PTEN Hamartoma Tumor Syndrome Research Articles

Neuropsychological functioning of adults with PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndrome (PHTS) might be associated with a distinct cognitive and psychological profile. However, previous studies are limited, predominantly based on small and pediatric cohorts, likely affected by selection bias, and show a broad range of findings. We aimed to characterize the neuropsychological functioning of adults with PHTS. A total of 40 participants, with intellectual disability as exclusion criterium, completed an extensive clinical neuropsychological assessment including cognitive tasks, questionnaires, and a clinical diagnostic interview. The cognitive tasks and questionnaire data were categorized as below and above average based on 1.5 SD. About 80% of participants showed an average level of intelligence. In addition, 30% and 24% of participants scored below average on immediate memory recall and speed of information processing, respectively. Furthermore, about 25% reported above average scores on the majority of the questionnaires, indicating psychological distress, signs of alexithymia, and cognitive complaints. Personality of participants was characterized by inflexibility, social withdrawal, and difficulties in recognizing and describing their own emotions. Adults with PHTS demonstrate a heterogeneous yet distinct neuropsychological profile that is characterized by slower information processing, psychological problems, and specific personality traits. These findings provide directions on how to optimize the care and daily lives of adults with PHTS.

Facial Features of Hereditary Cancer Predisposition.

In the age of telehealth medicine, an individual's facial features may provide the only physical clues signaling the presence of a heritable cancer predisposition syndrome. These syndromes include APC-associated polyposis, Birt-Hogg-Dubé syndrome, CYLD cutaneous syndrome, hereditary leiomyomatosis and renal cell cancer, multiple endocrine neoplasia, neurofibromatosis type 1, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome, and tuberous sclerosis complex 1 and 2, among others. Correctly identifying characteristic features is important for genetic and nongenetic specialists as early detection can enable prompt intervention, improving patient outcomes. Advancements in the availability of genetic testing allow patients and their relatives to have more information about their genetic risk profile than before. These changes in clinical pathways, combined with improvements in screening and risk-reducing treatment, highlight the need to outline the cutaneous and morphologic features of high-risk cancer syndromes for clinicians. In this review, we describe the important facial features of hereditary cancer predisposition, with emphasis on diagnosis, cutaneous and extracutaneous manifestations, and screening.

Exploring the Prevalence of Oral Features for Early Detection of PTEN Hamartoma Tumour Syndrome

AimsPatients with PTEN hamartoma tumour syndrome (PHTS) have an increased risk of developing cancer due to a pathogenic germline variant in the PTEN tumour suppressor gene. Early recognition of PHTS facilitates initiation of cancer surveillance which is highly effective in preventing the development of advanced malignancies. PHTS is rare and due to its varied phenotype, even within families, oral abnormalities may be a valuable tool in the identification of these patients at an early stage before cancer development. Materials and methodsBetween 1997 and 2020, phenotypic characteristics were evaluated in 81 paediatric (median age: 9 years) and 86 adult (median age: 40 years) PHTS patients by one of 2 medical experts during yearly surveillance visits at a Dutch PHTS expertise centre. Oral features evaluated included gingival hypertrophy, oral papillomas, and high palate (in adults). ResultsWithin adults, gingival hypertrophy was present in 94%, oral papillomas in 88%, and a high palate in 89%. All adult patients had at least one of these oral features, and 99% showed at least 2 oral features. Oral features were less common in paediatric patients, especially under 11 years of age. Gingival hypertrophy was observed in 44% and oral papillomas in 54% of paediatric patients. ConclusionsThe presence of 2 or 3 oral features may indicate PHTS in adults or adolescents, especially if macrocephaly is present. Dental professionals are well-positioned to recognise these oral manifestations could be related to PHTS. They can initiate an overall clinical assessment of the patient by alerting the patient's medical practitioner of the findings and the possible need for genetic testing. This could significantly improve outcomes, including life expectancy, for patients and possibly for their relatives. Clinical relevanceDental professionals are ideally placed to recognise oral features and initiate early assessment of PHTS which could significantly improve patient outcomes.

PTEN Hamartoma Tumor Syndrome Presenting with a Rare Phenotype of Hemimegalencephaly and Intractable Epilepsy (P9-8.004)

PTEN Hamartoma Tumor Syndrome Presenting with a Rare Phenotype of Hemimegalencephaly and Intractable Epilepsy (P9-8.004)

Developmental and behavioral phenotypes of pediatric patients with PTEN hamartoma tumor syndrome.

Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life-impacting neurodevelopmental features of PHTS. Our study recruited 20 children/adolescents with PHTS, who were then administered assessments for autism spectrum disorder (ASD) and other neurocognitive measures, including assessment of IQ, executive and adaptive functioning, and health-related quality of life. Thirteen individuals (65%) were identified as having ASD, of which five were newly diagnosed during the study. Of those, ASD symptom severity was in the mild-moderate range for 77%. Overall, IQ was in the average range, with a mean of 92.61 (SD 24.45, p = 0.5), though there was a non-statistically significant trend toward individuals without ASD having a higher mean IQ (102.7 vs 82.3; p = 0.1). Subjects had significant impairment in processing speed (mean 75.38, SD 24.75, p < 0.05), decreased adaptive functioning skills across all domains, and a trend toward having more executive functioning problems. Individuals with PHTS are at increased risk of neurodevelopmental disorders, including ASD and impaired executive and adaptive functioning. Although clear guidelines exist for cancer surveillance for individuals with PHTS, additional guidelines and screening for neurodevelopmental disorders are warranted.

Autism spectrum disorder and PTEN hamartoma tumor syndrome Ó? Child and adolescent psychiatric perspective

Autism spectrum disorder and PTEN hamartoma tumor syndrome Ó? Child and adolescent psychiatric perspective

Abstract 979: Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome

Abstract Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers, and a 7-fold increased risk of second primary malignant neoplasms (SMNs). Currently, there is no reliable biomarker that can accurately predict which individuals with PHTS will develop malignancies, let alone SMN. Currently, there is no reliable biomarker that can accurately predict which individuals with PHTS will develop malignancies, let alone SMN. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with hereditary forms of cancer remains poorly understood. Thus, we performed a retrospective study in prospectively accrued patients with PHTS investigating whether plasma cfDNA profiles can be leveraged as a predictive marker of cancer risk. We performed ultra-low pass whole genome sequencing of cfDNA of archived plasma samples from patients with PHTS without cancer (N = 50), and those with cancer (N = 49). Those with cancer included patients with only a single primary malignant neoplasm (PMN, N = 23) and patients with second malignant neoplasms (SMN, N = 26). To investigate cfDNA profiles in patients with PHTS and subclinical cancer, we included nine patients with plasma archived before their cancer diagnosis. We observed that patients with PHTS and SMNs have significantly decreased proportion of di- and tri-nucleosome-associated cfDNA fragments compared to patients with PMNs and those without cancer. Furthermore, SMN status was associated with increased genome-wide fragmentation (ratio of short to long fragments) of mono- (OR 2.37, 95% CI [1.09, 7.27]; P = 0.025) and di-nucleosome-associated (OR 3.03, 95% CI [1.07, 15.7]; P = 0.029) cfDNA fragments, even after controlling for age at plasma draw and phenotypic burden. Fragment end profiling was performed by calculating the frequencies of the first 4-nucleotide sequence (4-mer end motif) at each 5’ end of cfDNA fragments. We identified 35 differentially abundant 4-mer end motifs when comparing patients with SMN to those without cancer. Patients with PHTS and SMNs were characterized by a decrease in A-end motifs with concurrent increases in G- and T-end motifs. Increased frequency of C-motifs—namely CC- and CA-end motifs—appeared to be unique to patients who had plasma drawn before their SMN diagnosis, a potential marker for active cancer. Our findings provide evidence that cfDNA fragmentomic features can be leveraged as a potential marker of individual SMN risk in PHTS. These results may facilitate earlier cancer detection and intervention as well as prevent unnecessary high-risk cancer surveillance and prophylactic surgeries in this vulnerable population. Citation Format: Darren Liu, Lamis Yehia, Andrew Dhawan, Ying Ni, Charis Eng. Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 979.

Abstract 6233: Characterizing variants of uncertain significance in the tumor suppressor gene known as phosphatase and tensin homolog (PTEN)

Abstract PTEN is an important tumor suppressor that plays an essential role in regulating cell proliferation. Loss of PTEN function is implicated in approximately 50% of metastatic cancers. Individuals with pathogenic PTEN variants are at significantly elevated risk of developing hereditary cancer syndromes such as PTEN hamartoma tumor syndrome. While genetic testing for PTEN is valuable for identifying individuals at risk, 47% of 3065 publicly reported PTEN variants are not conclusively classified; they either have conflicting interpretations of pathogenicity or are labeled as “Variants of Uncertain Significance (VUS)” and are not clinically actionable. The lack of a clear interpretation for these PTEN variants hinders the targeted care and surveillance of patients and places a strain on the healthcare system. To overcome this issue, our aim is to develop a clinically relevant tool for assessing the pathogenic effects of PTEN variants.We hypothesize that loss of function (LoF) PTEN variants will lead to changes in cellular phenotypic profiles that can be measured through single-cell phenotypic profiling. Thus, our goal is to investigate the functional status of exogenously expressed PTEN variants in PTEN-/- HEK 293 cells. We developed a multiplexed high content imaging assay to characterize PTEN and its key signaling partners such as phospho-Akt. Additionally, we developed a deep learning based single-cell phenotypic profiling pipeline named Paracell that uses subcellular segmentation to extract 540 phenotypic features. Cells that exhibit abnormal phenotypic profiles are indicative of loss of PTEN function. Preliminary results from testing 73 missense variants of PTEN showed that functional and LoF PTEN variants form distinctive clusters in a two-dimensional UMAP plot based on Paracell outputs, suggesting that our approach can identify potentially pathogenic variants of PTEN.Through characterizing novel VUS, we can elucidate structural domains involved in PTEN’s tumor suppressing activity. The result of these classifications will enable more optimized detection, diagnosis, and surveillance strategies for PTEN-related cancers. Ultimately, we aim to contribute to improving the genetic testing of PTEN and the development of targeted therapies. Citation Format: Ajay P. Singh, Jasmine Wen, David Nguyen, Vedanta Khan, Kiran Dhami, Kaitlynn Meier-Ross, Benjamin Martin, Jesse T. Chao. Characterizing variants of uncertain significance in the tumor suppressor gene known as phosphatase and tensin homolog (PTEN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6233.

Exploring the neurological features of individuals with germline PTEN variants: A multicenter study.

PTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described. Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6-12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported. One hundred and seven patients with PHTS (median age 8.7 years; range 3-21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service. This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.

Cerebellar phenotypes in germline PTEN mutation carriers.

PTEN hamartoma tumour syndrome (PHTS) comprises different hereditary conditions caused by germline PTEN mutations, predisposing to the development of multiple hamartomas in many body tissues and also increasing the risk of some types of cancer. Cerebellar involvement in PHTS patients has been long known due to the development of a pathognomonic cerebellar hamartoma (known as dysplastic gangliocytoma of the cerebellum or Lhermitte-Duclos disease). Recently, a crucial role of the cerebellum has been highlighted in the pathogenesis of autism spectrum disorders, now recognised as a phenotype expressed in a variable percentage of PHTS children. In addition, rare PTEN variants are indeed identified in medulloblastoma as well, even if they are less frequent than other germline gene mutations. The importance of PTEN and its downstream signalling enzymatic pathways, PI3K/AKT/mTOR, has been studied at different levels in both human clinical settings and animal models, not only leading to a better understanding of the pathogenesis of different disorders but, most importantly, to identify potential targets for specific therapies. In particular, PTEN integrity makes an important contribution to the normal development of tissue architecture in the nervous system, including the cerebellum. Thus, in patients with PTEN germline mutations, the cerebellum is an affected organ that is increasingly recognised in different disorders, whereas, in animal models, cerebellar Pten loss causes a variety of functional and histological alterations. In this review, we summarise the range of cerebellar involvement observed in PHTS and its relationships with germline PTEN mutations, along with the phenotypes expressed by murine models with PTEN deficiency in cerebellar tissue.

SOLAMEN syndrome in a toddler

BackgroundSegmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus (SOLAMEN) syndrome is a segmental overgrowth syndrome that is part of Cowden’s Syndrome, a subset of the PTEN hamartoma tumor syndrome cluster. Due to SOLAMEN disease’s rarity, clinical suspicion should arise if multiple small nonspecific variably low-attenuated nodular lesions in the back, shoulders, and upper arms are present on CT, which are associated with mucocutaneous lesions. We present a rare case of SOLAMEN syndrome with widespread lipomatous growth, greater than reported in literature, with confirmed PTEN genetic testing.Case presentationWe describe a case of a 2-year-old boy with a slowly growing left neck mass since birth. Physical exam revealed macrocephaly and epidermal nevi on left axilla, arm, and fingers, appearing as pink verrucous and has visible veins on chest wall/abdomen. CT and MRI imaging showed a lipomatous hibernoma extending from the leftward neck to the abdominal cavity, encasing vascular structures form the left carotid and subclavian arteries to the diaphragmatic hiatus, in addition to the spleen and kidney. Biopsy of the left shoulder revealed hibernoma, a fatty neoplasm of benign brown fat. Patient had a resection of his left shoulder hibernoma and is currently asymptomatic, undergoing surveillance.ConclusionDue to SOMAMEN syndrome’s rarity, clinical suspicion should arise if a patient presents with multiple small-nonspecific variably low-attenuated nodular lesions on CT and mucocutaneous lesions. Ongoing monitoring should be done as there is an increased risk of cancer.

Lifestyle Factors and Breast Cancer in Females with PTEN Hamartoma Tumor Syndrome (PHTS).

Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020-March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0-1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3-2.6); consumed daily about 1.2-1.8 times more often ≥1 than 0-1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4-4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4-6.9); were about 1.04-1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4-2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4-4.2)); and overweight or obesity (72%) was about 1.02-1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4-2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3-2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients' breast cancer risk is important.

PTEN hamartoma tumor syndrome: Clinical and genetic characterization in pediatric patients.

The aim of this study was to provide a full characterization of a cohort of 11 pediatric patients diagnosed with PTEN hamartoma tumor syndrome (PHTS). Eleven patients with genetic diagnostic of PHTS were recruited between February 2019 and April 2023. Clinical, imaging, demographic, and genetic data were retrospectively collected from their hospital medical history. Regarding clinical manifestations, macrocephaly was the leading sign, present in all patients. Frontal bossing was the most frequent dysmorphism. Neurological issues were present in most patients. Dental malformations were described for the first time, being present in 27% of the patients. Brain MRI showed anomalies in 57% of the patients. No tumoral lesions were present at the time of the study. Regarding genetics, 72% of the alterations were in the tensin-type C2 domain of PTEN protein. We identified four PTEN genetic alterations for the first time. PTEN mutations appear with a wide variety of clinical signs and symptoms, sometimes associated with phenotypes which do not fit classical clinical diagnostic criteria for PHTS. We recommend carrying out a genetic study to establish an early diagnosis in children with significant macrocephaly. This facilitates personalized monitoring and enables anticipation of potential PHTS-related complications.

Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome

Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor pathogenic germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers including second primary malignant neoplasms (SMNs). Currently, there are no reliable biomarkers that can predict individual-level cancer risk. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with known cancer-associated germline variants and subclinical cancers remains poorly understood. We perform ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA from plasma samples from patients with PHTS and cancer as well as those without cancer. Analysis of cfDNA reveals that patients with PHTS and SMNs have distinct cfDNA size distribution, aberrant genome-wide fragmentation, and differential fragment end motif frequencies. Our work provides evidence that cfDNA profiles may be used as a marker for SMN risk in patients with PHTS.

PTEN hamartoma tumor syndrome; arginine vasopressin; self-harm assessment tools

PTEN hamartoma tumor syndrome; arginine vasopressin; self-harm assessment tools

Germline PTEN genotype-dependent phenotypic divergence during the early neural developmental process of forebrain organoids.

PTEN germline mutations account for ~0.2-1% of all autism spectrum disorder (ASD) cases, as well as ~17% of ASD patients with macrocephaly, making it one of the top ASD-associated risk genes. Individuals with germline PTEN mutations receive the molecular diagnosis of PTEN Hamartoma Tumor Syndrome (PHTS), an inherited cancer predisposition syndrome, about 20-23% of whom are diagnosed with ASD. We generated forebrain organoid cultures from gene-edited isogenic human induced pluripotent stem cells (hiPSCs) harboring a PTENG132D (ASD) or PTENM134R (cancer) mutant allele to model how these mutations interrupt neurodevelopmental processes. Here, we show that the PTENG132D allele disrupts early neuroectoderm formation during the first several days of organoid generation, andresults in deficient electrophysiology. While organoids generated from PTENM134R hiPSCs remained morphologically similar to wild-type organoids during this early stage in development, we observed disrupted neuronal differentiation, radial glia positioning, and cortical layering in both PTEN-mutant organoids at the later stage of 72+ days of development. Perifosine, an AKT inhibitor, reduced over-activated AKT and partially corrected the abnormalities in cellular organization observed in PTENG132D organoids. Single cell RNAseq analyses on early-stage organoids revealed that genes related to neural cell fate were decreased in PTENG132D mutant organoids, and AKT inhibition was capable of upregulating gene signatures related to neuronal cell fate and CNS maturation pathways. These findings demonstrate that different PTEN missense mutations can have a profound impact on neurodevelopment at diverse stages which in turn may predispose PHTS individuals to ASD. Further study will shed light on ways to mitigate pathological impact of PTEN mutants on neurodevelopment by stage-specific manipulation of downstream PTEN signaling components.

A Bi-Institutional Study of Gastrointestinal and Hepatic Manifestations in Children With PTEN Hamartoma Tumor Syndrome

A Bi-Institutional Study of Gastrointestinal and Hepatic Manifestations in Children With PTEN Hamartoma Tumor Syndrome

Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication.

Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.

SHH medulloblastoma and very early onset of bowel polyps in a child with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis.

Novel anti-PTEN C2 domain monoclonal antibodies to analyse the expression and function of PTEN isoform variants.

PTEN is a major tumor suppressor gene frequently mutated in human tumors, and germline PTEN gene mutations are the molecular diagnostic of PTEN Hamartoma Tumor Syndrome (PHTS), a heterogeneous disorder that manifests with multiple hamartomas, cancer predisposition, and neurodevelopmental alterations. A diversity of translational and splicing PTEN isoforms exist, as well as PTEN C-terminal truncated variants generated by disease-associated nonsense mutations. However, most of the available anti-PTEN monoclonal antibodies (mAb) recognize epitopes at the PTEN C-terminal tail, which may introduce a bias in the analysis of the expression of PTEN isoforms and variants. We here describe the generation and precise characterization of anti-PTEN mAb recognizing the PTEN C2-domain, and their use to monitor the expression and function of PTEN isoforms and PTEN missense and nonsense mutations associated to disease. These anti-PTEN C2 domain mAb are suitable to study the pathogenicity of PTEN C-terminal truncations that retain stability and function but have lost the PTEN C-terminal epitopes. The use of well-defined anti-PTEN mAb recognizing distinct PTEN regions, as the ones here described, will help to understand the deleterious effects of specific PTEN mutations in human disease.