PATH-22. GENETIC VARIATION BETWEEN IDH MUTANT AND IDH WILD-TYPE GLIOMA

OBJECTIVE The prognosis of IDH mutant glioma was significantly different from that of IDH wild-type glioma. In order to explore the differences between them at the genetic level, we analyzed the genetic results of IDH mutant and IDH wild-type glioma. METHODS This study analyzed the clinical data and genetic results of 45 glioma patients from Jan. 2017 to Dec. 2019, exploring relevant prognostic indicators and the difference in genetic profile between IDH mutant glioma and IDH wild-type glioma. RESULTS 45 patients were included in this study, including 15 IDH mutant glioma patients and 30 IDH wild-type glioma patients. Genetic analysis showed that there was no difference in tumor mutation burden (TMB) and microsatellite instability (MSI) between IDH mutant glioma and IDH wild-type glioma. But somatic mutation between IDH mutant and IDH wild-type glioma was different. The expressions of IDH1, CIC, SYNE1 and TP53 were different in the two groups, among which IDH1 and CIC were more significantly different. Copy number variations (CNV) was also different between IDH mutant glioma and IDH wild-type glioma. STIL occured more frequently in IDH wild-type gliomas. Genetic analysis also showed the difference in variant allel frequence (VAF). IDH mutant gliomas were more likely to be combined with ATRX and TP53 mutations, while IDH wild-type gliomas, in addition to the combination of TP53 mutations, often also combined with the mutations of NF1, BRAF and PTEN. In survival analysis, glioma with IDH mutation has a good prognosis, and IDH wild-type patients have a poor prognosis. In IDH wild-type patients, patients with PTEN mutation have a worse prognosis. CONCLUSION There is an obvious genetic difference between IDH mutation and IDH wild-type glioma, and PTEN mutation is a poor prognostic factor for IDH wild-type patients.

Significance of PTEN Mutational Status Associated Gene Signature in the Progression and Prognosis of Endometrial Carcinoma

BackgroundPTEN mutation had been reported to be involved in the development and prognosis of endometrial carcinoma (EC). However, a prognostic genes signature associated with PTEN mutational status has not been developed. In this study, we aim to conduct a PTEN mutation associated prognostic genes signature for EC.MethodsWe obtained the simple nucleotide variation and transcriptome profiling data from The Cancer Genome Atlas database as training data. Lasso Cox regression algorithm was used to establish PTEN mutation associated prognostic genes signature. The overall survival rate of the high-risk and low-risk groups was determined by Kaplan-Meier (K-M) method. The accuracy of risk score prediction was tested by ROC curve.ResultsK-M curves revealed that the EC patients with PTEN mutation have favorable survival outcome. Differential expression analysis between the EC patients with PTEN mutation and PTEN wild identified 224 differential expression genes (DEGs). Eighty-four DEGs with prognostic value was fitted into least absolute shrinkage and selection operator (LASSO)–Cox analysis and a seven PTEN mutation associated prognostic genes signature with robust prognostic ability was constructed, which was successfully validated in the other two datasets from cBioPortal database as well as 60 clinical specimens. Furthermore, the PTEN mutation associated prognostic genes signature had been proved to be an independent prognostic predictor for EC. Remarkably, the EC patients in high-risk group were characterized with higher stages and grades as well as lower tumor mutation burden of EC, with poor survival outcome. Collectively, the PTEN mutation associated prognostic genes signature was a favorable prognostic biomarker for EC.ConclusionIn summary, we conducted and validated a prognostic predictor for EC associated with PTEN mutational status, which may be used as favorable prognostic biomarkers and therapeutic targets for EC.

Redefining the PTEN Promoter: Identification of Two Upstream Transcription Start Regions

Germline mutation of PTEN is causally observed in Cowden syndrome (CS) and is one of the most common genetic causes of autism spectrum disorder (ASD). However, the majority of individuals who present with CS-like clinical features are found to be PTEN-mutation negative. Reassessment of PTEN promoter regulation may help explain abnormal PTEN dosage, as only the minimal promoter and coding regions are currently included in diagnostic PTEN mutation analysis. We reanalyzed the architecture of the PTEN promoter using next-generation sequencing datasets. Specifically, run-on sequencing assays identified two additional TSRs at -2052 and -1907 basepairs from the start of PTEN, thus redefining the PTEN promoter and extending the PTEN 5-UTR. The upstream TSRs described are active in cancer cell lines and human cancer and normal tissue. Further, these TSRs can produce novel PTEN transcripts due to the introduction of new splice sites. Evaluation of transcription factor binding specific to the upstream TSRs shows overrepresentation of TFs involved in inflammatory processes. Together, these data suggest that potentially clinically relevant promoter variants upstream of the known promoter may be overlooked in indivduals considered PTEN germline mutation-negative and may also explain lack of PTEN expression in sporadic neoplasias without PTEN somatic structural defects.

Superficial radiotherapy and volumetric modulated Arc therapy for skin cancers within hamartomatous skin in patient with PTEN mutation: A case report

Phosphatase and tensin homolog (PTEN) gene acts as a tumour suppressor gene. Mutations of this gene are a step in the development of many cancers. Sufferers can have large fields of symptomatic hamartomatous skin change especially in sun exposed areas. RT has been reported to cause increased acute toxicity in this cohort. A 78-year-old fit male had a confirmed PTEN variant LRG_311t1 Exon 5, c353A>C. Symptomatic skin lesions of left frontal scalp and left nasal ala were confirmed on punch biopsy to be basal cell carcinoma (BCC) and he was referred for definitive radiotherapy (RT). He was treated with lesion based superficial radiotherapy to the left nasal ala to a total dose of 50 Gy in 25 fractions given at 5 fractions per week using a Xstrahl 300 machine via a 3cm circle applicator at 30cm source surface distance with a generating energy of 100 kV. The left frontal scalp was treated with a field-based volumetric modulated arc therapy technique to a planning target volume (PTV) of 74.8cm3 to 45 Gy with a simultaneous integrated boost PTV to 55 Gy of 4.1 cm3 to the BCC, all in 25 fractions. He developed the expected desquamation, erythema and mucositis within the nasal field and desquamation and erythema in the left temple. The PTEN mutation had no visible increase on the acute side effect profile compared with those without the mutation. After more than 6 months, the areas treated with RT remained clear of symptomatic hamartomatous skin change with no late toxicities. To our knowledge this is the longest benefit received of any treatment for fields of symptomatic hamartomatous skin change associated with PTEN mutation. It is also a report of not observing increased acute toxicity of RT in the definitive treatment of skin cancer in those with proven PTEN mutation. This one case adds evidence that definitive RT to skin may be delivered safely in this cohort. More studies with multiple patients with longer follow up are needed to confirm that those suffering with PTEN mutation can be safely and successfully treated with definitive RT for skin cancer and fields of symptomatic hamartomatous skin change with no increase in late effects.

Fetal Megalencephaly with Cortical Dysplasia at 18 Gestational Weeks Related to Paternal UPD Mosaicism with PTEN Mutation

The phosphatase and tensin homolog (PTEN) gene is a tumor-suppressor gene located on 10q22-23. Since the introduction of molecular genetics in prenatal diagnostics, various birth defects associated with gene mutations have been diagnosed. However, no reports on fetal cases related to PTEN mutation have been found, so far. We encountered a rare case of fetal PTEN mutation. Fetal macrocephaly was noted at 16 weeks. At 18 and 20 weeks, neurosonography revealed megalencephaly with an asymmetrical structure and multifocal polygyria. The head circumference (HC) was +6.2 SD at 18 weeks and +8.1 SD at 20 weeks. The parents opted for pregnancy termination, and the male fetus was delivered at 21 weeks, with HC +9.3 SD. Single-nucleotide polymorphism (SNP) array for amniotic cells showed paternal uniparental disomy (UPD) 10q mosaicism, and the mosaic ratio was calculated as 56% from B-allele frequency. Exome sequencing revealed the pathogenic PTEN mutation with mosaicism. The heterozygous PTEN mutation may not cause early manifestations from the fetal period, and an abnormal phenotype may appear after birth. This may be the reason why fetal defects associated with PTEN mutation are not detected. Since this case had homozygous and heterozygous mutations, survival was possible, exhibiting an incredibly huge head with cortical dysplasia from early pregnancy.

New PTEN mutation identified in a patient with rare bilateral choroidal ganglioneuroma

Background: Choroidal ganglioneuroma is an extremely rare tumor, and there is little knowledge regarding its pathogenesis. We aimed to investigate the phenotypic and genetic alterations in one sporadic patient with a rare case of bilateral choroidal ganglioneuroma. Methods: A 6-year-old boy with histological diagnosis of bilateral ganglioneuroma was recruited for the study. Comprehensive ophthalmic examinations were performed. Genomic DNA was extracted from the peripheral blood samples collected from the patient, his unaffected family members, and 200 unrelated control subjects from the same population. Whole exome sequencing was performed and raw reads were aligned to the human genome reference (hg19) using Burrows-Wheeler Aligner. DNA from all available family members was Sanger sequenced for segregation analysis. Results: Extensive bilateral retinal detachments were observed via optical coherence tomography. Diffuse thickening of choroid was identified with ultrasound B scan and magnetic resonance imaging. Genetic analysis revealed the presence of a novel heterozygous PTEN frameshift mutation, c.498delA (p.Thr167LeufsTer16), in exon 6. It was present in the affected individual, but not in any of the family members. Genetic analysis revealed that there was no mutation in neurofibromatosis-related genes in the family. Upon performing comprehensive systemic examinations, no obvious abnormalities in other organs were observed. Conclusions: A novel de novo PTEN mutation was identified in a patient with bilateral choroidal ganglioneuroma. Although PTEN mutations are known to induce multiple abnormalities, choroidal ganglioneuroma can be the first manifestation without abnormalities in other organs. Further studies are needed to confirm the association between choroidal ganglioneuroma and PTEN mutation.

CBIO-04. MUTATION-SPECIFIC NON-CANONICAL PATHWAY OF PTEN AS A DISTINCT THERAPEUTIC TARGET FOR GLIOBLASTOMA

The dominant-negative effect of PTEN mutation has been described previously, suggesting that aberrant gain of function attributed to mutation might be more disastrous than deletion in respect to malignant potential. In present study, we explored the functional implications of hot spot mutations of PTEN in GBM tumors. Subcellular location of PTEN is important for its distinct function and spatial distribution within the cytoplasm is known to be associated with cellular locomotion. We evaluated the subcellular compartmentalization of different PTEN mutants and found that some PTEN mutants located at cellular edges of chemotaxing cells. Moreover, these PTEN mutations exhibited invasive phenotype, which was not disrupted by PI3K inhibitor, but microtubule inhibitors. This finding suggests that cytoskeletal assembly as a novel non-canonical pathway of PTEN, thus unraveling a novel therapeutic vulnerability of PTEN. Mutation-specific therapeutic options should be considered in treating GBM patients with PTEN mutations.