PTEN Gene Mutations Research Articles

Immunohistochemical Expression of PTEN in Canine Gliomas.

Phosphatase and tensin homolog (PTEN) is a critical tumor suppressor gene with a vital role in regulating cell proliferation, migration, and survival. The loss of PTEN function, either by genetic alterations or decreased protein expression, is frequent in human gliomas and has been correlated with tumor progression, grade, therapeutic resistance, and decreased overall survival in patients with glioma. While different genetic mutations in PTEN gene have been occasionally reported in canine gliomas, no alterations in protein expression have been reported. This study investigates the immunohistochemical expression of PTEN in canine gliomas to evaluate possible alterations, as those reported in human gliomas. Immunohistochemical PTEN expression and pattern distribution were analyzed in 37 spontaneous canine gliomas. Among gliomas, 52.6% cases showed high PTEN expression and 48.6% displayed reduced (13.5%) or highly reduced (35.1%) immunopositivity. Most oligodendrogliomas showed high expression (73.7%), while the majority of astrocytomas (69.2%) showed a reduced or highly reduced expression. A reduced PTEN expression was mostly associated with a heterogeneous loss of PTEN immunopositivity. These observations are in line with those reported in human gliomas and provide a rationale for future studies regarding abnormalities in PTEN expression and PI3K/Akt/mTor pathway in canine gliomas, to evaluate its prognostic and therapeutic implications.

Incidence of common gene mutations in early-onset colorectal cancer and the association with cancer survival: a meta-analysis

Objective: The incidence of early-onset colorectal cancer (EOCRC) is increasing globally; however, the molecular characteristics and prognosis of sporadic EOCRC are unclear. In this systematic review and meta-analysis, we aimed to investigate the incidence of gene mutations and their association with cancer survival in sporadic EOCRC, focusing on six common gene mutations (TP53, BRAF, KRAS, NRAS, PTEN, and APC). Methods: Ovid Embase and Ovid Medline electronic databases were searched for studies involving patients with sporadic EOCRC (i.e., diagnosed with colorectal cancer before the age of 50 years and with no evidence of hereditary syndromes predisposing to colorectal cancer). The included articles were evaluated using quality assessment tools. Meta-analysis was performed using random-effects and fixed-effects models. Cochran's Q statistic and the I2 index were used to assess heterogeneity. The incidence of the six common gene mutations listed above in sporadic EOCRC and their association with cancer survival were evaluated. Results: (1) Incidence of specific gene mutations in sporadic EOCRC. A total of 34 articles were included in this meta-analysis. The incidence of APC gene mutation was 36% (from 13 articles, 95%CI: 19%-55%, P=0.043); of KRAS gene mutation 30% (from 26 articles, 95%CI: 24%-35%, P=0.190); of BRAF gene mutation 7% (from 18 articles, 95%CI: 5%-11%, P=0.422); of NRAS gene mutation 4% (from five articles, 95%CI: 3%-5%, P=0.586); of PTEN gene mutation 6% (from six articles, 95%CI: 4%-10%, P=0.968); and of TP53 gene mutation 59% (from 13 articles, 95%CI: 49%-68%, P=0.164). (2) Association between gene mutations and survival in sporadic EOCRC. A total of six articles were included in this meta-analysis. Compared with wild-type BRAF, mutant BRAF was significantly associated with increased overall mortality risk in patients with EOCRC (pooled HR=2.85, 95%CI: 1.45-5.60, P=0.002). Subgroup analysis showed that the incidence of BRAF gene mutation was higher in Eastern than in Western countries, whereas the incidence of TP53, KRAS, NRAS, and APC gene mutations was lower. There was no significant difference in the incidence of PTEN gene mutation between different regions. Conclusion: Compared with colorectal cancer occurring in the general population, the incidence of APC and KRAS mutations is lower in EOCRC, whereas the incidence of TP53 mutation remains consistent. BRAF mutation is associated with increased overall mortality risk in patients with EOCRC.

Immunohistochemical and molecular profiles of heterogeneous components of metaplastic breast cancer: a squamous cell carcinomatous component was distinct from a spindle cell carcinomatous component

Metaplastic breast carcinoma (MBC), a category of breast cancer, includes different histological types, which are occasionally mixed and heterogeneous. Considering the heterogeneity of cancer cells in a tumour mass has become highly significant, not only from a biological aspect but also for clinical management of recurrence. This study aimed to analyse the immunohistochemical and molecular profiles of each MBC component of a tumour mass. Twenty-five MBC tumours were histologically evaluated, and the most frequent MBC component (c) was squamous cell carcinoma (SCC), followed by spindle cell carcinoma (SpCC). A total of 69 components of MBC and non-MBC in formalin-fixed paraffin-embedded sections were examined for 7 markers by immunohistochemistry. SCC(c) were significantly PTEN negative and CK14 positive, and SpCC(c) were significantly E-cadherin negative and vimentin positive. Multivariate analyses revealed that immunohistochemical profiles of normal/intraductal (IC)(c), no special type (NST)(c), and MBC(c) differed; moreover, SCC(c) and SpCC(c) were distinctly grouped. PTEN gene mutation was detected only in SCC(c) (2/7), but not in SpCC(c). Next-generation sequence analyses for 2 cases with tumours containing SCC(c) demonstrated that PTEN gene mutation increased progressively from IC(c) to NST(c) to SCC(c). In conclusion, the immunohistochemical and molecular profiles of the SCC(c) of MBC are distinct from those of the SpCC(c).

Mutation of PTEN: Loss and Likelihood of Being a Non-responder to Trastuzumab in a Sample of Iraqi Her2+ Breast Cancer Patients.

PTEN controls upstream PI3K relatives, such as AKT. PTEN gene mutations have been documented to affect outcomes in main or distant malignancies, including breast cancer (BC). PTEN gene deletions are common in a variety of humancancers. A key factor in the response to this kind of therapy is genetic diversity. The purpose of this research is to determine whether a PTEN loss mutation influences a patient's propensity to not respond to trastuzumab (TRS) in cases of Her2+ BC. Diwaniya Teaching Hospital's oncology ward provided 60 patients with Her2+ BC who had been on TRS for at least 12 months for this study. Patients were split in half using the RECIST criteria for evaluating responses to therapy in solid tumors: responders and non-responders. A PTEN polyclonal primary antibody was used for the detection of PTEN in breast tissue in the current study. This research employs a rating system based on eight specimens (26.67%) among non-responsive women who demonstrated PTEN loss compared with one specimen (3.33%) among responsive women. Statistically, PTEN loss varied significantly between the responsive and non-responsive groups. Loss of PTEN was also not linked to shifts in creatine kinase-myocardial band (CK-MB), troponin T (TnT), or any other biomarker, or troponin I (Tn1) at baseline or after 12 months of TRS therapy. These results give us important information about how PTEN deletion mutations might work as a predictor for TRS response in women with Her2+ BC.

Prognostic role of immunohistochemical PTEN (phosphatase and tensin homolog) expression and PTEN (rs701848) genotypes among Egyptian patients with different stages of colorectal cancer.

Colorectal cancer (CRC) is the third most frequent cancer worldwide and the second major cause of cancer-related death. Thus, we attempted to ascertain the relationship between the genotype and allele frequencies of phosphatase and tensin homolog (PTEN) and immunohistochemical PTEN expression with clinicopathological characteristics in patients with CRC. 150 individuals were allocated into two groups for this cross-sectional randomized case-control study: Group I consisted of 100 patients with histopathologically proven CRC of various stages. Group II: Fifty healthy volunteers. Genetic analysis of PTEN (rs701848 T / C) single nucleotide polymorphism (SNP) was performed using TaqManTM assays and real-time PCR, while PTEN expressions were assessed using immunohistochemical staining. PTN SNP genotypes and alleles did not significantly differ between CRC patients and controls. PTEN expression was lost in 28% of CRC patients, while all healthy controls exhibited PTEN expression. Negative PTEN expression was present in 16 (80%) of stage IV CRC cases, 9 (23.7%) of stage III cases, 3 (37.5%) of stage II cases, and none of stage I cases. It was shown that PTEN expression was weakly positive, moderately positive, and strongly positive in 15, 10, and 9 (respectively) cases of CRC stage I. However, the expression was only weekly positive in 4 (20%) of the patients in stage IV. In the stage IV group, neither moderately nor strongly positive PTEN expressions were found. So, Among Egyptians, the emergence or course of colorectal cancer is unrelated to the PTEN gene mutation. However, the formation and progression of CRC may be influenced by weak or lost PTEN expression.

Fertility-preserving treatment outcomes in endometrial cancer and atypical hyperplasia patients with different molecular profiles

Objective: To investigate the impact of molecular classification and key oncogenes on the oncologic outcomes in patients with endometrial carcinoma (EC) and atypical endometrial hyperplasia (AEH) receiving fertility-preserving treatment. Methods: Patients with EC and AEH undergoing progestin-based fertility-preserving treatment and receiving molecular classification as well as key oncogenes test at Obstetrics and Gynecology Hospital, Fudan University from January 2021 to March 2023 were reviewed. Hysteroscopic lesion resection and endometrial biopsy were performed before initiating hormone therapy and every 3 months during the treatment to evaluate the efficacy. The risk factors which had impact on the treatment outcomes in EC and AEH patients were further analyzed. Results: Of the 171 patients analyzed, the median age was 32 years, including 86 patients with EC and 85 patients with AEH. The distribution of molecular classification was as follows: 157 cases (91.8%) were classified as having no specific molecular profile (NSMP); 9 cases (5.3%), mismatch repair deficient (MMR-d); 3 cases (1.8%), POLE-mutated; 2 cases (1.2%), p53 abnormal. No difference was found in the cumulative 40-week complete response (CR) rate between the patients having NSMP or MMR-d (61.6% vs 60.0%; P=0.593), while the patients having MMR-d had increased risk than those having NSMP to have recurrence after CR (50.0% vs 14.4%; P=0.005). Multi-variant analysis showed PTEN gene multi-loci mutation (HR=0.413, 95%CI: 0.259-0.658; P<0.001) and PIK3CA gene mutation (HR=0.499, 95%CI: 0.310-0.804; P=0.004) were associated with a lower cumulative 40-week CR rate, and progestin-insensitivity (HR=3.825, 95%CI: 1.570-9.317; P=0.003) and MMR-d (HR=9.014, 95%CI: 1.734-46.873; P=0.009) were independent risk factors of recurrence in EC and AEH patients. Conclusions: No difference in cumulative 40-week CR rate is found in the patients having NSMP or MMR-d who received progestin-based fertility-preserving treatment, where the use of hysteroscopy during the treatment might be the reason, while those having MMR-d have a higher risk of recurrence after CR. Oncogene mutation of PTEN or PIK3CA gene might be associated with a lower response to progestin treatment. The molecular profiles help predict the fertility-preserving treatment outcomes in EC and AEH patients.

Comprehensive assessment of mismatch repair and microsatellite instability status in molecular classification of endometrial carcinoma

Objective: To explore the concordance and causes of different mismatch repair (MMR) and microsatellite instability (MSI) detection results in endometrial carcinoma (EC) molecular typing. Methods: A total of 214 EC patients diagnosed from January 2021 to April 2023 were selected at the Department of Pathology, Peking University Third Hospital. The immunohistochemistry (IHC) results of MMR protein were reviewed. Tumor specific somatic mutations, MMR germline mutations, microsatellite scores and tumor mutation burden (TMB) were detected by next-generation sequencing (NGS) with multi-gene panel. Methylation-specific PCR was used to detect the methylation status of MLH1 gene promoter in cases with deficient MLH1 protein expression. In cases with discrepant results between MMR-IHC and MSI-NGS, the MSI status was detected again by PCR (MSI-PCR), and the molecular typing was determined by combining the results of TMB and MLH1 gene promoter methylation. Results: (1) In this study, there were 22 cases of POLE gene mutation subtype, 55 cases of mismatch repair deficient (MMR-d) subtype, 29 cases of p53 abnormal subtype, and 108 cases of no specific molecular profile (NSMP). The median age at diagnosis of MMR-d subtype (54 years old) and the proportion of aggressive histological types (40.0%, 22/55) were higher than those of NSMP subtype [50 years old and 12.0% (13/108) respectively; all P<0.05]. (2) Among 214 patients, MMR-IHC test showed that 153 patients were mismatch repair proficient (MMR-p), 49 patients were MMR-d, and 12 patients were difficult to evaluate directly. MSI-NGS showed that 164 patients were microsatellite stable (MSS; equal to MMR-p), 48 patients were high microsatellite instability (MSI-H; equal to MMR-d), and 2 patients had no MSI-NGS results because the effective sequencing depth did not meet the quality control. The overall concordance between MMR-IHC and MSI-NGS was 94.3% (200/212). All the 12 discrepant cases were MMR-d or subclonal loss of MMR protein by IHC, but MSS by NGS. Among them, 10 cases were loss or subclonal loss of MLH1 and (or) PMS2 protein. Three discrepant cases were classified as POLE gene mutation subtype. In the remaining 9 cases, 5 cases and 3 cases were confirmed as MSI-H and low microsatellite instability (MSI-L) respectively by MSI-PCR, 6 cases were detected as MLH1 gene promoter methylation and 7 cases demonstrated high TMB (>10 mutations/Mb). These 9 cases were classified as MMR-d EC. (3) Lynch syndrome was diagnosed in 27.3% (15/55) of all 55 MMR-d EC cases, and the TMB of EC with MSH2 and (or) MSH6 protein loss or associated with Lynch syndrome [(71.0±26.2) and (71.5±20.1) mutations/Mb respectively] were significantly higher than those of EC with MLH1 and (or) PMS2 loss or sporadic MMR-d EC [(38.2±19.1) and (41.9±24.3) mutations/Mb respectively, all P<0.01]. The top 10 most frequently mutated genes in MMR-d EC were PTEN (85.5%, 47/55), ARID1A (80.0%, 44/55), PIK3CA (69.1%, 38/55), KMT2B (60.0%, 33/55), CTCF (45.5%, 25/55), RNF43 (40.0%, 22/55), KRAS (36.4%, 20/55), CREBBP (34.5%, 19/55), LRP1B (32.7%, 18/55) and BRCA2 (32.7%, 18/55). Concurrent PTEN, ARID1A and PIK3CA gene mutations were found in 50.9% (28/55) of MMR-d EC patients. Conclusions: The concordance of MMR-IHC and MSI-NGS in EC is relatively high.The discordance in a few MMR-d EC are mostly found in cases with MLH1 and (or) PMS2 protein loss or MMR protein subclonal staining caused by MLH1 gene promoter hypermethylation. In order to provide accurate molecular typing for EC patients, MLH1 gene methylation, MSI-PCR, MMR gene germline mutation and TMB should be combined to comprehensively evaluate MMR and MSI status.

RISK FACTORS AND EARLY SIGNS OF CRITICAL CONDITIONS IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA ADMITTED TO THE INTENSIVE CARE UNIT

Relevance: Acute lymphoblastic leukemia (ALL) is the most common cancer among children, accounting for nearly a quarter of all childhood cancers.&#x0D; The study aimed to determine the risk factors and signs of critical conditions in children with acute lymphoblastic leukemia admitted to an intensive care unit (ICU).&#x0D; Methods: The approach used was a systematic review. Data was collected from sources published in 2019-2023. Four cohort studies, four retrospective analyses, two literature reviews, one case-control study, and one case study were included in this systematic review.&#x0D; Results: The prognosis in pediatric ALL depends on the initial number of blast cells in the peripheral blood. Patients with B-cell precursor acute lymphoblastic leukemia (BCP ALL) and low blast cell numbers survived better than patients with T-cell acute lymphoblastic leukemia (T-ALL) and low cell count. IL1B and NLRP1 genetic polymorphisms enhanced ALL risk and reduced infectious comorbidity. However, these gene polymorphisms must be confirmed in juvenile leukemia. KRAS, FLT3, NRAS, PTPN11, KMT2D, PTEN, and NOTCH1 gene mutations affected pediatric ALL patient features and treatment results. These mutations demonstrate the relevance of genetic profiling in risk classification and tailored management. Gene variations and availability of effective medication contributed. Pediatric BCP-ALL patients with the PAX5P80R mutation had worse 5-year overall survival, higher white blood cell counts, male preponderance, and more genetic abnormalities. Pediatric BCP-ALL focused on genetic analysis and risk stratification. Children of African American and European American ancestry showed varied incidence, recurrence, and outcome rates for ALL. African American children exhibited lower incidence but greater recurrence rates and poorer prognosis than European American children.&#x0D; Conclusion: Risk factors for these patients’ admission to ICU include comorbidities, infectious diseases, hypoxia, and hemodynamic instability, as well as age and baseline white blood cell count at diagnosis.

A young Female of Cowden Syndrome Presenting with Lhermitte- Duclos Disease: A Case Study

Cowden Syndrome (CS) is a rare autosomal dominant inherited genetic disorder due to germline mutations in the phosphatase and tensing homologue (PTEN) tumor suppressor gene in chromosome 10 characterized by multiple hamartomata’s lesions of ectodermal, mesodermal and endodermal origin. Lhermitte-Duclos Disease (LDD), or dysplastic gangliocytoma, which is a benign hamartomata’s condition involving the cerebellum with less than 300 cases reported in the literature. Previous studies suggest an association between CS and LDD. We present here a case of a 28-year female patient presented at the emergency department of our hospital with severe headache associated with vertigo, vomiting &amp; cerebellar ataxia. Papilledema was noted on fundoscopy. Non-attenuating hypodense mass lesion in posterior fossa was found in CT scan. MRI scan T1WI film revealed mixed intensity posterior fossa lesion and T2WI film revealed inhomogeneous hyperintense lesion with almost preserved cerebellar cortical striations. USG revealed numerous polyps in the gallbladder with cholelithiasis. Her facial skin has extensive trichilemmoma. Her symptoms improved after excision of posterior fossa lesion through suboccipital craniectomy and histopathology revealed dysplastic cerebellar gangliocytoma i.e., Lhermitte-Duclos disease. Using the Cleveland Clinic Adult Clinical Scoring for PTEN Testing, the patient had an 82-98% chance for a PTEN gene mutation. Finally, she along with her family was adequately counseled and was advised for regular screening and monitoring. Bang. J Neurosurgery 2022; 12(1): 41-46

The Association of PTEN Gene Mutations with the Breast Cancer Risk: A Systematic Review and Meta-analysis.

Breast cancer (BC) is the most common malignancy in women in western countries. A significant part of malignant cases is caused by genetic mutation. Mutations in the gene phosphatase and tensin homologue deleted on chromosome (PTEN) have been proven in various malignancies. The present study was conducted with the aim of investigating the prevalence of BC due to PTEN gene mutation, as well as estimating the chance of developing BC due to the occurrence of PTEN gene mutation. The present study was conducted using a systematic review method based on PRISMA 2020 statements. The search was done in PubMed, Web of Science (WOS), Scopus, and direct scientific databases. The search was performed using the keywords breast cancer, breast malignancy, PTEN, polymorphism, mutation, variant, and their equivalents. Statistical analysis was performed using the second version of Comprehensive Meta-Analysis Software. A total of 2138 articles were collected. After removing duplicate articles, checking the title and abstract, and then checking the full text of the documents, finally 64 articles were approved and entered the systematic review process. Analysis of these studies with a sample size of 231,179 showed the prevalence of breast cancer patients with PTEN mutations. The combined results of 64 studies showed that the prevalence of PTEN mutations has a 3.3 (95% CI 2.2-5) in BC patients, and an analysis of 6 studies showed that the odds ratio of developing BC due to PTEN mutation is 3.7 (95% CI 1.1-11.9). The results of this study show that mutation in the PTEN gene increases the chance of developing BC. However, it was found that a small part of patients gets BC due to the occurrence of mutation in this gene.

Novel anti-PTEN C2 domain monoclonal antibodies to analyse the expression and function of PTEN isoform variants.

PTEN is a major tumor suppressor gene frequently mutated in human tumors, and germline PTEN gene mutations are the molecular diagnostic of PTEN Hamartoma Tumor Syndrome (PHTS), a heterogeneous disorder that manifests with multiple hamartomas, cancer predisposition, and neurodevelopmental alterations. A diversity of translational and splicing PTEN isoforms exist, as well as PTEN C-terminal truncated variants generated by disease-associated nonsense mutations. However, most of the available anti-PTEN monoclonal antibodies (mAb) recognize epitopes at the PTEN C-terminal tail, which may introduce a bias in the analysis of the expression of PTEN isoforms and variants. We here describe the generation and precise characterization of anti-PTEN mAb recognizing the PTEN C2-domain, and their use to monitor the expression and function of PTEN isoforms and PTEN missense and nonsense mutations associated to disease. These anti-PTEN C2 domain mAb are suitable to study the pathogenicity of PTEN C-terminal truncations that retain stability and function but have lost the PTEN C-terminal epitopes. The use of well-defined anti-PTEN mAb recognizing distinct PTEN regions, as the ones here described, will help to understand the deleterious effects of specific PTEN mutations in human disease.

Potential Role of VHL, PTEN, and BAP1 Mutations in Renal Tumors.

The genetic profiling of renal tumors has revealed genomic regions commonly affected by structural changes and a general genetic heterogeneity. The VHL, PTEN, and BAP1 genes are often mutated in renal tumors. The frequency and clinical relevance of these mutations in renal tumors are still being researched. In our study, we investigated VHL, PTEN, and BAP1 genes and the sequencing of 24 samples of patients with renal tumors, revealing that VHL was mutated at a noticeable frequency (25%). Six of the investigated samples showed mutations, and one genetic polymorphism (rs779805) was detected in both heterozygote and homozygote forms. PTEN gene mutation was observed in only one sample, and one specimen showed genetic polymorphism. In the case of the BAP1 gene, all of the samples were wild types. Interestingly, VHL mutation was detected in two female patients diagnosed with AML and in one with oncocytoma. We assume that VHL or PTEN mutations may contribute to the development of human renal cancer. However, the overall mutation rate was low in all specimens investigated, and the development and prognosis of the disease were not exclusively associated with these types of genetic alterations.

Neuropathological signatures revealed by transcriptomic and proteomic analysis in Pten-deficient mouse models

PTEN hamartoma tumour syndrome is characterised by mutations in the human PTEN gene. We performed transcriptomic and proteomic analyses of neural tissues and primary cultures from heterozygous and homozygous Pten-knockout mice. The somatosensory cortex of heterozygous Pten-knockout mice was enriched in immune response and oligodendrocyte development Gene Ontology (GO) terms. Parallel proteomic analysis revealed differentially expressed proteins (DEPs) related to dendritic spine development, keratinisation and hamartoma signatures. However, primary astrocytes (ASTs) from heterozygous Pten-knockout mice were enriched in the extracellular matrix GO term, while primary cortical neurons (PCNs) were enriched in immediate-early genes. In ASTs from homozygous Pten-knockout mice, cilium-related activity was enriched, while PCNs exhibited downregulation of forebrain neuron generation and differentiation, implying an altered excitatory/inhibitory balance. By integrating DEPs with pre-filtered differentially expressed genes, we identified the enrichment of traits of intelligence, cognitive function and schizophrenia, while DEPs in ASTs were significantly associated with intelligence and depression.

PTEN gen polimorfizmleri, protein seviyeleri ve endometrium kanseri ilişkisi: Hastane bazlı vaka-kontrol çalışması

Association of PTEN Gene Polymorphisms, Protein Levels and Endometrial Cancer: A Hospital-Based Case-Control Study &#x0D; &#x0D; Emine Yagci1, Hikmet Melike Ozturk1, Tufan Oge2, Cansu Ozbayer3, Hulyam Kurt1&#x0D; 0000-0003-2179-1318, 0000-0002-1951-9713,0000-0002-1120-1874, 0000-0003-2433-9925&#x0D; &#x0D; 1Eskisehir Osmangazi University, Faculty of Medicine, Department of Medical Biology, Eskisehir, Turkey.&#x0D; 2 Eskisehir Osmangazi University, Faculty of Medicine, Department of Gynecology, Eskisehir, Turkey.&#x0D; 3 Kutahya Health Sciences University, Medical Faculty, Department of Medical Biology, Kutahya, Turkey.&#x0D; &#x0D; Corresponding Author: Emine Yagci, Telephone: +90 (222) 2392979/4598, e-mail adress: eminetsci@gmail.com&#x0D; Abstract&#x0D; Endometrial cancer is a type of cancer that develops in the inner lining of the uterus, called the endometrium. After breast, lung, and colon cancer, endometrial cancer is the most prevalent malignancy of the female genital system in industrialized nations like North America and Europe.&#x0D; Phosphatase and Tensin homolog (PTEN), deleted on chromosome 10, is a tumor suppressor gene located on chromosome 10q23.31, which encodes a 403 amino acid protein with both lipid and protein phosphatase activities. One of the most common genetic abnormalities identified in human malignancies are somatic mutations in the PTEN gene. The tumor suppressor activity of the PTEN enzyme is reduced or completely lost as a result of PTEN gene mutations. Considering this information, it is thought that PTEN gene polymorphisms may be associated with the pathogenesis of the disease. The purpose of our study is to determine the relationship between functional PTEN polymorphisms IVS4 (–/+) and -9 C/G and endometrial cancer.&#x0D; DNAs belonging to 63 endometrial cancer patients and 63 control individuals were genotyped by PCR-RFLP method for 2 genetic variants of PTEN IVS4 (–/+) and -9 C/G gene. The expression level of PTEN protein was measured by the Elisa method from serum samples. Our results were evaluated with appropriate statistical methods.&#x0D; As a result of our study, no statistically significant difference was found in the risk of endometrial cancer and genotype frequencies of –9 C/G and IVS4 (-/+) variants (p&gt; 0.05). It was detected that the serum level of PTEN lessened significantly in patients with endometrial cancer in comparison to the control (p

PD04-03 GENETIC AND PATHWAY ALTERATIONS OF PROSTATE CANCER: FROM LOCALIZED TO METASTATIC PROSTATE CANCER

You have accessJournal of UrologyCME1 Apr 2023PD04-03 GENETIC AND PATHWAY ALTERATIONS OF PROSTATE CANCER: FROM LOCALIZED TO METASTATIC PROSTATE CANCER Chang Eil Yoon, Seung Ah Rhew, Hyeok Jae Kwon, Dongho Shin, and Ji Youl Lee Chang Eil YoonChang Eil Yoon More articles by this author , Seung Ah RhewSeung Ah Rhew More articles by this author , Hyeok Jae KwonHyeok Jae Kwon More articles by this author , Dongho ShinDongho Shin More articles by this author , and Ji Youl LeeJi Youl Lee More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although prostate cancer is one of the most commonly diagnosed male cancer, because of it’s heterogeneity the treatment options are limited and the prognosis varies widely. Recently, interest in genetic analysis and targeted therapy has been increasing. In particular, Mutation in DNA repair pathways, such as BRCA1/2 genes, has been found to be associated with poor prognosis. Accordingly, the purpose of this study was to identify genetic mutations in patients with localized and metastatic prostate cancer, and to analyze the association between these genes and each patient's clinical course. METHODS: We analyzed 74 patients diagnosed with prostate cancer. Tissue specimens were obtained from prostate biopsy or surgical excision, and were analyzed through Next-generation sequencing at Seoul St. Mary's Hospital between July 1, 2021 and September 31, 2022. We retrospectively evaluated baseline characteristics including PSA score, TNM staging, Gleason’s score and the clinical course including additional treatment and biochemical recurrence. RESULTS: The patients are classified as follows: 49 localized prostate cancer and 25 metastatic prostate cancer. The average age of the patients and initial PSA values were 69.8±8.4 years and 155.6±588.1 ng/dL. 8p copy number alteration (24.3%), and SPOP(18.9%), IGF2R (17.6%), BRCA2(12.2%), NOTCH2(10.8%) gene mutations were most frequently detected gene mutations. BRCA2, NOTCH2 mutations showed a significant relationships with high M stage (p=0.041, 0.001 respectively) and high Gleason's score. (p= 0.01, 0.043 respectively. KMT2C (associated with histone methyltransferase) and TP53 (known as Tumor suppressor gene) mutations also showed high frequency (21.6%, 13.5% respectively), with KMT2C frequently found in local prostate cancer (p=0.011) and TP53 frequently found in metastatic prostate cancer (p=0.046). Although the incidence was low, PI3K pathway aberrations including PTEN (4.1%) and PIK3CA (5.4%) gene mutation was identified. Both were associated with high Gleason’s score (p=0.002, 0.048 respectively). CONCLUSIONS: Through genetic analysis of prostate cancer, it was possible to analyze numerous gene mutations, and to find clinically significant mutations. Several genes, such as BRCA2, NOTCH2 and TP53 gene mutations have been found to be associated with advanced prostate cancer. The prognosis of prostate cancer can be predicted by genetic analysis, and the better prognosis can be expected through the application of a proper targeted therapy for each pathway alterations. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e143 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Chang Eil Yoon More articles by this author Seung Ah Rhew More articles by this author Hyeok Jae Kwon More articles by this author Dongho Shin More articles by this author Ji Youl Lee More articles by this author Expand All Advertisement PDF downloadLoading ...

Symphony in the crowd: Key genetic alterations in prostate cancer.

Androgen receptor (AR) signaling have been frequently targeted for treating prostate cancer (PCa). Even though primarily patients receive a good therapeutic outcome by targeting AR signaling axis, eventually it emerges resistance by altering the genetic makeup of prostate cells. However, to develop an effective therapeutic regime, it is essential to recognize key genetic alterations in PCa. The most common genetic alterations that give rise to distinct androgen different differentiation states are gene fusion of TMPRSS2 with ETS family genes, deletion, or mutation of tumor suppressor PTEN and TP53 gene, amplification or splicing of AR, altered DNA repair genes. In this review, we describe key genes and genetic changes that have been recognized to contribute to altered prostate environment.

PTEN mutation predicts unfavorable fertility preserving treatment outcome in the young patients with endometrioid endometrial cancer and atypical hyperplasia.

This study aimed to investigate the impact of molecular classification and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment in the patients with endometrioid endometrial cancer (EEC) and endometrial atypical hyperplasia (EAH). This is a single-center retrospective study. A total of 135 patients with EEC and EAH receiving fertility-preserving treatment and molecular classification were reviewed. The distribution of the four types of molecular classification was described. The impact of non-specific molecular profile (NSMP), mismatch repair-deficiency (MMRd), and PTEN, KRAS and PIK3CA gene mutation on the outcome of fertility-preserving treatment was analyzed. Of the patients analyzed, 86.7% (117/136) were classified as having NSMP; 14 (10.4%), MMRd; 1 (0.7%), POLEmut EAH; and 3 (2.2%), p53abn EEC. The patients having NSMP and MMRd achieved similar 16-, 32-, and 48-week complete response rates. The patients harboring tier I and tier II PTEN mutations (PTENmut-Clin) achieved lower cumulative 32-week CR rates than those with PTEN-others (without PTENmut-Clin) (22/47, 46.8% vs. 50/74, 67.6%; p=0.023; odds ratio=0.422; 95% confidence interval [CI]=0.199-0.896). Insulin-resistance (hazard ratio [HR]=0.435; 95% CI=0.269-0.702; p=0.001) and PTENmut-Clin (HR=0.535; 95% CI=0.324-0.885; p=0.015) were independent negative predictors for lower 32-week CR rates. PTENmut-Clin is an independent risk factor for unfavorable fertility-preserving treatment outcomes in the patients with EEC and EAH. The patients with MMRd receiving fertility-preserving treatment achieved outcomes similar to those of the patients with NSMP. The molecular profiles might guide fertility-preserving treatment in the prognosis and clinical decisions.

Functional analysis of PTEN variants of unknown significance from PHTS patients unveils complex patterns of PTEN biological activity in disease.

Heterozygous germline mutations in PTEN gene predispose to hamartomas and tumors in different tissues, as well as to neurodevelopmental disorders, and define at genetic level the PTEN Hamartoma Tumor Syndrome (PHTS). The major physiologic role of PTEN protein is the dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), counteracting the pro-oncogenic function of phosphatidylinositol 3-kinase (PI3K), and PTEN mutations in PHTS patients frequently abrogate PTEN PIP3 catalytic activity. PTEN also displays non-canonical PIP3-independent functions, but their involvement in PHTS pathogeny is less understood. We have previously identified and described, at clinical and genetic level, novel PTEN variants of unknown functional significance in PHTS patients. Here, we have performed an extensive functional characterization of these PTEN variants (c.77 C > T, p.(Thr26Ile), T26I; c.284 C > G, p.(Pro95Arg), P95R; c.529 T > A, p.(Tyr177Asn), Y177N; c.781 C > G, p.(Gln261Glu), Q261E; c.829 A > G, p.(Thr277Ala), T277A; and c.929 A > G, p.(Asp310Gly), D310G), including cell expression levels and protein stability, PIP3-phosphatase activity, and subcellular localization. In addition, caspase-3 cleavage analysis in cells has been assessed using a C2-domain caspase-3 cleavage-specific anti-PTEN antibody. We have found complex patterns of functional activity on PTEN variants, ranging from loss of PIP3-phosphatase activity, diminished protein expression and stability, and altered nuclear/cytoplasmic localization, to intact functional properties, when compared with PTEN wild type. Furthermore, we have found that PTEN cleavage at the C2-domain by the pro-apoptotic protease caspase-3 is diminished in specific PTEN PHTS variants. Our findings illustrate the multifaceted molecular features of pathogenic PTEN protein variants, which could account for the complexity in the genotype/phenotype manifestations of PHTS patients.

A prognostic risk model for glioma patients by systematic evaluation of genomic variations.

The overall survival rate of gliomas has not significantly improved despite new effective treatments, mainly due to tumor heterogeneity and drug delivery. Here, we perform an integrated clinic-genomic analysis of 1, 477 glioma patients from a Chinese cohort and a TCGA cohort and propose a potential prognostic model for gliomas. We identify that SBS11 and SBS23 mutational signatures are associated with glioma recurrence and indicate worse prognosis only in low-grade type of gliomas and IDH-Mut subtype. We also identify 42 genomic features associated with distinct clinical outcome and successfully used ten of these to develop a prognostic risk model of gliomas. The high-risk glioma patients with shortened survival were characterized by high level of frequent copy number alterations including PTEN, CDKN2A/B deletion, EGFR amplification, less IDH1 or CIC gene mutations, high infiltration levels of immunosuppressive cells and activation of G2M checkpoint and Oxidative phosphorylation oncogenic pathway.

S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway.

Sorafenib is currently the first-line treatment for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a significant challenge. Aberrant AKT signaling activation is a crucial mechanism driving sorafenib resistance in HCC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a vital role in antitumor immune responses. In this study, we demonstrate that aberrant PCSK9 upregulation promotes cell proliferation and sorafenib resistance in HCC by inducing AKT-S473 phosphorylation. After palmitoylation at cysteine 600, the binding affinity between PCSK9 and tensin homolog (PTEN) is dramatically increased, inducing lysosome-mediated PTEN degradation and subsequent AKT activation. We identify zinc finger DHHC-type palmitoyltransferase 16 (ZDHHC16) as a palmitoyltransferase that promotes PCSK9 palmitoylation at cysteine 600. We also develop a biologically active PCSK9-derived peptide that competitively inhibits PCSK9 palmitoylation, suppressing AKT phosphorylation and augmenting the antitumor effects of sorafenib in HCC.