrophages in tumor tissue from CDKN2A-MUT or DEL pan-cancer patients compared to CDKN2A-WT patients in TCGA cohort. Gastric cancer scRNA-seq data also showed that CDKN2A-ALT cancer contained less CD8 T cells but more exhausted T cells than CDKN2A-WT cancer. A crucial finding of the pathway analysis was the inhibition of three immune-related pathways in the CDKN2A ALT gastric cancer patients, including the interferon alpha response, inflammatory response, and interferon gamma response. CONCLUSIONS: This study illustrates the CDKN2A MUT and DEL were associated with a poor outcome across cancers. CDKN2A ALT, on the other hand, have the potential to be used as a biomarker for choosing patients for ICI treatment, notably in esophageal carcinoma and stomach adenocarcinoma.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16 , Stomach Neoplasms , Tumor Microenvironment , Humans , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/immunology , Cyclin-Dependent Kinase Inhibitor p16/genetics , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Male , Female , Immune Checkpoint Inhibitors/therapeutic use , Middle Aged , Biomarkers, Tumor/genetics , Aged , Prognosis , DNA Copy Number Variations/genetics , Mutation/genetics , Microsatellite Instability
4.
Sci Rep ; 14(1): 13058, 2024 06 06.
Article in English | MEDLINE | ID: mdl-38844774

ABSTRACT

The incidence of vulvar carcinoma varies by race; however, it is a rare disease, and its genomic profiles remain largely unknown. This study examined the characteristics of vulvar squamous cell carcinoma (VSCC) in Japanese patients, focusing on genomic profiles and potential racial disparities. The study included two Japanese groups: the National Cancer Center Hospital (NCCH) group comprised 19 patients diagnosed between 2015 and 2023, and the Center for Cancer Genomics and Advanced Therapeutics group comprised 29 patients diagnosed between 2019 and 2022. Somatic mutations were identified by targeted or panel sequencing, and TP53 was identified as the most common mutation (52-81%), followed by HRAS (7-26%), CDKN2A (21-24%), and PIK3CA (5-10%). The mutation frequencies, except for TP53, were similar to those of Caucasian cohorts. In the NCCH group, 16 patients of HPV-independent tumors were identified by immunohistochemistry and genotyping. Univariate analysis revealed that TP53-mutated patients were associated with a poor prognosis (log-rank test, P = 0.089). Japanese VSCC mutations resembled those of Caucasian vulvar carcinomas, and TP53 mutations predicted prognosis regardless of ethnicity. The present findings suggest potential molecular-targeted therapies for select VSCC patients.


Subject(s)
Carcinoma, Squamous Cell , Mutation , Tumor Suppressor Protein p53 , Vulvar Neoplasms , Humans , Female , Vulvar Neoplasms/genetics , Vulvar Neoplasms/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Middle Aged , Aged , Tumor Suppressor Protein p53/genetics , Japan/epidemiology , Aged, 80 and over , Cyclin-Dependent Kinase Inhibitor p16/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Prognosis , Adult , Asian People/genetics , Genomics/methods , Proto-Oncogene Proteins p21(ras)/genetics , East Asian People
5.
Cancer J ; 30(3): 133-139, 2024.
Article in English | MEDLINE | ID: mdl-38753746

ABSTRACT

PURPOSE: In this study, we used a series of immunohistochemical measurements of 2 cell cycle regulators, p16 and p21, to evaluate their prognostic value, separately and in combination, for the disease outcomes. METHOD: A total of 101 patients with high-grade osteosarcoma were included in this study. Clinicopathologic data were collected, and immunohistochemistry for p16 and p21 was performed and interpreted by 3 independent pathologists. Statistical analysis was performed to assess the strength of each of these markers relative to disease outcome. RESULTS: Our results indicate that more than 90% expression (high) of p16 by immunohistochemistry on the initial biopsy has a strong predictive value for good histologic response to chemotherapy. The patients are also more likely to survive the past 5 years and less likely to develop metastasis than patients with less than 90% p16 (low) expression. The results for p21, on the other hand, show a unique pattern of relationship to the clinicopathologic outcomes of the disease. Patients with less than 1% (low) or more than 50% (high) expression of p21 by immunohistochemistry show a higher chance of metastasis, poor necrotic response to chemotherapy, and an overall decreased survival rate when compared with p21 expression between 1% and 50% (moderate). Our results also showed that the expression of p16 and combined p16 and p21 demonstrates a stronger predictive relationship to 5-year survival than tumor histologic necrosis and p21 alone. DISCUSSION: The results of this study, once proven to be reproducible by a larger number of patients, will be valuable in the initial assessment and risk stratification of the patients for treatment and possibly the clinical trials.


Subject(s)
Biomarkers, Tumor , Bone Neoplasms , Cyclin-Dependent Kinase Inhibitor p16 , Cyclin-Dependent Kinase Inhibitor p21 , Osteosarcoma , Humans , Osteosarcoma/mortality , Osteosarcoma/pathology , Osteosarcoma/metabolism , Osteosarcoma/drug therapy , Osteosarcoma/diagnosis , Osteosarcoma/therapy , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Male , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Female , Adult , Prognosis , Adolescent , Bone Neoplasms/pathology , Bone Neoplasms/mortality , Bone Neoplasms/metabolism , Child , Biomarkers, Tumor/metabolism , Young Adult , Middle Aged , Immunohistochemistry , Neoplasm Grading , Cell Cycle Checkpoints , Aged
6.
Pol J Pathol ; 75(1): 19-24, 2024.
Article in English | MEDLINE | ID: mdl-38741426

ABSTRACT

Breast cancer is the most common cancer and a leading cause of death in women in Saudi Arabia. P16 is a tumour suppressor gene that plays a crucial role in regulating cell cycle. Several studies have investigated the significance of p16 expression in various cancer types. However, the significance of p16 in breast cancer remains controversial and insufficiently studied. The present study aims to examine the association between p16 expression and clinicopathological factors in breast cancer using immunohistochemistry staining. The study utilised 475 prospectively collected tissue samples from 475 women with breast cancer in Saudi Arabia. Nuclear and cytoplasmic immunohistochemical staining of p16 was observed in 338 (71%) of the cases and showed significant direct associations with adverse tumour features, including high tumour grade (p < 0.0001), negative oestrogen receptor/progesterone receptor status (p < 0.001), and lymph node metastasis (p = 0.02). Our study revealed a significant association between p16 protein expression and the established negative prognostic parameters in breast carcinoma including tumour grade, lymph node metastasis, and oestrogen receptor and progesterone receptor status.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms , Cyclin-Dependent Kinase Inhibitor p16 , Immunohistochemistry , Humans , Female , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Cyclin-Dependent Kinase Inhibitor p16/analysis , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Middle Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Adult , Aged , Receptors, Progesterone/metabolism , Aged, 80 and over , Lymphatic Metastasis , Receptors, Estrogen/metabolism , Prognosis
7.
Stomatologiia (Mosk) ; 103(2): 5-11, 2024.
Article in Russian | MEDLINE | ID: mdl-38741528

ABSTRACT

OBJECTIVE: The aim of the study. Improving the efficiency of diagnosis and detailing the features of the clinic of «potentially malignant¼ diseases of the oral mucosa. MATERIALS AND METHODS: Clinical and laboratory examination of 124 patients of the department of oral mucosa diseases aged 35 to 80 years, among whom there were 75 women and 49 men, with diseases such as erythroplakia - 12 patients, verrucous leukoplakia - 52 patients, erosive form of leukoplakia - 35 patients, cheilitis Manganotti - 25 patients. Histological and immunohistochemical methods of investigation were used as diagnostics. To assess the proliferative activity of epithelial cells, the determination of the Ki-67 index was used. The synthesis of keratin 15 (K15) in epithelial layers was determined as a diagnostic criterion for the severity of neoplasia. The expression of human papillomavirus type 16 (HPV 16) antigens and p16INK4a protein in epithelial cells was studied, as well as the expression of p53 protein. RESULTS: A high prevalence of p53 mutations was observed in patients with erythroplakia. In leukoplakia, the expression of the Ki-67 protein was detected in the cell nuclei in both the basal and parabasal layers of the multilayer squamous epithelium, in 77% of cases, the expression of the p16INK4a protein in the epithelial nuclei with varying degrees of dysplastic changes was noted, and a positive reaction to HPV16 was also observed in the cell nuclei and cytoplasm of epithelial cells in the basal, parabasal and spiny epithelial layers. The appearance of K15 in the cytoplasm of cells above the basal layer with abrasive precancerous cheilitis was found in 48% of cases. CONCLUSION: To diagnose early manifestations of neoplastic processes in «potentially malignant¼ diseases of the oral mucosa, it is necessary to use both classical histological and immunohistochemical methods of investigation with various markers.


Subject(s)
Ki-67 Antigen , Mouth Mucosa , Precancerous Conditions , Humans , Middle Aged , Male , Female , Aged , Adult , Mouth Mucosa/pathology , Aged, 80 and over , Ki-67 Antigen/analysis , Precancerous Conditions/pathology , Precancerous Conditions/diagnosis , Mouth Neoplasms/pathology , Mouth Neoplasms/diagnosis , Leukoplakia, Oral/pathology , Leukoplakia, Oral/diagnosis , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/metabolism , Cheilitis/pathology , Cheilitis/diagnosis , Human papillomavirus 16/isolation & purification , Human papillomavirus 16/genetics , Cyclin-Dependent Kinase Inhibitor p16/analysis , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Erythroplasia/pathology , Erythroplasia/diagnosis
8.
Rev Assoc Med Bras (1992) ; 70(4): e20231358, 2024.
Article in English | MEDLINE | ID: mdl-38716944

ABSTRACT

OBJECTIVE: This prospective study aimed to provide a comprehensive analysis of the methylation status of two pivotal genes, CDKN2A/p16INK4A (cyclin-dependent kinase inhibitor 2A) and RB1 (retinoblastoma transcriptional corepressor 1), in breast cancer patients. METHODS: Samples were obtained from 15 women diagnosed with breast cancer and who underwent a total mastectomy. DNA was extracted from the tumor, non-tumor tissue, and peripheral blood (circulating cell-free DNA). The methylation pattern of cell-free DNA extracted from blood collected on the day of mastectomy was compared with the methylation pattern of cell-free DNA from blood collected 1 year post-surgery. The methylation analysis was carried out by sodium bisulfite conversion and polymerase chain reaction, followed by electrophoresis. RESULTS: Methylation of CDKN2A/p16INK4A was identified in 13 tumor samples and 12 non-tumor tissue samples. Two patients exhibited CDKN2A/p16INK4A methylation in the cell-free DNA of the first blood collection, while another showed methylation only in the cell-free DNA of the subsequent blood collection. Regarding RB1, 11 tumors and 8 non-tumor tissue samples presented methylation of the gene. CONCLUSION: This study presents a novel approach for monitoring breast cancer patients through the analysis of cell-free DNA methylation. This analysis can detect changes in methylation patterns before any visible sign of cancer appears in breast tissue and could help predict the recurrence of malignant breast tumors.


Subject(s)
Breast Neoplasms , Cyclin-Dependent Kinase Inhibitor p16 , DNA Methylation , Retinoblastoma Binding Proteins , Adult , Aged , Female , Humans , Middle Aged , Biomarkers, Tumor/genetics , Biomarkers, Tumor/blood , Breast Neoplasms/genetics , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/blood , Cell-Free Nucleic Acids/analysis , Cyclin-Dependent Kinase Inhibitor p16/genetics , DNA Methylation/genetics , Mastectomy , Polymerase Chain Reaction , Prospective Studies , Retinoblastoma Binding Proteins/genetics , Ubiquitin-Protein Ligases/genetics
9.
Int J Mol Sci ; 25(9)2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38731817

ABSTRACT

MCPH1 has been identified as the causal gene for primary microcephaly type 1, a neurodevelopmental disorder characterized by reduced brain size and delayed growth. As a multifunction protein, MCPH1 has been reported to repress the expression of TERT and interact with transcriptional regulator E2F1. However, it remains unclear whether MCPH1 regulates brain development through its transcriptional regulation function. This study showed that the knockout of Mcph1 in mice leads to delayed growth as early as the embryo stage E11.5. Transcriptome analysis (RNA-seq) revealed that the deletion of Mcph1 resulted in changes in the expression levels of a limited number of genes. Although the expression of some of E2F1 targets, such as Satb2 and Cdkn1c, was affected, the differentially expressed genes (DEGs) were not significantly enriched as E2F1 target genes. Further investigations showed that primary and immortalized Mcph1 knockout mouse embryonic fibroblasts (MEFs) exhibited cell cycle arrest and cellular senescence phenotype. Interestingly, the upregulation of p19ARF was detected in Mcph1 knockout MEFs, and silencing p19Arf restored the cell cycle and growth arrest to wild-type levels. Our findings suggested it is unlikely that MCPH1 regulates neurodevelopment through E2F1-mediated transcriptional regulation, and p19ARF-dependent cell cycle arrest and cellular senescence may contribute to the developmental abnormalities observed in primary microcephaly.


Subject(s)
Cell Cycle Checkpoints , Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p16 , Mice, Knockout , Microcephaly , Animals , Mice , Cellular Senescence/genetics , Microcephaly/genetics , Microcephaly/metabolism , Microcephaly/pathology , Cell Cycle Checkpoints/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p16/deficiency , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/metabolism , Fibroblasts/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism
10.
Acta Neuropathol ; 147(1): 82, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38722375

ABSTRACT

Aging affects all cell types in the CNS and plays an important role in CNS diseases. However, the underlying molecular mechanisms driving these age-associated changes and their contribution to diseases are only poorly understood. The white matter in the aging brain as well as in diseases, such as Multiple sclerosis is characterized by subtle abnormalities in myelin sheaths and paranodes, suggesting that oligodendrocytes, the myelin-maintaining cells of the CNS, lose the capacity to preserve a proper myelin structure and potentially function in age and certain diseases. Here, we made use of directly converted oligodendrocytes (dchiOL) from young, adult and old human donors to study age-associated changes. dchiOL from all three age groups differentiated in an comparable manner into O4 + immature oligodendrocytes, but the proportion of MBP + mature dchiOL decreased with increasing donor age. This was associated with an increased ROS production and upregulation of cellular senescence markers such as CDKN1A, CDKN2A in old dchiOL. Comparison of the transcriptomic profiles of dchiOL from adult and old donors revealed 1324 differentially regulated genes with limited overlap with transcriptomic profiles of the donors' fibroblasts or published data sets from directly converted human neurons or primary rodent oligodendroglial lineage cells. Methylome analyses of dchiOL and human white matter tissue samples demonstrate that chronological and epigenetic age correlate in CNS white matter as well as in dchiOL and resulted in the identification of an age-specific epigenetic signature. Furthermore, we observed an accelerated epigenetic aging of the myelinated, normal appearing white matter of multiple sclerosis (MS) patients compared to healthy individuals. Impaired differentiation and upregulation of cellular senescence markers could be induced in young dchiOL in vitro using supernatants from pro-inflammatory microglia. In summary, our data suggest that physiological aging as well as inflammation-induced cellular senescence contribute to oligodendroglial pathology in inflammatory demyelinating diseases such as MS.


Subject(s)
Aging , Cellular Senescence , Multiple Sclerosis , Oligodendroglia , Humans , Oligodendroglia/pathology , Oligodendroglia/metabolism , Cellular Senescence/physiology , Aging/pathology , Multiple Sclerosis/pathology , Multiple Sclerosis/metabolism , Adult , Aged , Middle Aged , Male , Female , Young Adult , Inflammation/pathology , Inflammation/metabolism , White Matter/pathology , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p21
11.
PLoS One ; 19(5): e0300354, 2024.
Article in English | MEDLINE | ID: mdl-38691559

ABSTRACT

Oral cancer (OC) is the most common cancer in Pakistani males and the second most common in females. Major risk factors include peculiar chewing habits, human papillomavirus (HPV) infection and molecular pathways. However, less data is available for this avertible cancer regarding its association with high-risk HPV (HR-HPV) and chewing habits in this region. Therefore, this study was done to determine the prevalence of HR-HPV in oral squamous cell carcinoma (OSCC) and its correlation with p16 and chewing habits. Formalin-fixed paraffin-embedded (FFPE) biopsy specimens of 186 samples were tested for HR-HPV type 16/18 by PCR, followed by p16 immunostaining (IHC) in a subset of cases (n = 50). Appropriate statistical tests were applied to find the association between HR-HPV/p16 and peculiar chewing habits with significance criteria of p<0.05 with 95% CI. HR-HPV (type 16 &18) was present in seven out of 186 cases (3.8%). Of these seven cases, five were positive for HPV16, whereas two were positive for HPV16/18. The overall expression of p16 protein in 50 samples was 38% (n = 19), and among these 19-IHC positive samples, 26% were positive for HR-HPV DNA. No significant association was found between HR-HPV positivity and p16 and chewing habits (p>0.05). It was concluded that HR-HPV prevalence in OSCC was very low in our population, with no statistically significant correlation with p16 and chewing habits. These results suggest the role of HR-HPV as an independent risk factor in OSCC in the local setting.


Subject(s)
Carcinoma, Squamous Cell , Human papillomavirus 16 , Mouth Neoplasms , Papillomavirus Infections , Humans , Mouth Neoplasms/virology , Mouth Neoplasms/epidemiology , Male , Female , Carcinoma, Squamous Cell/virology , Carcinoma, Squamous Cell/epidemiology , Middle Aged , Prevalence , Papillomavirus Infections/epidemiology , Papillomavirus Infections/virology , Adult , Human papillomavirus 16/genetics , Human papillomavirus 16/isolation & purification , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Risk Factors , Aged , Human papillomavirus 18/isolation & purification , Human papillomavirus 18/genetics , Mastication , Pakistan/epidemiology , Human Papillomavirus Viruses
12.
Anticancer Res ; 44(6): 2699-2707, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38821577

ABSTRACT

BACKGROUND/AIM: Organs of the digestive system are frequent sites of cancer development, and digestive tract cancers are the leading causes of death worldwide, including in Japan. Most of these cancers are associated with smoking or drinking habits. This study focused on the clinical and genomic characteristics of patients with these cancers using the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, which comprises a large volume of data on Japanese patients who have undergone tumor profiling gene panel tests. PATIENTS AND METHODS: The genomic and clinical data from patients with digestive tract cancers registered in C-CAT between 2019 and 2023 were retrospectively reviewed. The data were derived from 412 patients with esophageal squamous cell carcinoma, 558 with gastric adenocarcinoma, 3,368 with colorectal adenocarcinoma, 139 with hepatocellular carcinoma, 2,050 with cholangiocarcinoma, and 2,552 with pancreatic ductal adenocarcinoma. RESULTS: CDKN2A, CDKN2B, and MTAP mutations were associated with both smoking and drinking history, and patients with these mutations had a worse prognosis. Almost all gene alterations in CDKN2B and MTAP were deletions, often accompanied by CDKN2A deletion. CDKN2A mutation emerged as the most decisive prognostic factor among these mutations. Although CDKN2A mutations were frequently seen in esophageal squamous cell carcinoma, cholangiocarcinoma, and pancreatic ductal adenocarcinoma, statistically significant differences in survival outcomes were only identified in the latter two. CONCLUSION: CDKN2A mutations were associated with smoking and drinking in digestive cancers. This mutation was prevalent among patients with cholangiocarcinoma and pancreatic ductal adenocarcinoma, for whom they could serve as prognostic factors.


Subject(s)
Alcohol Drinking , Cyclin-Dependent Kinase Inhibitor p16 , Digestive System Neoplasms , Mutation , Smoking , Humans , Male , Prognosis , Alcohol Drinking/adverse effects , Alcohol Drinking/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Female , Japan/epidemiology , Smoking/adverse effects , Smoking/genetics , Digestive System Neoplasms/genetics , Middle Aged , Retrospective Studies , Aged , Adult , East Asian People
13.
Cell Death Dis ; 15(5): 339, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38750022

ABSTRACT

The therapeutic efficacy of adoptive T cell therapy is largely restricted by reduced viability and dysfunction of CD8+ T cells. Continuous antigen stimulation disrupts the expansion, effector function, and metabolic fitness of CD8+ T cells, leading to their differentiation into an exhausted state within the tumor microenvironment (TME). While the function of the cell cycle negative regulator p16 in senescent cells is well understood, its role in T cell exhaustion remains unclear. In this study, we demonstrated that TCR stimulation of CD8+ T cells rapidly upregulates p16 expression, with its levels positively correlating with TCR affinity. Chronic TCR stimulation further increased p16 expression, leading to CD8+ T cell apoptosis and exhaustion differentiation, without inducing DNA damage or cell senescence. Mechanistic investigations revealed that p16 downregulates mTOR, glycolysis, and oxidative phosphorylation (OXPHOS) associated gene expression, resulting in impaired mitochondrial fitness, reduced T cell viability, and diminished effector function. Furthermore, the deletion of p16 significantly enhances the persistence of CD8+ T cells within tumors and suppresses the terminal exhaustion of tumor-infiltrating T cells. Overall, our findings elucidate how increased p16 expression reshapes T cell intracellular metabolism, drives T cell apoptosis and exhaustion differentiation, and ultimately impairs T cell anti-tumor function.


Subject(s)
Apoptosis , CD8-Positive T-Lymphocytes , Cyclin-Dependent Kinase Inhibitor p16 , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Animals , Mice , Humans , Mice, Inbred C57BL , Tumor Microenvironment/immunology , Cell Differentiation , Receptors, Antigen, T-Cell/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Glycolysis , T-Cell Exhaustion
14.
J Cell Mol Med ; 28(9): e18394, 2024 May.
Article in English | MEDLINE | ID: mdl-38751024

ABSTRACT

This study aims to enhance the prognosis prediction of Head and Neck Squamous Cell Carcinoma (HNSCC) by employing artificial intelligence (AI) to analyse CDKN2A gene expression from pathology images, directly correlating with patient outcomes. Our approach introduces a novel AI-driven pathomics framework, delineating a more precise relationship between CDKN2A expression and survival rates compared to previous studies. Utilizing 475 HNSCC cases from the TCGA database, we stratified patients into high-risk and low-risk groups based on CDKN2A expression thresholds. Through pathomics analysis of 271 cases with available slides, we extracted 465 distinctive features to construct a Gradient Boosting Machine (GBM) model. This model was then employed to compute Pathomics scores (PS), predicting CDKN2A expression levels with validation for accuracy and pathway association analysis. Our study demonstrates a significant correlation between higher CDKN2A expression and improved median overall survival (66.73 months for high expression vs. 42.97 months for low expression, p = 0.013), establishing CDKN2A's prognostic value. The pathomic model exhibited exceptional predictive accuracy (training AUC: 0.806; validation AUC: 0.710) and identified a strong link between higher Pathomics scores and cell cycle activation pathways. Validation through tissue microarray corroborated the predictive capacity of our model. Confirming CDKN2A as a crucial prognostic marker in HNSCC, this study advances the existing literature by implementing an AI-driven pathomics analysis for gene expression evaluation. This innovative methodology offers a cost-efficient and non-invasive alternative to traditional diagnostic procedures, potentially revolutionizing personalized medicine in oncology.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16 , Machine Learning , Squamous Cell Carcinoma of Head and Neck , Humans , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/diagnosis , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/mortality , Prognosis , Male , Female , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/pathology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Middle Aged , Aged
15.
Int J Mol Sci ; 25(10)2024 May 14.
Article in English | MEDLINE | ID: mdl-38791395

ABSTRACT

In cervical biopsies, for diagnosis of Human Papilloma Virus (HPV) related conditions, the immunohistochemical staining for p16 has a diagnostic value only if diffusely and strongly positive, pattern named "block-like". "Weak and/or focal (w/f) p16 expression" is commonly considered nonspecific. In our previous study, we demonstrated the presence of high-risk HPV (hrHPV) DNA by LiPa method in biopsies showing w/f p16 positivity. The aim of the present study was to investigate the presence of hrHPV-DNA by CISH in the areas showing w/f p16 expression. We assessed the presence of hrHPV16, 18, 31, 33, 51 by CISH in a group of 20 cervical biopsies showing w/f p16 expression, some with increased Ki67, and in 10 cases of block-like expression, employed as control. The immunohistochemical p16 expression was also assessed by digital pathology. hrHPV-CISH nuclear positivity was encountered in 12/20 cases of w/f p16 expression (60%). Different patterns of nuclear positivity were identified, classified as punctate, diffuse and mixed, with different epithelial distributions. Our results, albeit in a limited casuistry, show the presence of HPV in an integrated status highlighted by CISH in w/f p16 positive cases. This could suggest the necessity of a careful follow-up of the patients with "weak" and/or "focal" immunohistochemical patterns of p16, mainly in cases of increased Ki67 cell proliferation index, supplemented with molecular biology examinations.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16 , Immunohistochemistry , Papillomavirus Infections , Humans , Female , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Immunohistochemistry/methods , Papillomavirus Infections/virology , Papillomavirus Infections/diagnosis , Papillomavirus Infections/metabolism , Biopsy , Uterine Cervical Neoplasms/virology , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Papillomaviridae/genetics , Papillomaviridae/isolation & purification , Cervix Uteri/virology , Cervix Uteri/pathology , Cervix Uteri/metabolism , DNA, Viral/genetics , DNA, Viral/analysis , Adult , Ki-67 Antigen/metabolism , Middle Aged
16.
Aging (Albany NY) ; 16(10): 8599-8610, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38752873

ABSTRACT

Higher intensity exercise, despite causing more tissue damage, improved aging conditions. We previously observed decreased p16INK4a mRNA in human skeletal muscle after high-intensity interval exercise (HIIE), with no change following equivalent work in moderate-intensity continuous exercise. This raises the question of whether the observed senolytic effect of exercise is mediated by inflammation, an immune response induced by muscle damage. In this study, inflammation was blocked using a multiple dose of ibuprofen (total dose: 1200 mg), a commonly consumed nonsteroidal anti-inflammatory drug (NSAID), in a placebo-controlled, counterbalanced crossover trial. Twelve men aged 20-26 consumed ibuprofen or placebo before and after HIIE at 120% maximum aerobic power. Multiple muscle biopsies were taken for tissue analysis before and after HIIE. p16INK4a+ cells were located surrounding myofibers in muscle tissues. The maximum decrease in p16INK4a mRNA levels within muscle tissues occurred at 3 h post-exercise (-82%, p < 0.01), gradually recovering over the next 3-24 h. A concurrent reduction pattern in CD11b mRNA (-87%, p < 0.01) was also found within the same time frame. Ibuprofen treatment attenuated the post-exercise reduction in both p16INK4a mRNA and CD11b mRNA. The strong correlation (r = 0.88, p < 0.01) between p16INK4a mRNA and CD11b mRNA in muscle tissues suggests a connection between the markers of tissue aging and pro-inflammatory myeloid differentiation. In conclusion, our results suggest that the senolytic effect of high-intensity exercise on human skeletal muscle is mediated by acute inflammation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal , Cross-Over Studies , Ibuprofen , Inflammation , Muscle, Skeletal , Humans , Male , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Adult , Ibuprofen/pharmacology , Inflammation/metabolism , Young Adult , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Exercise/physiology , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , CD11b Antigen/metabolism , CD11b Antigen/genetics , RNA, Messenger/metabolism , High-Intensity Interval Training
17.
Int J Med Sci ; 21(6): 1103-1116, 2024.
Article in English | MEDLINE | ID: mdl-38774759

ABSTRACT

Background: Colorectal cancer (CRC) has a high morbidity and mortality. Ferroptosis is a phenomenon in which metabolism and cell death are closely related. The role of ferroptosis-related genes in the progression of CRC is still not clear. Therefore, we screened and validated the ferroptosis-related genes which could determine the prevalence, risk and prognosis of patients with CRC. Methods: We firstly screened differentially expressed ferroptosis-related genes by The Cancer Genome Atlas (TCGA) database. Then, these genes were used to construct a risk-score model using the least absolute shrinkage and selection operator (LASSO) regression algorithm. The function and prognosis of the ferroptosis-related genes were confirmed using multi-omics analysis. The gene expression results were validated using publicly available databases and qPCR. We also used publicly available data and ferroptosis-related genes to construct a prognostic prediction nomogram. Results: A total of 24 differential expressed genes associated with ferroptosis were screened in this study. A three-gene risk score model was then established based on these 24 genes and GPX3, CDKN2A and SLC7A11 were selected. The significant prognostic value of this novel three-gene signature was also assessed. Furthermore, we conducted RT-qPCR analysis on cell lines and tissues, and validated the high expression of CDKN2A, GPX3 and low expression of SLC7A11 in CRC cells. The observed mRNA expression of GPX3, CDKN2A and SLC7A11 was consistent with the predicted outcomes. Besides, eight variables including selected ferroptosis related genes were included to establish the prognostic prediction nomogram for patients with CRC. The calibration plots showed favorable consistency between the prediction of the nomogram and actual observations. Also, the time-dependent AUC (>0.7) indicated satisfactory discriminative ability of the nomogram. Conclusions: The present study constructed and validated a novel ferroptosis-related three-gene risk score signature and a prognostic prediction nomogram for patients with CRC. Also, we screened and validated the ferroptosis-related genes GPX3, CDKN2A, and SLC7A11 which could serve as novel biomarkers for patients with CRC.


Subject(s)
Amino Acid Transport System y+ , Biomarkers, Tumor , Colorectal Neoplasms , Ferroptosis , Gene Expression Regulation, Neoplastic , Nomograms , Humans , Ferroptosis/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/mortality , Prognosis , Biomarkers, Tumor/genetics , Amino Acid Transport System y+/genetics , Male , Female , Cyclin-Dependent Kinase Inhibitor p16/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Middle Aged , Gene Expression Profiling , Risk Assessment/methods , Risk Assessment/statistics & numerical data , Aged
18.
Aging (Albany NY) ; 16(9): 8361-8377, 2024 May 06.
Article in English | MEDLINE | ID: mdl-38713173

ABSTRACT

BACKGROUND: Globally, Acute Myocardial Infarction (AMI) is a common cause of heart failure (HF), which has been a leading cause of mortality resulting from non-communicable diseases. On the other hand, increasing evidence suggests that the role of energy production within the mitochondria strongly links to the development and progression of heart diseases, while Cuproptosis, a newly identified cell death mechanism, has not yet been comprehensively analyzed from the aspect of cardiovascular medicine. MATERIALS AND METHODS: 8 transcriptome profiles curated from the GEO database were integrated, from which a diagnostic model based on the Stacking algorithm was established. The efficacy of the model was evaluated in a multifaced manner (i.e., by Precision-Recall curve, Receiver Operative Characteristic curve, etc.). We also sequenced our animal models at the bulk RNA level and conducted qPCR and immunohistochemical staining, with which we further validated the expression of the key contributor gene to the model. Finally, we explored the immune implications of the key contributor gene. RESULTS: A merged machine learning model containing 4 Cuproptosis-related genes (i.e., PDHB, CDKN2A, GLS, and SLC31A1) for robust AMI diagnosis was developed, in which SLC31A1 served as the key contributor. Through in vivo modeling, we validated the aberrant overexpression of SLC31A1 in AMI. Besides, further transcriptome analysis revealed that its high expression was correlated with significant potential immunological implications in the infiltration of many immune cell types, especially monocyte. CONCLUSIONS: We constructed an AMI diagnostic model based on Cuproptosis-related genes and validated the key contributor gene in animal modeling. We also analyzed the effects on the immune system for its overexpression in AMI.


Subject(s)
Biomarkers , Computational Biology , Myocardial Infarction , Myocardial Infarction/genetics , Myocardial Infarction/diagnosis , Myocardial Infarction/metabolism , Animals , Biomarkers/metabolism , Humans , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , Transcriptome , Disease Models, Animal , Machine Learning , Mice , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Male , Gene Expression Profiling
19.
Medicina (Kaunas) ; 60(5)2024 May 05.
Article in English | MEDLINE | ID: mdl-38792946

ABSTRACT

The CDKN2A gene remains understudied in melanoma compared to BRAF alterations. Inactivation of this tumor suppressor gene through homozygous deletions in the 9p21 chromosomal region leads to cellular proliferation and disrupts pro-apoptotic pathways. Genetic changes in CDKN2A are linked to multiple primary melanomas (MPM), with patients diagnosed with melanoma facing an elevated risk of developing additional primaries. We present the rare case of a 72-year-old Caucasian woman with nine metastasizing melanomas across diverse anatomical sites, posing a diagnostic challenge. Initial diagnosis in 2022 revealed ulcerated superficial spreading melanomas, progressing to intradermal and papillary dermal populations with neurotropism and angiotropism by early 2023. Lymph node metastases were identified, classifying the condition as pT3b N3b. Subsequent assessments in April 2023 revealed clinically suspicious melanocytic lesions diagnosed as intradermal and traumatized junctional nevi. In late 2023, cutaneous pigmented lesions and subcutaneous metastases were confirmed as nodular nevoid low-CSD multiple melanomas. Fluorescence in situ hybridization testing revealed homozygous CDKN2A deletion, necessitating close multidisciplinary collaboration for an optimized care plan for effective monitoring and intervention in this intricate clinical scenario. In summary, this case report highlights the diagnostic challenges of MPM in a single patient. Stressing the importance of immuno-histochemistry and CDKN2A genetic testing, our findings underscore the crucial role of these tools in accurately distinguishing malignant melanocytic proliferations from nevi and characterizing MPM cases.


Subject(s)
Cyclin-Dependent Kinase Inhibitor p16 , Melanoma , Skin Neoplasms , Humans , Melanoma/genetics , Melanoma/diagnosis , Female , Aged , Cyclin-Dependent Kinase Inhibitor p16/genetics , Skin Neoplasms/genetics , Mutation , Neoplasms, Multiple Primary/genetics
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