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Results for “PTEN Phosphohydrolase”

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PubMed2026

Recognizing genetic association between Lhermitte-Duclos Disease and Autism Spectrum Disorder in PTEN-related patients: a case report and literature comprehension.

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare autosomal dominant disorder that increases the risk of various tumors and systemic malignancies, including Lhermitte-Duclos disease (LDD), known as dysplastic cerebellar gangliocytoma. Both conditions result from a PTEN gene mutation, which disrupts cellular growth and proliferation. Some children with such a mutation exhibit developmental delay or autism spectrum disorder (ASD), associated with PHTS. Herein, we report on a mother with LDD/PHTS and her child with ASD, discuss screening, genetic counseling, and management of PHTS-affected, PTEN-related, family-connected patients, and provide a narrative literature review. METHODS: Clinical and diagnostic evaluation and genetic analysis were performed on a female patient with LDD/PHTS and on her 14-year-old daughter, diagnosed with ASD. Genomic DNA was extracted from the peripheral blood of both, using a commercial DNA isolation kit to detect a PTEN mutation. RESULTS: Ten-year follow-up of the LDD/PHTS patient showed no evidence of tumor recurrence after partial tumor resection, resulting in full neurological recovery. Genetic testing of both the mother and her child confirmed the same genetic variant-PTEN c.370 T > C p.(Cys124Arg), NM_000314.8, in heterozygous status-classified as pathogenic for PHTS. CONCLUSIONS: This paper highlights the importance of timely diagnosis of PHTS in an ASD-affected child after identifying a parent with LDD/PHTS, a disorder with significant implications linked to a PTEN mutation. Given the risk of malignancy and neurodevelopmental disorders associated with PTEN mutation, patients suspected of having LDD/PHTS and children with ASD should undergo regular screening for PTEN-related diseases and receive appropriate genetic counseling.

Humans↗

PubMed2002

Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit.

Phosphoinositide 3-kinase (PI3K) type IA is a heterodimer of a catalytic subunit, p110, and a regulatory subunit, p85. Here we show that p85 contains a GTPase-responsive domain and an inhibitory domain, which together form a molecular switch that regulates PI3K. H-Ras and Rac1 activate PI3K by targeting the GTPase-responsive domain. The stimulatory effect of these molecules, however, is blocked by the inhibitory domain, which functions by binding to tyrosine-phosphorylated molecules and is neutralized by tyrosine phosphorylation. The complementary effects of tyrosine kinases and small GTPases on the p85 molecular switch result in synergy between these two classes of molecules toward the activation of the PI3K/Akt pathway.

3T3 Cells↗

PubMed2026

DNA copy number patterns reveal prognostic markers and elucidate mechanisms of evolution in IDH-mutant astrocytoma.

BACKGROUND: Current literature suggestsisocitrate dehydrogenase (IDH)-mutant astrocytoma contains several molecular subgroups. In this study, we are interested in determining the connection between different molecular subgroups with grade and/or survival. METHODS: A cohort of 470 Mayo Clinic adult patients (≥18 years, 56.2% male) with primary IDH-mutant astrocytoma diagnosed by World Health Organization (WHO) 2021 criteria were examined. Results were validated in an independent cohort of 614 Mayo Clinic Neuropathology consult patients and 235 The Cancer Genome Atlas (TCGA) patients. RESULTS: The Mayo Clinic Practice cohort confirmed the association of CDKN2A/B deletion with overall survival (OS, homozygous vs hemizygous vs intact, 2.7 vs 9.6 vs 17.2 years, P < .001). Phosphatase and tensin homolog (PTEN) deletion was also associated with poor OS (7.3 vs 17.4 years, P < .001). Increased number of copy number alterations was associated with OS (continuous variable, HR = 1.027, P < .001). Carrying one or more copies of the germline risk allele at rs55705857 was associated with earlier age of onset (median age 33 vs 35 years, P = .01), and a shorter OS after adjusting for age, grade, sex and treatment (HR = 1.81, P = .007). The Mayo Clinic Neuropathology Consult cohort and TCGA were utilized to validate age of onset and survival, respectively. Unsupervised clustering of the copy number alterations identified several clinically significant groups that may define pathways to disease progression. Losses of chromosomes 11p, 13q, 1p, and 10q were all associated with reduced overall survival in the Mayo Clinic cohort. CONCLUSIONS: Patients with hemizygous loss of CDKN2A/B, loss of PTEN, increased number of copy number alterations, specific chromosomal arm losses or rs55705857 germline risk allele have reduced overall survival.

Humans↗

PubMed2007

Big roles for small GTPases in the control of directed cell movement.

Small GTPases are involved in the control of diverse cellular behaviours, including cellular growth, differentiation and motility. In addition, recent studies have revealed new roles for small GTPases in the regulation of eukaryotic chemotaxis. Efficient chemotaxis results from co-ordinated chemoattractant gradient sensing, cell polarization and cellular motility, and accumulating data suggest that small GTPase signalling plays a central role in each of these processes as well as in signal relay. The present review summarizes these recent findings, which shed light on the molecular mechanisms by which small GTPases control directed cell migration.

Actins↗

PubMed2026

Reversible exacerbation of parkinsonism during epirubicin-cyclophosphamide chemotherapy in a patient with PTEN hamartoma tumor syndrome and young-onset Parkinson's disease.

BACKGROUND: PTEN hamartoma tumor syndrome (PHTS), caused by germline loss-of-function variants in PTEN, typically manifests as macrocephaly, neurodevelopmental disorders, and cancer susceptibility. Parkinson's disease has not been recognized as part of its known neurological spectrum. METHODS: We describe the clinical course of a patient with a germline PTEN nonsense variant (p.Arg130Ter) who developed young-onset Parkinson's disease before being diagnosed with bilateral breast cancer. RESULTS: The patient developed asymmetric, levodopa-responsive parkinsonism at 35 years of age, with reduced bilateral striatal dopamine transporter uptake. During two cycles of epirubicin-cyclophosphamide chemotherapy, her previously well-controlled parkinsonism showed reproducible and severe exacerbations. Symptoms began several days after chemotherapy, reached their maximum severity approximately one week after treatment, and resolved completely within approximately two weeks without modification of her antiparkinsonian medications. No dehydration, electrolyte disturbance, infection, or exposure to dopamine-receptor antagonists was identified. The chemotherapy regimen was discontinued after the second episode because of the reproducible temporal association. CONCLUSIONS: This case demonstrates reproducible, fully reversible exacerbations of parkinsonism during epirubicin-cyclophosphamide chemotherapy in a patient with PHTS and young-onset Parkinson's disease. These episodes may reflect transient vulnerability of dopaminergic neurons to chemotherapy-related systemic stress, although the causal role of PTEN haploinsufficiency remains uncertain.

Humans↗

PubMed2025

Divergent PTEN-p53 interaction upon DNA damage in a human thyroid organoid model with germline PTEN mutations.

Germline mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) cause PTEN hamartoma tumor syndrome (PHTS). PHTS is characterized by an elevated lifetime risk of differentiated thyroid cancer (DTC), 30 times higher than the general population. However, only 1 in 3 PHTS patients develop DTC, and it remains unknown whether specific PTEN variants are associated with an increased risk of DTC. PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway, a frequently affected pathway in sporadic DTC. PTEN also acts as a guardian of the genome by interacting with other tumor suppressors. Here, we report how ionizing radiation, an environmental tumorigenic contributor, modifies the DNA damage response based on the type of germline PTEN variants. We hypothesized that certain PTEN variants associated with DTC create a pro-oncogenic molecular signature upon radiation-induced DNA damage. DTC-associated (PTEN M134R ) or DTC-non-associated (PTEN G132D ) germline PTEN mutant alleles were introduced into a human induced pluripotent cell (hiPSC) line derived from a healthy donor utilizing CRISPR-Cas9 gene editing technology. We determined radiation-induced transcriptomic changes in functional thyroid organoids induced from wild-type and both heterozygous PTEN mutant hiPSCs. Both bulk and single-cell RNA sequencing data indicated that radiation upregulated the p53 network more potently in the thyroid organoids with PTEN WT/G132D than those with PTEN WT/M134R , which could be mediated by AKT-dependent MDM2 inactivation and PTEN-p53 physical interaction. Our data suggest that the lack of p53 pathway activation through PTEN-p53 network interactions explains why PTEN M134R is a DTC-susceptible variant.

Humans↗

PubMed2025

The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS).

PURPOSE: Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk. METHODS: This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires. RESULTS: Overall, 279 adult PHTS patients with (a history of) cancer were included (80% female). Among females, 106 (54%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5% (95% CI = 18.1-32.5) and 45.7% (95% CI = 36.9-55.4) in females and 14.5% (95% CI = 5.7-34.1) and 19.8% (95% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3% (95% CI = 14.9-35.2) and 45.6% (95% CI = 33.0-60.2) in females, respectively. CONCLUSION: This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.

Humans↗

PubMed2026

A spotlight on PTEN alterations in prostate cancer: A narrative review.

Among the molecular alterations observed in prostate cancer, PTEN loss represents a key event, functionally linked to aberrant activation of the PI3K/AKT/mTOR pathway. Loss of PTEN function contributes to disease progression, therapy resistance and poor prognosis. This review highlights the biological significance and the prognostic role of PTEN in prostate cancer, the biologically relevant crosstalk between the PI3K and androgen receptor pathways, and the implications of this interaction for tumour adaptation and treatment resistance. We also discuss current methodologies for PTEN assessment, including immunohistochemistry and genomic techniques, and provide an overview of clinical trials targeting the PI3K/AKT axis in prostate cancer. Understanding PTEN alterations is essential for improving prognostic stratification and guiding precision oncology approaches.

Humans↗

PubMed2026

MicroRNA-181a-5p promotes papillary thyroid carcinoma progress via the PTEN/AKT pathway.

The objective of this investigation was to determine the expression profile and latent mechanism of microRNA-181a-5p (miR-181a-5p) in the genesis and progression of papillary thyroid cancer (PTC). MiR-181a-5p was discovered to be upregulated in PTC tissues and cells in this study, as confirmed by RT‒qPCR and The Cancer Genome Atlas database. Notably, in PTC patients, the miR-181a-5p level was linked to tumor size and thyroid capsule invasion. A series of experiments demonstrated that miR-181a-5p upregulation in PTC cells notably enhanced proliferation, motility, and invasion, whereas suppressing miR-181a-5p hindered these functions. Western blotting revealed that miR-181a-5p suppressed PTEN expression, boosting the activation of phosphorylated AKT (P-AKT). According to predictive bioinformatics research and luciferase reporter gene tests, miR-181a-5p may target a specific binding site on the PTEN 3'UTR. To sum up, this study indicated that miR-181a-5p promoted PTC progression through the PTEN/Akt pathway. This investigation reveals a potential mechanism for PTC progression and provides a foundation for clinical therapies.

MicroRNAs↗

PubMed2001

Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway.

Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). Expression of six of them (PINK1, EGR2, HCLS1, DUSP1, BPOZ, and NFIL3) was decreased in ovarian tumors compared with corresponding normal tissues. Colony-formation assays using plasmid clones designed to express each gene indicated that EGR2 and BPOZ were able to suppress growth of cancer cells significantly; in particular, cancer-cell lines stably expressing BPOZ grew more slowly than control cells containing mock vector. Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G(1)/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. Therefore both genes appear to be novel candidates as mediators of the PTEN growth-suppressive signaling pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome.

BACKGROUND: The spectrum of clinical findings associated with PTEN tumor suppressor gene germline mutations, referred to as PTEN hamartoma-tumor syndrome (PHTS), includes Cowden and Bannayan-Riley-Ruvalcaba syndromes. Although the skin is the ectodermal structure most often affected by these autosomal dominant genodermatoses, abnormalities of neural tissues are frequently observed. OBSERVATIONS: We describe a 5-year-old boy with macrocephaly, prominent corneal nerves, and progressive development of multiple painful, dome-shaped, translucent pink to skin-colored papules on the vermilion portion of the upper lip, fingers, palms, and shins. Histologic evaluation demonstrated dermal proliferation of well-demarcated nerve bundles associated with abundant mucin and surrounded by a distinct perineural sheath, findings diagnostic of a nonencapsulated neuroma. Genetic analysis revealed a novel heterozygous germline nonsense mutation in PTEN, predicted to result in a truncated PTEN protein. To our knowledge, this represents the first report of multiple neuromas as the sole mucocutaneous manifestation of PHTS. CONCLUSIONS: This article highlights neuromas as a cutaneous sign of PHTS, drawing attention to manifestations of PHTS in neural tissues of the skin, eye, gastrointestinal tract, and brain. Along with multiple endocrine neoplasia type 2B, PHTS should be considered in the differential diagnosis of multiple mucocutaneous neuromas, particularly those involving extrafacial sites.

Child, Preschool↗

PubMed1999

Targeting in gene therapy for gliomas.

Cancer is a disease of a series of genes. Thus, theoretically, brain tumors could be treated by targeting their fundamental molecular defects. Currently, most of the approved clinical protocols for gene therapy involve cancer patients. Several of these protocols are designed to improve the treatment of brain tumors. In this brief report, we analyze the rationale, advantages, and disadvantages of a series of gene therapy approaches against brain tumors that include transfer of tumor suppressor genes and cell-cycle modulators; suicide or prodrug strategies; immunogene therapy; antiangiogenesis; and oncolytic virus therapy. In summary, in this review, we highlight the translational advances in molecular medicine that broaden our battery of therapies for patients with brain tumors.

Brain Neoplasms↗

PubMed2001

Loss of PTEN expression as a prognostic marker for tongue cancer.

BACKGROUND: Abnormalities of PTEN, a candidate tumor suppressor gene located at 10q23.3, play an important role in the tumorigenesis of multiple tumor types. OBJECTIVES: To investigate the expression of PTEN and its clinical implication in squamous cell carcinoma of the tongue. DESIGN: Retrospective analysis of PTEN protein expression in archived primary oral tongue tumor samples. SETTING: Academic center. PATIENTS AND METHODS: PTEN expression was determined by immunohistochemical analysis in tissue samples from 41 patients with stage II, III, and IV squamous cell carcinoma of the tongue. All the patients underwent curative surgical treatment with a median follow-up of 81 months. The Kaplan-Meier method was used for survival analysis. Multivariate analysis was performed according to the Cox proportional hazards model. RESULTS: Lack of staining for PTEN was demonstrated in 12 (29%) of the 41 tumors. Patients whose tumors lacked PTEN expression had a significantly shorter overall survival time (P = .03) and event-free survival time (P = .01) than those patients with positive PTEN expression. Multivariate regression analysis demonstrated that PTEN expression is an independent predictor of poor outcome when compared with tumor stage and nodal status. CONCLUSIONS: Although genetic alterations of the PTEN gene are rare in head and neck squamous cell carcinoma, loss of PTEN is not an uncommon event in squamous cell carcinoma of the tongue. Lack of PTEN expression may be an independent prognostic indicator for clinical outcome in patients with this tumor type.

Carcinoma, Squamous Cell↗

PubMed2005

Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.

CONTEXT: Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery. OBJECTIVE: To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results. DESIGN, SETTING, AND PATIENTS: Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed. MAIN OUTCOME MEASURES: Molecular, clinical, and histopathological findings in patients with unexplained polyposis. RESULTS: Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen. CONCLUSIONS: Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.

AMP-Activated Protein Kinase Kinases↗

PubMed2006

Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.

CONTEXT: Genetic testing for inherited mutations in BRCA1 and BRCA2 has become integral to the care of women with a severe family history of breast or ovarian cancer, but an unknown number of patients receive negative (ie, wild-type) results when they actually carry a pathogenic BRCA1 or BRCA2 mutation. Furthermore, other breast cancer genes generally are not evaluated. OBJECTIVE: To determine the frequency and types of undetected cancer-predisposing mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN among patients with breast cancer from high-risk families with negative (wild-type) genetic test results for BRCA1 and BRCA2. DESIGN, SETTING, AND PARTICIPANTS: Between 2002-2005, probands from 300 US families with 4 or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic test results for BRCA1 and BRCA2 were screened by multiple DNA-based and RNA-based methods to detect genomic rearrangements in BRCA1 and BRCA2 and germline mutations of all classes in CHEK2, TP53, and PTEN. MAIN OUTCOME MEASURES: Previously undetected germline mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN that predispose to breast cancer; frequencies of these mutations among families with negative genetic test results. RESULTS: Of the 300 probands, 52 (17%) carried previously undetected mutations, including 35 (12%) with genomic rearrangements of BRCA1 or BRCA2, 14 (5%) with CHEK2 mutations, and 3 (1%) with TP53 mutations. At BRCA1 and BRCA2, 22 different genomic rearrangements were found, of sizes less than 1 kb to greater than 170 kb; of these, 14 were not previously described and all were individually rare. At CHEK2, a novel 5.6-kb genomic deletion was discovered in 2 families of Czechoslovakian ancestry. This deletion was found in 8 of 631 (1.3%) patients with breast cancer and in none of 367 healthy controls in the Czech and Slovak Republics. For all rearrangements, exact genomic breakpoints were determined and diagnostic primers validated. The 3 families with TP53 mutations included cases of childhood sarcoma or brain tumors in addition to multiple cases of breast cancer. CONCLUSIONS: The mutational spectra of BRCA1 and BRCA2 include many high-penetrance, individually rare genomic rearrangements. Among patients with breast cancer and severe family histories of cancer who test negative (wild type) for BRCA1 and BRCA2, approximately 12% can be expected to carry a large genomic deletion or duplication in one of these genes, and approximately 5% can be expected to carry a mutation in CHEK2 or TP53. Effective methods for identifying these mutations should be made available to women at high risk.

Adult↗

PubMed1999

Severe Lhermitte-Duclos disease with unique germline mutation of PTEN.

Germline mutations in the PTEN gene have recently been identified in some individuals with Cowden disease (CD), Lhermitte-Duclos disease (LDD), and Bannayan-Zonana syndrome. We report on a patient with CD and LDD in whom a unique de novo germline missense mutation is present in the PTEN gene. Direct sequence analysis detected a transitional change (T-->C) at nucleotide 335, resulting in substitution of the amino acid proline for leucine. The mutation is in exon 5, which has been proposed as a "hot-spot" for germline mutations. Comparison of this patient's clinical course with the previously reported cases of CD and LDD shows more extensive and more severe clinical findings than reported previously. Findings in this patient contribute to the current understanding of germline PTEN mutations and clinical outcome.

Adult↗

PubMed1999

Long-chain L 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency does not appear to be the primary cause of lipid myopathy in patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS).

In order to test the hypothesis that long-chain L 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency is associated with the lipid myopathy and muscle carnitine deficiency observed in Bannayan-Riley-Ruvalcaba syndrome (BRRS), we studied the enzyme activity in cultured skin fibroblasts from three generations of a family with a clear dominant inheritance of BRRS. Enzyme activities were normal while the germline PTEN missense mutation P246L segregated with BRRS in this family. No PTEN mutations were identified in the original patient with BRRS and LCHAD deficiency. These data suggest that the previously reported case of LCHAD and BRRS either represents the coincidental concurrence of two rare genetic events or that a gene other than PTEN is related to LCHAD and BRRS.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2000

Investigation of germline PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 alterations in familial glioma.

Epidemiological studies suggest that some familial aggregations of glioma may be due to inherited predisposition. Many genes involved in familial cancers are frequently altered in the corresponding sporadic forms. We have investigated several genes known to be altered in sporadic gliomas for their potential contribution to familial glioma. Fifteen glioma patients with a family history of brain tumors were identified through the Mayo Clinic Department of Neurology (nine diffuse astrocytomas, two oligodendrogliomas, two mixed oligoastrocytomas, one pilocytic astrocytoma, and one pineal glioma). Eleven of the propositi had one or more first degree relative with a glioma. Lymphocyte DNA was derived from each of the patients and analyzed by polymerase chain reaction (PCR) and direct sequencing of the PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 genes. In addition, fluorescence in situ hybridization (FISH) was performed on EBV-transformed lymphocytes from each affected individual to detect germline copy number of the p16(INK4A)/p14(ARF) tumor suppressor region. A p53 germline point mutation was identified in one family with some findings of Li-Fraumeni syndrome, and a hemizygous germline deletion of the p16(INK4A)/p14(ARF) tumor suppressor region was demonstrated by FISH in a family with history of both astrocytoma and melanoma. Thus, whereas germ-line mutations of PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 are not common events in familial glioma, outside of familial cancer syndromes, point mutations of p53 and hemizygous deletions and other rearrangements of the p16(INK4A)/p14(ARF) tumor suppressor region may account for a subset of familial glioma cases. Collectively, these data lend genetic support to the heritable nature of some cases of glioma.

Adult↗