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Cowden syndrome (CS) is a rare disease that was first described in 1963 and later included in the large group of genodermatoses. It is the most common syndrome among the PTEN-associated hamartomatous tumor syndromes (PHTS). CS has an autosomal dominant inheritance pattern, with increased penetrance and variable expressivity, making early diagnosis difficult. Mutations in the PTEN gene (phosphatase and TENsin homolog) are involved in its pathogenesis, involving many organs and systems originating in the three embryonic layers (ectodermum, endodermum, and mesodermum). The consequence is the development of hamartomatous lesions in various organs (brain, intestines, thyroid, oropharyngeal cavity, colon, rectum, etc.). Multiple intestinal polyps are common in patients with CS, being identified in over 95% of patients undergoing colonoscopy. The authors describe the case of a patient who presented the first signs of the disease at 3 ½ years (tonsil polyp) but was diagnosed only at the age of 20 following a colonoscopy that revealed hundreds of intestinal polyps, suggesting further molecular testing. A heterozygous frameshift mutation was identified in the PTEN gene, classified as a potentially pathogenic variant (c.762del.p(Val255*)). The authors present this case to highlight the path taken by the patient from the first symptoms to the diagnosis and to emphasize the clinical aspects of this mutational variant that have still not been identified in other patients with this syndrome. [ABSTRACT FROM AUTHOR]

Objectives: Recognizing preoperative characteristics of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is important for clinical management. Therefore, we assessed presurgical NIFTP molecular profiles using fine-needle aspiration (FNA) material.Methods: Presurgical FNA reports of 39 surgically confirmed NIFTP cases from January 2013 through May 2017 were assessed for Afirma and ThyroSeq results.Results: Twenty-one of 39 NIFTP nodules were preoperatively tested with Afirma with two benign and 19 suspicious results. Twenty-seven of 39 nodules were tested with ThyroSeq (nine of 39 had both Afirma and Thyroseq): 18 (67%) had RAS mutations (13 NRAS, four HRAS, one KRAS), and three of 18 had multiple alterations (NRAS + TP53, n = 1; NRAS + PTEN, n = 2). BRAF T599_R603 + EIF1AX mutation (n = 1), PTEN mutation (n = 1), MET overexpression (n = 1), PAX8/PPARG fusion (n = 3), and THADA/IGF2BP3 fusion (n = 3) comprised the remainder.Conclusions: NIFTP cases most commonly displayed suspicious Afirma results and RAS mutations on ThyroSeq, lacking aggressive/BRAF-V600E-like mutations. While NIFTP remains a surgical entity, the lack of aggressive/BRAF-V600E-like mutations can aid in determining the extent of surgery. [ABSTRACT FROM AUTHOR]

PTEN hamartoma tumor syndrome (PHTS) refers to a group of clinical conditions caused by germline mutations in the PTEN tumor suppressor gene. Increasing evidence has documented that PHTS may be associated with a broader spectrum of structural brain abnormalities, including dysplastic gangliocytoma of the cerebellum, brain tumors, vascular malformations, white matter abnormalities, dilated perivascular spaces and cortical dysplasia. We report a PTEN -mutated child showing macrocephaly, mild intellectual disability and epilepsy symptomatic of right occipital polymicrogyria, who also developed Chiari I Malformation (CIM) that repeatedly required surgical correction. We suppose that the association between PHTS and CIM could be not coincidental, thus extending the spectrum of neurological manifestations of PHTS and highlighting the role of brain MRI in the management of PHTS patients. We suggest that genes within the RAS-MAPK and PI3-AKT pathways might have a significant role in the pathogenesis of CIM in such patients. [ABSTRACT FROM AUTHOR]

Background: Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with a high risk of malignancy in childhood. This syndrome is an autosomal dominant cancer predisposing syndrome due to a germline mutation in the TP53 tumor suppressor gene. Methods: In this study, a representative family case of Li-Fraumeni syndrome is described. The proband of this family was a 43-year-old male who had osteosarcoma of the mandible and a positive family history of cancer. His mother died at the age of 29 of brain cancer; his sister died at the age of 18 of breast cancer; his brother died at the age of 36 of liver cancer; and another sister of his died at the age of 16 of leukemia. Complete sequence analysis of the TP53 and PTEN genes was performed in this family. We used standard diagnostic tools such as sequencing and multiplex ligation-dependent probe amplification (MLPA) to analyze these two genes in this family. The exons and flanking exon-intron junctions of the TP53 and PTEN genes were sequenced. Results: We detected a germline mutation in the TP53 gene in this family that was previously reported as somatic mutation in LFS in the catalogue of somatic mutations in cancer (COSMIC). In addition, according to the International Agency for Research of Cancer (IARC) database, a 19-year-old male patient with sarcoma was recently reported to have this germline mutation. We also found two new IVS variations in the PTEN gene, one of which can be a suggestive evidence of an effect on the splicing of PTEN. Conclusion: Genomic modifications for tumor risk and genotype-phenotype correlations in LFS are still to be identified. We believe every new finding in this area can provide new insights into the pathogenesis and progression of Li-Fraumeni syndrome. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most frequently diagnosed cancers in China, but the etiology and mode of carcinogenesis of this disease remain poorly understood. The phosphatase and tensin homolog deleted from chromosome 10 (PTEN) with putative tumor suppressing is frequently mutated in many cancers.Aims: The aim of this study was to investigate whether there exists a mutation in the PTEN gene of the ESCC cells, and the effects of the wild type and mutated PTEN genes on the proliferation and apoptosis of the ESCC cells.Methods: The wild type and mutated PTEN genes were cloned from human placenta and ESCC cells, respectively, and their effects on the proliferation and apoptosis of the ESCC cells were investigated. Also, the relationship between the PTEN gene status and sensitivity of the EC9706 cells to cisplatin was determined in the xenografts of nude mice.Results: There were mutations in the PTEN gene from ESCC cells. The proliferation of the EC9706 cells was clearly inhibited by the wild type PTEN gene, but not by the mutated PTEN gene in vitro. Furthermore, the wild type PTEN gene inhibited the growth of transplantable tumor, induced cell apoptosis, and improved the sensitivity of the EC9706 cells to cisplatin in vivo.Conclusion: The findings of the present study demonstrate that there are mutations in the PTEN gene of the ESCC cells and that the wild type PTEN gene has important effects on the ESCC cells in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Background: In 1997 MMAC1 or the PTEN gene, was identified as a tumor suppressor gene on the long arm of chromosome 10.PTEN involves in the balance between proliferation, and differentiation, apoptosis and regulation of angiogenesis, and eventually mutation in this gene causes a strong potential for tumorigenesis cells. This study is the first report of the correlation between PTEN gene mutations with histological markers and the age of Glioblastoma patients with the purpose of using it to remove diagnostic ambiguities and identify the type of glioma. Methods: In this study, we screened for PTEN mutations in exon 4-8 in glioblastoma patients in Isfahanian population. Genomic DNA ware extract from 60 formalin fixed frozen glioblastoma tumors, 4 normal tissue sample and 60 blood samples. Mutational analysis was performed using polymerase chain reaction, single strand conformation polymorphism (SSCP) and heteroduplex mobility techniques. In order to augment the accuracy, the experiments (PCR, SSCP, HMA) was repeated at least 3 times. The correlation between PTEN mutations with Clinical Pathologic markers (pleomorphism, Necrosis, cellularity, mitosis and endothelial proliferation) in Glioblastoma tumors and the age of patients were investigated With the help of statistical tests (t-test, Manvitni and Fisher's exact test). Results: A total of 4 mutations (7%) were detected in 60 glioblastoma tumors. In this study, there was no significant relation between clinic pathologic markers and PTEN mutations (p-value > 0.05). Our data shows a positive association between the age of onset of cancer and PTEN mutations (p-value < 0.001) . Conclusion: Our results suggested that PTEN mutations are Low in Iranian glioblastoma patients. People with PTEN mutations are more likely to develop glioblastoma before the age of 20. [ABSTRACT FROM AUTHOR]

Somatic mutations of the phosphatase and tensin ( PTEN) gene have been frequently detected in many types of human cancer. However, germline mutations can determine multiple hamartoma syndromes and, as more recently ascertained, syndromes clinically characterized by autism associated with macrocephaly. To determine whether germline mutations of PTEN may lead to different phenotypes, we screened all the nine exons of the PTEN gene in 40 patients with neurodevelopmental disorders, with or without features of autism spectrum disorder, associated with macrocephaly. Three novel de novo missense mutations were found (p.H118P, p.Y176C, p.N276S) in two severely mentally retarded patients with autism and in a subject with neurodevelopmental disorders without autistic features. Our results provide evidence that PTEN germline mutations may sustain a more wide phenotypical spectrum than previously suggested. [ABSTRACT FROM AUTHOR]

Background: The phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays an important role in thyroid tumorigenesis and progression. Genetic alterations, particularly PIK3CA amplification and mutations and ras mutations, are the major cause of aberrant activation of this pathway in thyroid tumors. Epigenetic silencing of the PTEN gene, a negative regulator of the PI3K/AKT pathway, also occurs in thyroid tumors, but its relationship with genetic alterations in this pathway is unclear.Methods: By using quantitative methylation-specific polymerase chain reaction, the authors examined PTEN methylation and its relationship with genetic alterations in the PI3K/AKT pathway in various types of thyroid tumors.Results: The authors found PTEN methylation to become progressively higher from benign thyroid adenoma to follicular thyroid cancer and to aggressive anaplastic thyroid cancer, which harbored activating genetic alterations in the PI3K/AKT pathway correspondingly with a progressively higher prevalence. The association of PTEN methylation was seen with both overall genetic alterations and individual genetic alterations, particularly PIK3CA alterations and ras mutations, in the PI3K/AKT pathway within each of the 3 types of thyroid tumors. In contrast, no such relationship was observed for the tumor suppressor gene RASSF1A.Conclusions: The authors found an interesting association of PTEN methylation with the activating genetic alterations in the PI3K/AKT pathway in thyroid tumors. This finding is consistent with a model in which aberrant methylation and hence silencing of the PTEN gene, which coexists with activating genetic alterations of the PI3K/AKT pathway, may enhance the signaling of this pathway aberrantly activated by genetic alterations and hence contribute to the progression of thyroid tumors. Cancer 2008. [ABSTRACT FROM AUTHOR]

Background.Lhermitte-Duclos Disease (LDD) is an infrequent cerebellar disorder characterized by focal or diffuse enlargement of cerebellar folia presenting as a slowly growing mass in the posterior fossa. Over the past decade its association with Cowden disease (CD) has been recognized with increasing frequency. This latter disease is a genetic condition leading to the presence of multiple hamartomas and neoplasias which affect mainly the skin, thyroid, breast and genito-urinary and gastro-intestinal tracts. It has even been hypothesized that LDD and CD constitute a single entity. This work is aimed to analyse to what extent this association was present in patients treated for LDD at our institution.Method. We reviewed the medical records of five patients and performed clinical studies for CD manifestations, among them, genetic investigation for PTEN mutations. The International Cowden Consortium Criteria were applied for the diagnosis of CD.Findings. Four of the five patients treated for LDD were also diagnosed of CD. The genetic study found PTEN mutations in two of them.Interpretation. LDD has been found to be closely related to CD in this series, in accordance with previous literature. However, the absence of CD diagnosis in one of the patients led us to suggest that, despite the strong association between these two diseases, LDD can also appear as an isolated condition. [ABSTRACT FROM AUTHOR]

Background The utility of next generation sequencing (NGS) is rapidly evolving within our medical practice with various applications. The 100K Genomes Project was established to sequence 100 000 genomes from NHS patients with cancer or rare diseases, and to date actionable findings have been found for approximately 50% of cancer cases. Data from the 100K Genomes Project were reviewed at Guy's Hospital Molecular Tumour Board (MTB). Methods Whole genome sequencing (WGS) was performed for the 100K Genomes Project and Genomics England using an Illumina platform. Results Between December 2016 and August 2018, 66 patients with colorectal cancer (CRC) were treated with surgery at GSTT. Median age was 68.5 (52-95). Majority were left sided (69%) vs right sided (30%) adenocarcinomas. TNM status was 1.5% / 47% / 37.9% / 13.6% for stage I/II/III/IV respectively. Analyses were performed in FFPE (35.8%) and frozen tissue (64.2%). Median estimated tumour purity was 53.5% (20-100%). Median tumour mutational burden (TMB) was 5.92 (2.94-173.26). Mutational signatures 6, 10 and 15 were found for 8 patients and were associated with high TMB. A total of 557 Domain 1 (actionable) variants (range 1-68) were identified for this cohort. After review in the MTB, at least one clinically relevant actionable variant was identified for 59.7% of the patients; KRAS 37.3%, NRAS 6%, BRAF 11.9%, TP53 70.1%, PIK3CA 35.8%, ATM 17.9%, RICTOR 14.9%, APC and PTEN 11.9% each and mTOR 8.6%. Somatic BRCA1 and BRCA2 variants were found in 7.6% and 12.1% respectively. Further validation was recommended for 9 patients (13.4%). DPYD alterations were identified in 11.9%, but none of the clinically relevant DPYD mutations related to 5FU toxicity were discovered for 2 of the patients that were tested. 9.4% were identified with potentially pathogenic germline variants (7.6% with RAD51D, RAD51C, MUTYH, MSH6 and PMS2 class 4 & 5 variants) and referral to Clinical Genetics was recommended. Conclusions GSTT MTB identified actionable mutations in more than half patients in the CRC cohort, out of whom 14% had alterations that made them eligible for clinical trials. Over 9% had potentially pathogenic germline variants. Our data from this small cohort resemble data in the literature from other MTBs. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Advanced gynecologic cancers have a poor prognosis and constitute a major challenge for adequate treatment strategies. By analyzing and targeting molecular alterations, precision cancer medicine (PCM) may be a viable option for the treatment of advanced gynecologic cancers. Methods In this single center, real-world retrospective analysis of our PCM platform, we describe the molecular profiling of 72 patients diagnosed with different types of metastasized BTC. Tumor samples of the patients were examined by a 162-gene next-generation sequencing (NGS) panel, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and RNA fusion panel. Results In total, we identified 209 molecular aberrations in 72 patients. The ten most frequently alterations were TP53 (n = 42), KRAS (n = 14), PIK3CA (n = 11), PIK3R1 (n = 9), ATR (n = 8), PTEN (n = 8), BRCA1 (n = 6), NF1 (n = 4), NOTCH1 (n = 4), POLE (n = 4) that make up together over half of the molecular alterations (52.6%). BRAF mutations and gene fusions each were observed in two patients. 21 patients were found to have only one mutation and 44 patients had more than one mutation. No mutations were detected in 7 patients. IHC detected expression of p-mTOR and EGFR in 58 and 53 patients, respectively. In over two-thirds (n = 51) of the 72 patients, a targeted therapy was suggested, based on the identified genetic mutations. The most frequently recommended specific treatment was the combination of everolimus with exemestan (n = 19). The median turnaround time from biopsy to discussion in our multidisciplinary tumor board was 20 days. The median turnaround time from biopsy to therapy initiation was 26 days. Conclusions Based on our observations, it seems that PCM might be a feasible treatment approach for advanced gynecologic cancers with limited treatment options. Legal entity responsible for the study Medical University of Vienna. Funding Has not received any funding. Disclosure H. Taghizadeh: Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: Pathogenic PTEN gene mutations are known to cause PTEN tumor hamartoma syndrome. Recent studies also suggest a role for PTEN mutations in the pathogenesis of obesity. No PTEN mutations have been reported among bariatric surgery patients and obesity treatment results are unknown. Since preventive screening for associated tumors is offered to patients with molecular proven PTEN hamartoma tumor syndrome, recognition of this condition in the bariatric surgery clinic is important. Method: We present a patient with morbid obesity who carries a known pathogenic PTEN mutation, identified at the bariatric surgery clinic using an obesity gene panel consisting of 52 obesity–associated genes. We analyzed the weight loss response during the first 3 years after Sleeve Gastrectomy. Results: At 1, 2 and 3 years after surgery, the patient achieved a Total Body Weight Loss of 39.4%, 48.8% and 44.9%, respectively. This corresponds to the results of a control group of 18 female patients with normal genetic test results. Conclusion: Our patient illustrates the importance of recognizing this serious genetic condition for which preventive cancer screening options are available. The positive weight loss results after Sleeve Gastrectomy suggest that this could be a successful treatment option for obesity patients with PTEN mutations. [ABSTRACT FROM AUTHOR]

Recent studies in mammals have suggested that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) - phosphatidylinositol-3, 4, 5-trisphosphate pathway in oocytes might be related to the pathogenesis of premature ovarian failure (POF). The aim of this study was to investigate whether mutations of the PTEN gene are present in women with POF. We analyzed the coding region of the PTEN gene in 20 women with idiopathic POF and 20 normal controls. The PTEN gene was amplified by the polymerase chain reaction using genomic DNA isolated from blood samples. Amplified DNA was analyzed by denaturing gradient gel electrophoresis and direct sequencing. No causative mutation was detected in the coding regions of this gene. Although we found a point variation in exon 7 of one POF patient, this was a single nucleotide polymorphism that has already been reported. [ABSTRACT FROM AUTHOR]