Barrett esophagus (BE) occurs in 1% to 10% of the general population and is believed be precursor esophageal adenocarcinoma (EAC). The incidence EAC has increased 350% last 3 decades without clear etiology. Finding predisposition genes may improve premorbid risk assessment, genetic counseling, management. Genome-wide multiplatform approaches lead identification important BE/EAC development.To identify alleles or mutated associated with BE/EAC.Model-free linkage analyses 21...

The tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome 10) the androgen receptor (AR) play important roles in development progression prostate carcinogenesis. Among many functions, negatively regulates cytoplasmic phosphatidylinositol-3-kinase/AKT anti-apoptotic pathway; nuclear affects cell cycle by also regulating MAPK pathway via cyclin D. Decreased expression is correlated with cancer progression. Over-expression of AR upregulation transcriptional activity...

PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks multiple cancers via dysregulation the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation cell size. Although much known about how intracellular localization cancer lines, we know little...

PTEN, a tumor suppressor phosphatase that dephosphorylates both protein and lipid substrates, is mutated in heritable sporadic breast cancer. Until recently, PTEN-mediated cell cycle arrest apoptosis were thought to occur through its well-documented cytoplasmic activities. We have shown PTEN localizes the nucleus coincident with G0–G1 phases of compartmentalization may regulate progression dependent upon down-regulation cyclin D1. However, mechanism for D1-dependent growth suppression by...

We identified a novel XPC variant, c.2420+5G>A (XPCvar), in siblings with multiple melanomas, inherited alongside c.779+1G>T, which results an absent or disrupted protein. Despite this, they exhibited nucleotide excision repair (NER) deficits comparable to their unaffected parents, suggesting NER-independent tumor suppressor function for XPC. knockdown increased cell proliferation and tumorigenicity vitro without affecting NER. Single-cell RNA sequencing revealed lower Cdkn2a...

Abstract MC1R, a G-protein coupled receptor, triggers ultraviolet light-induced melanin synthesis and DNA repair in melanocytes is implicated the pathogenesis of melanoma. Although widely expressed different tissue types, its function non-cutaneous relatively unknown. Herein, we demonstrate that disruptive MC1R variants associated with melanomagenesis are less frequently found patients several cancers. Further exploration revealed breast cancer shows significantly higher expression than...

Germline and somatic PTEN mutations are found in Cowden syndrome (CS) multiple sporadic malignancies, respectively. function appears to be modulated by subcellular compartmentalization, mislocalization may affect function. We have shown that cellular ATP levels nuclear levels. Here, we examined the ATP-binding capabilities of functional consequences, relevant cancer-associated mutations. mutation analysis CS patients colorectal carcinomas comparative aminoacid were utilized identify motifs....

Germline mutations in the tumor-suppressor gene PTEN predispose to subsets of Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, and autism. Evidence-based classification variants as either deleterious or benign is urgently needed for accurate molecular diagnosis gene-informed genetic counseling. We studied 34 different germline intronic from 61 CS patients, characterized their mRNA processing, analyzed expression downstream readouts P-AKT P-ERK1/2. While we found that many near splice...

Somatic and germline mutations in PTEN (phosphatase tensin homolog deleted on chromosome 10) are found sporadic cancers Cowden syndrome patients, respectively. Recent identification of naturally occurring cancer within the ATP-binding motifs (heretofore referred to as mutations) has revealed that these disrupted subcellular localization tumor-suppressor activity PTEN. However, very little is known about underlying mechanisms tumorigenesis. Here we show impair PTEN's function both...

The tumour suppressor gene PTEN plays an important somatic role in both hereditary and sporadic breast carcinogenesis. While the of PTEN's lipid phosphatase activity, as a negative regulator cytoplasmic phosphatidylinositol-3-kinase/Akt pathway is well known, it now established that exists functions nucleus. Multiple mechanisms regulating subcellular localization have been reported. However none are ubiquitous across multiple cancer cell lines tissue types. We show here adenosine...

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairment in social communication/interaction and inflexible/repetitive behavior. Several lines evidence support genetic factors as predominant cause ASD. Among those autism susceptibility genes that have been identified, the PTEN tumor suppressor gene, initially identified predisposing to Cowden heritable cancer syndrome, was found be mutated subset ASD patients with extreme macrocephaly. However,...

NVP-BEZ235 is a newly developed dual PI3K/mTOR inhibitor, being tested in multiple clinical trials, including breast cancer. selectively induces cell growth inhibition subset, but not all, cancer lines. However, it remains challenge to distinguish between sensitive and resistant tumors, particularly the pretreatment setting. Here, we used ten lines compare sensitivity context of androgen receptor (AR) activation during treatment. We also female SCID mice bearing tumor xenografts investigate...

There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ-CAMTA1 (TC) fusion gene. Here, we aimed to understand regulation of TC using pharmacologic tools and identify vulnerabilities that can potentially be exploited EHE.

Abstract Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with low survival rates in advanced stages. To facilitate timely diagnosis improve outcome, early detection markers (e.g., DNA methylation) are crucial for diagnosis. In a recent publication, epigenome-wide screen revealed set of genes that commonly methylated downregulated head cancers (SEPT9, SLC5A8, FUSSEL18, EBF3, IRX1). Interestingly, these candidates potentially involved the transforming growth factor-β...

Germline mutations in PTEN have been described a spectrum of syndromes that are collectively known as hamartoma tumor syndrome (PHTS). In addition to being mutated the germline PHTS, somatic loss-of-function seen wide range sporadic human tumors. Here, we show evidence upregulated proteasome activity PHTS-derived lymphoblasts, Pten knock-in mice and cell lines expressing missense nonsense mutations. Notably, elevated nuclear occurred cells mislocalized PTEN-K62R mutant, whereas cytosolic was...

Cowden syndrome (CS) is an autosomal dominant disorder that predisposes to breast, thyroid, and other epithelial cancers. Differentiated thyroid carcinoma (DTC), as one of the major component cancers CS, fastest rising incident cancer in USA, most familial all solid tumours. To identify additional candidate genes CS potentially DTC, we analysed a multi-generation CS-like family with papillary (PTC), applying combined linkage-based whole-genome sequencing strategy identified in-frame germline...

The phosphatase and tensin homolog (PTEN) exerts its function, in part, by negatively regulating the well-known phosphatidylinositol-3-kinase/AKT signaling pathway. Previous histological work has suggested that alterations nuclear/cytoplasmic compartmentalization of PTEN may play a role development progression melanoma. In this study, we examined melanoma cell lines correlation with cycle. Studies were performed cells using classic biological techniques. contrast to breast cancer lines,...

Activator protein 2 alpha (AP-2alpha) is involved in a variety of physiological processes. Increased AP-2alpha expression correlates with progression various squamous cell carcinomas, and recent publication found to be overexpressed approximately 70% Head Neck Squamous Cell Carcinoma (HNSCC) patient samples. It was repress transcription the tumor suppressor gene C/CAAT Enhancer Binding Protein (C/EBPalpha), its binding site correlated upstream methylation C/EBPalpha promoter. Therefore, we...

Thyroid cancer is a major component of Cowden syndrome (CS). CS patients with an underlying PTEN mutation (PTEN(mut+)) have 70-fold increased risk developing epithelial thyroid cancer. In contrast, less than 1% sporadic carry germline mutation. Cost-efficient markers capable shortlisting cancers for genetic testing would be clinically useful.Our objective was to analyze the utility patient blood phosphate and tensin homolog deleted on chromosome 10 (PTEN) protein levels in predicting...

Germline mutations in PTEN are associated with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartoma tumor syndrome including Cowden (CS) Cowden-like (CSL) that predisposes to high risks of benign malignant tumors thyroid breast.The objective the study was analyze subcellular pattern phosphorylated (P)-AKT expression nonmedullary cancers from patients investigate whether lack nucleus and/or proper function affect(s) nuclear AKT activity CS patients.In all, 664 CS/CSL were...

Abstract The tumor suppressor C/CAAT enhancer binding protein alpha ( C/EBP α) is a transcription factor involved in cell cycle control and cellular differentiation. A recent study showed that α frequently downregulated head neck squamous carcinoma (HNSCC) by DNA methylation an upstream regulatory region. Here, we investigated how the region disrupts transcriptional regulation of HNSCC. results reveal aberrant correlates with methyl domain repressive histone modifications. This methylated...

Gene transcription is a highly complex and strictly regulated process. RNA polymerase II (Pol II) C-terminal domain (CTD) undergoes massive cycles of phosphorylation dephosphorylation during the process gene transcription. These post-translational modifications CTD provide an interactive platform for various factors required initiation, elongation, termination, co-transcriptional processing. Pol kinases phosphatases are key regulators any deviation may cause genome-wide transcriptional...