UNASSIGNED: The Phosphatase and Tensin Homolog gene (PTEN) is pivotal in regulating diverse cellular processes, including growth, differentiation, proliferation, and cell survival, mainly by modulating the PI3K/AKT/mTOR pathway. Alterations in the expression of the PTEN gene have been associated with epigenetic mechanisms, particularly the regulation by small non-coding RNAs, such as miRNAs. Modifications in the expression levels of miRNAs that control PTEN have been shown to lead to its underexpression. This underexpression, in turn, impacts the PI3K/AKT/mTOR pathway, thereby influencing crucial mechanisms like proliferation and apoptosis, playing an important role in the initiation and progression of prostate cancer (PCa). Thus, we aimed to systematically reviewed available information concerning the regulation of PTEN mediated by miRNA in PCa.
UNASSIGNED: Electronic databases were searched to identify studies assessing PTEN regulation via PCa miRNAs, the search included combination of the words microRNAs, PTEN and prostatic neoplasms. The quality assessment of the articles included was carried out using an adapted version of SYRCLE and CASP tool.
UNASSIGNED: We included 39 articles that measured the relative gene expression of miRNAs in PCa and their relationship with PTEN regulation. A total of 42 miRNAs were reported involved in the development and progression of PCa via PTEN dysregulation (34 miRNAs up-regulated and eight miRNAs down-regulated). Sixteen miRNAs were shown as the principal regulators for genetic interactions leading to carcinogenesis, being the miR-21 the most reported in PCa associated with PTEN down-regulation. We showed the silencing of PTEN could be promoted by a loop between miR-200b and DNMT1 or by direct targeting of PTEN by microRNAs, leading to the constitutive activation of PI3K/AKT/mTOR and interactions with intermediary genes support apoptosis inhibition, proliferation, invasion, and metastasis in PCa.
UNASSIGNED: According to our review, dysregulation of PTEN mediated mainly by miR-21, -20a, -20b, -93, -106a, and -106b up-regulation has a central role in PCa development and could be potential biomarkers for diagnosis, prognostic, and therapeutic targets.

Atherosclerosis is a chronic inflammatory disease of the arterial wall caused by an imbalance of lipid metabolism and a maladaptive inflammatory response. A variety of harmful cellular changes associated with atherosclerosis include endothelial dysfunction, the migration of circulating inflammatory cells to the arterial wall, the production of proinflammatory cytokines, lipid buildup in the intima, local inflammatory responses in blood vessels, atherosclerosis-associated apoptosis, and autophagy. PTEN inhibits the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT)/mammalian target of rapamycin (mTOR) pathway through its lipid phosphatase activity. Previous studies have shown that PTEN is closely related to atherosclerosis. This article reviews the role of PTEN in atherosclerosis from the perspectives of autophagy, apoptosis, inflammation, proliferation, and angiogenesis.

Borderline ovarian tumours (BOTs) show intriguing characteristics distinguishing them from other ovarian tumours. The aim of the systematic review was to analyse the spectrum of molecular changes found in BOTs and discuss their significance in the context of the overall therapeutic approach. The systematic review included articles published between 2000 and 2023 in the databases: PubMed, EMBASE, and Cochrane. After a detailed analysis of the available publications, we qualified for the systematic review: 28 publications on proto-oncogenes: BRAF, KRAS, NRAS, ERBB2, and PIK3CA, 20 publications on tumour suppressor genes: BRCA1/2, ARID1A, CHEK2, PTEN, 4 on adhesion molecules: CADM1, 8 on proteins: B-catenin, claudin-1, and 5 on glycoproteins: E-Cadherin. In addition, in the further part of the systematic review, we included eight publications on microsatellite instability and three describing loss of heterozygosity in BOT. Molecular changes found in BOTs can vary on a case-by-case basis, identifying carcinogenic mutations through molecular analysis and developing targeted therapies represent significant advancements in the diagnosis and treatment of ovarian malignancies. Molecular studies have contributed significantly to our understanding of BOT pathogenesis, but substantial research is still required to elucidate the relationship between ovarian neoplasms and extraneous disease, identify accurate prognostic indicators, and develop targeted therapeutic approaches.

PTEN Hamartoma Tumour Syndrome (PHTS) encompasses diverse clinical phenotypes, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. This autosomal dominant genetic predisposition with high penetrance arises from heterozygous germline variants in the PTEN tumour suppressor gene, leading to dysregulation of the PI3K/AKT/mTOR signalling pathway, which promotes the overgrowth of multiple and heterogenous tissue types. Clinical presentations of CS range from benign and malignant disorders, affecting nearly every system within the human body. CS is the most diagnosed syndrome among the PHTS group, notwithstanding its weak incidence (1:200,000), for which it is considered rare, and its precise incidence remains unknown among other important factors. The literature is notably inconsistent in reporting the frequencies and occurrences of these disorders, adding an element of bias and uncertainty when looking back at the available research. In this review, we aimed to highlight the significant disparities found in various studies concerning CS and to review the clinical manifestations encountered in CS patients. Furthermore, we intended to emphasize the great significance of early diagnosis as patients will benefit from a longer lifespan while being unceasingly advised and supported by a multidisciplinary team.

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.

PTEN hamartoma syndrome (PHTS) is an autosomal dominant disorder characterized by pathogenic variants in the tumor suppressor gene phosphatase and tensin homolog (PTEN). It is associated with an increased risk of muco-cutaneous features, hamartomatous tumors, and cancers. Mosaicism has been found in a few cases of patients with de novo PHTS, identified from blood samples. We report a PHTS patient with no variant identified from blood sample. Constitutional PTEN mosaicism was detected through sequencing of DNA from different tumoral and non-tumoral samples.
Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome.
This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered.

OBJECTIVE: The purpose of this article was to review the association between the ETS-related gene (ERG) and the phosphatase and tensin homolog (PTEN) genes with pathologic parameters of prostate cancer, emphasizing on Gleason score.
METHODS: We performed a PubMed-based search of the literature emphasizing on articles that use pathological techniques, and especially on those that report the use immunohistochemical staining and FISH to investigate the association between ERG and PTEN mutations with the histopathologic parameters of prostate cancer.
RESULTS: ERG expression is frequently marked in patients with prostate cancer, usually due to the occurrence of the TMPRSS2:ERG gene fusion. Although some studies reported a potential link between the expression of ERG and Gleason score, there is no strong evidence supporting this finding. On the contrary, there is more solid evidence correlating loss of PTEN expression with worse prognosis and higher Gleason scores. Few studies correlate the over-expression of ERG gene with the loss of PTEN expression. Finally, PTEN and ERG have been studied as potential therapeutic targets, and several promising results have been reported.
CONCLUSIONS: Although, at some degree, ERG expression seems to be associated with the morphological features of prostate cancer, different studies reported controversial results. However, expression of PTEN is more clearly associated with the pathology and clinical course of the disease. More research is required to elucidate the role of these molecules in the molecular pathology of prostate cancer, as well as their potential use as therapeutic targets.

PTEN hamartoma tumor syndrome (PHTS) comprises a group of rare genetic conditions caused by germline mutations in PTEN gene and characterized by development of both benign and malignant lesions in many body tissues. In this study, we aimed to evaluate the incidence of thyroid findings in both adult and pediatric PHTS patients.
A retrospectively analysis conducted in 19 (13 adult and 6 pediatric) patients with PHTS, all confirmed with genetic testing, observed from 2015 to 2021 at the Fondazione IRCCS Ca\' Granda Ospedale Maggiore Policlinico.
We found a thyroid involvement in 12 adult patients (92%): 11 patients had benign lesions (85%) and the remaining developed a follicular thyroid carcinoma (8.3%). The median age at time of the first available record was 30 years. Among benign lesions, multinodular goiter was the most observed finding (10/11, 91%). Only 1 out of 6 (16%) pediatric patients was diagnosed with a thyroid lesion (unifocal lesion in mild lymphocytic thyroiditis) at the age of 8 years.
Thyroid disorders affected nearly all adult PHTS patients, but a much lower proportion of pediatric patients. We discuss about the natural history of thyroid involvement, age of PHTS clinical onset, and optimized surveillance.

PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy.

Prostate cancer (PC) is mainly known to metastasize to bone, lung and liver, but isolated metastases of prostate cancer, including ductal carcinoma, in the urinary tract are very rare. We describe two patients with nodular masses in the urinary tract (the anterior urethra or the urinary bladder) that were found on cystoscopy during treatment of castration-resistant prostate cancer.
In both cases, the pathological diagnosis from transurethral tumor resection showed that they were androgen indifferent prostate cancer (AIPC), including aggressive variant prostate cancer (AVPC) in Case 1 and treatment-induced neuroendocrine differentiation prostate cancer (NEPC) in Case 2. In Case 1, Loss of genetic heterozygosity (LOH) of BRCA2 and gene amplification of KRAS was identified from the urethra polyps. In Case 2, homozygous deletion was observed in PTEN, and LOH without mutation was observed in RB1.
These are the first reports of two cases of urinary tract metastasis of AIPC.