Introduction Cyclin-dependent kinase inhibitor 2A (CDKN2A) is a suppressor carcinogenic gene that is upregulated across various types of cancer including breast, liver, thyroid, and bile duct cancer due to its crucial role in cell cycle regulation and cell division. Nevertheless, it is mostly investigated at the genetic level, but it is still poorly studied on pan-cancer analysis as a biomarker and this study shows its significant potential diagnostic and prognostic characteristics. However, this study aims to investigate the role of CDKN2A as a diagnostic and prognostic biomarker across various types of cancer focusing primarily on colon adenocarcinoma (COAD). Methods We investigated CDKN2A gene expression in a pan-cancer analysis across different types of cancer to show its diagnostic potential characteristics by using various bioinformatic tools, including Tumor Immune Estimation Resource (TIMER) 2.0, Gene Expression Profiling Interactive Analysis (GEPIA), and University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database. TIMER was used to profile gene expression across 32 types of cancer composed of 10,000 RNA-seq samples obtained from the Cancer Genome Atlas (TCGA) and to analyze the tumor-infiltrating immune cells. In addition, GEPIA and UALCAN were further used to analyze gene expression, in terms of gene regulation, pathological stages, and clinical parameters, including gender, age, and race. Therefore, we used GEPIA, UALCAN, and Kaplan-Meier plotter particularly across adenocarcinoma to investigate CDKN2A prognosis by studying its high expression association with the patient\'s overall survival rate to show the tumor progression. Then, we looked into the genetic alteration of CDKN2A by using the cBio Cancer Genomics Portal (cBioPortal), including 10 pan-cancer studies. We concluded the analysis with gene validation by using a public cohort in Gene Expression Omnibus (GEO). Results CDKN2A showed a trend of upregulation in most cancers and it was significantly upregulated in five cancers, which were commonly identifiable in three databases, including breast invasive carcinoma (p < 0.001), kidney chromophobe (p < 0.001), kidney renal clear cell carcinoma (p < 0.001), kidney renal papillary cell carcinoma (p < 0.001), and COAD (p < 0.001). The upregulation was significantly different in association with pathogenic stages II and III (pr(>F) = 0.00234) which was identifiable significantly in COAD more than in other cancers. The gene showed a high upregulation in association with poor prognosis of patient survival in three cancers, including COAD (log-rank p = 0.011), mesothelioma (log-rank p = 5.9e-07), and liver hepatocellular carcinoma (log-rank p = 0.0045). Therefore, COAD was the only comprehensively analyzed tumor to show a diagnostic and prognostic potential characteristic during high upregulation of CDKN2A. Furthermore, CDKN2A displayed a rare mutation in the form of deep deletion (9%) and revealed an upregulation associated with CD4+ T cells (p = 0.0108), macrophage (p = 0.0073), and neutrophils (p = 0.0272) as immune cells infiltrating COAD.  Conclusion Our study demonstrates the pan-cancer relevance of CDKN2A and revealed a novelty in showing CDKN2A underscores its potential as a diagnostic prognostic biomarker in COAD since CDKN2A is mostly studied at a genetic level across COAD.

Low-grade endometrial stromal sarcoma (LGESS) typically has a favorable prognosis. Hormone therapy is considered the first choice of treatment for recurrent LGESS. In this report, we describe a case of recurrent LGESS where hormone therapy was ineffective, chemotherapy showed a partial response (PR), and pazopanib resulted in stable disease (SD). A 50-year-old patient with LGESS underwent a simple total hysterectomy and bilateral adnexectomy (pT1aN0M0, stage IA). Five years later, pelvic tumors and ascites were observed. Exploratory laparoscopy revealed bloody ascites, an 8 cm pelvic tumor, and extensive peritoneal dissemination. Nuclear atypia of the tumor cells was mild, pleomorphism and mitotic figures could not be confirmed, and necrosis was not observed. Immunostaining was positive for CD10 and estrogen receptor, negative for the BCL6 corepressor (BCOR), and showed a low Ki-67 index. Fluorescence in situ hybridization (FISH) examination of the tissue showed rearrangement of the JAZF zinc finger 1 (JAZF1) gene. Multigene panel testing revealed a homozygous deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A). Accordingly, the patient was diagnosed with recurrent LGESS and was treated with an aromatase inhibitor, followed by medroxyprogesterone acetate; both were ineffective. The patient had a PR to chemotherapy (doxorubicin/ifosfamide) and SD to pazopanib. The patient died 1.5 years after recurrence. In conclusion, we present a case of LGESS with a poor prognosis where hormone therapy was ineffective, and chemotherapy and pazopanib were both partially effective. The poor prognosis may have been associated with the CDKN2A homozygous deletion.

UNASSIGNED: This study aimed to identify potential biomarkers in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) and further probe the prognostic implications of CDKN2A mutations, particularly within a subset receiving immunotherapy.
UNASSIGNED: In this retrospective single-center study, we evaluated the next-generation sequencing (NGS) data from Foundation Medicine (FM) for patients with recurrent or metastatic HNSCC between January 1, 2019, and December 31, 2021. Patients were stratified based on CDKN2A loss-of-function (LOF) versus wild-type (WT) categorizations, with a focused subgroup analysis on those administered immunotherapy.
UNASSIGNED: The study encompassed 77 patients, of which 62 had undergone immunotherapy. The median duration of follow-up was 22.6 months. For the CDKN2A LOF group, the median overall survival (OS) was 16.5 months, contrasted with 30.0 months in the CDKN2A WT group (P=0.014). Notably, female gender (hazard ratio [HR]=4.526, 95% confidence interval [CI]: 1.934-10.180, P=0.0003) and CDKN2A LOF (HR=2.311, 95% CI: 1.156-4.748, P=0.019) emerged as independent risk factors for mortality in patients with recurrent or metastatic HNSCC. Within the immunotherapy subset, the median OS was 11.7 months for the CDKN2A LOF group, and 22.5 months for the CDKN2A WT group (P=0.017). Further, the female gender (HR=4.022, 95% CI: 1.417-10.710, P=0.006), CDKN2A LOF (HR=4.389, 95% CI: 1.782-11.460, P=0.002), and a combined positive score below 1 (HR=17.20, 95% CI: 4.134-79.550, P<0.0001) were identified as significant predictors of mortality among patients with recurrent or metastatic HNSCC receiving immunotherapy.
UNASSIGNED: Alterations manifesting as LOF in the CDKN2A gene stand as robust indicators of unfavorable survival outcomes in HNSCC patients, including the subset that underwent immunotherapy.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease with limited therapeutic options. Cuproptosis is a recently proposed novel form of programmed cell death, which has been strongly implicated in the development of various human diseases. However, the prognostic and therapeutic value of cuproptosis-related genes (CRGs) in IPF remains to be elucidated.
METHODS: In the present study, weighted gene co-expression network analysis (WGCNA) was employed to identify the key CRGs associated with the development of IPF. The subsequent GSEA, immune cell correlation analysis, and single-cell RNA-Seq analysis were conducted to explore the potential role of the identified CRGs in IPF. In addition, ROC curves and survival analysis were used to assess the prognostic value of the key CRGs in IPF. Moreover, we explored the molecular mechanisms of participation of identified key CRGs in the development of pulmonary fibrogenesis through in vivo and in vitro experiments.
RESULTS: The expression level of cyclin-dependent kinase inhibitor 2A (CDKN2A) is upregulated in the lung tissues of IPF patients and associated with disease severity. Notably, CDKN2A was constitutively expressed by fibrosis-promoting M2 macrophages. Decreased CDKN2A expression sensitizes M2 macrophages to elesclomol-induced cuproptosis in vitro. Inhibition of CDKN2A decreases the number of viable macrophages and attenuates bleomycin-induced pulmonary fibrosis in mice.
CONCLUSIONS: These findings indicate that CDKN2A mediates the resistance of fibrosis-promoting M2 macrophages to cuproptosis and promotes pulmonary fibrosis in mice. Our work provides fresh insights into CRGs in IPF with potential value for research in the pathogenesis, diagnosis, and a new therapy strategy for IPF.

Background: This study is a retrospective study. The purpose of this study is to construct and validate an early warning model of lung cancer through machine learning. Methods: The CDKN2A gene expression profile and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database and divided into a tumor group and a normal group (n = 57). The top 5 somatic mutation-related genes were extracted from 567 somatic mutation data downloaded from TCGA database using random forest algorithm. Cox proportional hazard model and nomogram were constructed combining CDKN2A, 5 somatic mutation-related genes, gender, and smoking index. Patients were divided into high-risk and low-risk groups according to risk score. The predictability of the model in the prognosis of lung cancer was estimated by Kaplan-Meier survival analysis and receiver operating characteristics curve. Results: We constructed a prognostic model consisting of 5 somatic mutation-related genes (sphingosine 1-phosphate receptor 1 [S1PR1], dedicator of cytokinesis 7 [DOCK7], DEAD-box helicase 4 [DDX4], laminin subunit beta 3 [LAMB3], and importin 5 [IPO5]), cyclin-dependent kinase inhibitor 2A (CDKN2A), gender, and smoking indicators. The high-risk group had a lower overall survival rate compared to the low-risk group (hazard ratio = 2.14, P = 0 .0323). The area under the curve predicted for 3-year, 5-year, and 10-year survival rates are 0.609, 0.673, and 0.698, respectively. The accuracy, sensitivity, and specificity of the model for predicting the 10-year survival rate of lung cancer are 76.19%, 56.71%, and 86.23%. Conclusion: The lung cancer early warning model and nomogram may provide an essential reference for patients with lung cancer management in the clinic.

BACKGROUND: The carcinogenesis of colorectal cancer (CRC) involves many different molecules and multiple pathways, and the specific mechanism has not been elucidated until now. Existing studies on the proteomic signature profiles of CRC are relatively limited. Therefore, we herein aimed to provide a more comprehensive proteomic signature profile and discover new prognostic markers and therapeutic targets by performing proteomic analysis of CRC and paired normal tissues.
OBJECTIVE: To investigate the proteomic signature and identify novel protein prognostic biomarkers of CRC.
METHODS: Cancer tissues and paired normal tissues were collected from 48 patients who underwent surgical removal at the China-Japan Friendship Hospital from January 2020 to June 2021. Data independent acquisition (DIA) quantitative proteomic analysis was performed using high-performance liquid chromatography-mass spectrometry/mass spectrometry (nano-UHPLC-MS/MS) to identify differentially expressed proteins, among which those with a P adj value (t test, BH correction) < 0.05 and an absolute fold change (|log2FC|) > 2 were identified as potential markers. Differentially expressed proteins were selected by bioinformatics analysis and validated by immunohistochemical tissue microarrays, and their association with prognosis was further analyzed with the Gene Expression Profiling Interactive Analysis database to identify prognostic protein biomarkers of CRC.
RESULTS: Significantly differential protein expression was observed between cancer tissues and normal tissues. Compared with normal tissues, 1115 proteins were upregulated and 705 proteins were downregulated in CRC based on P adj < 0.05 and |log2FC| > 2, and bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes associated with tumorigenesis, including ribosome biogenesis in eukaryotes, focal adhesion, extracellular matrix-receptor interactions and other tumor metabolism processes. Moreover, cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was markedly upregulated in CRC, as validated by immunohistochemistry (0.228 vs 0.364, P = 0.0044), and was significantly enriched in tumor proliferation and signal transduction pathways such as the cell cycle and p53 signaling pathways. High CDKN2A expression was significantly correlated with poor prognosis (P = 0.021). These results demonstrated that CDKN2A functions as a driver of CRC.
CONCLUSIONS: Our study provides a comprehensive proteomic signature of CRC and highlights CDKN2A as a potential powerful prognostic marker and precision therapeutic target.

Currently, breast cancer (BRCA) has become the most common cancer in the world, whose pathological mechanism is complex. Among its subtypes, triple-negative breast cancer (TNBC) has the worst prognosis. With the increasing number of diagnosed TNBC patients, the urgent need of novel biomarkers is also rising. Cyclin-dependent kinase inhibitor 2A (CDKN2A) has recently emerged as a key regulator associated with ferroptosis and cuproptosis (FAC) and has exhibited a significant effect on BRCA, but its detailed mechanism remains elusive. Herein, we conducted the first converge comprehensive landscape analysis of FAC-related gene CDKN2A in BRCA and disclosed its prognostic value in BRCA. Then, an unsupervised cluster analysis based on CDKN2A-correlated genes unveiled three subtypes, namely cold-immune subtype, IFN-γ activated subtype and FTL-dominant subtype. Subsequent analyses depicting hallmarks of tumor microenvironment (TME) among three subtypes suggested strong association between TNBC and CDKN2A. Given the fact that the most clinically heterogeneous TNBC always displayed the most severe outcomes and lacked relevant drug targets, we further explored the potential of immunotherapy for TNBC by interfering CDKN2A and constructed the CDKN2A-derived prognostic model for TNBC patients by Lasso-Cox. The 21-gene-based prognostic model showed high accuracy and was verified in external independent validation cohort. Moreover, we proposed three drugs for TNBC patients based on our model via targeting epidermal growth factor receptor. In summary, our study indicated the potential of CDKN2A as a pioneering prognostic predictor for TNBC and provided a rationale of immunotherapy for TNBC, and offered fresh perspectives and orientations for cancer treatment via inducing ferroptosis and cuproptosis to develop novel anti-cancer treatment strategies.

Multiple primary cancers may occur in the same patient, with a prevalence that follows an ascendant trend. Their development is dictated by a complex interplay between a variety of factors, both patient-dependent and external. The case of a 38-year-old female patient diagnosed and treated for pancreatic cancer (PC) is presented in whom the digital dermoscopic monitoring of melanocytic nevi revealed a marked change of two nevi that acquired rapidly highly atypical features. They were surgically excised and the histopathological examination revealed two completely excised dysplastic compound nevi. Clinicians should be aware of the strong association between dysplastic nevus syndrome and PC, a malignancy associated with an extremely poor prognosis. Familial atypical multiple mole melanoma syndrome (FAMMM) predisposes to the development of melanoma, pancreatic cancer and other neoplasms. The common genetic background of PC and hereditary melanoma is discussed and the importance of regular skin checkup and screening for PC in these patients is underlined.

Following the publication of this paper, it was drawn to the Editors\' attention by a concerned reader that certain of the cell cycle assay data shown in Figs. 2D and 5C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 16: 4863‑4870, 2017; DOI: 10.3892/mmr.2017.7129].

BACKGROUND: Several genome-wide association studies showed that a series of genetic variants located at the chromosome 9p21 locus are strongly associated with coronary artery disease (CAD).
UNASSIGNED: In the present study, the relationship of rs3088440 (G > A) in cyclin-dependent kinase inhibitor 2A (CDKN2A) gene site with the presence of coronary artery disease (CAD) and its severity was evaluated in an Iranian population.
RESULTS: The presence of rs3088440 (G > A) genotypes was assessed by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) technique in 324 CAD patients and 148 normal controls. rs3088440 (G > A) polymorphism was associated with increased risk of CAD in the total population (adjusted OR = 1.76, 95% CI = 1.10-2.82; p-value = 0.017) or in women (adjusted OR = 2.96, 95% CI = 1.34-6.55; p-value = 0.007), but not in the men (adjusted OR = 1.35, 95% CI = 0.70-2.6; p-value = 0.368).
CONCLUSIONS: Our findings suggest that the presence of rs3088440 (G > A) is potentially linked with the risk of CAD and its severity in whole study subjects or in women only, independent of CAD risk factors.