Tumor Predisposition Syndrome Research Articles

Central Nervous System Tumors in Children.

Central Nervous System Tumors in Children.

45. Community curation for Von Hippel Lindau disease

Von Hippel Lindau disease (VHL) is a rare hereditary tumour predisposition syndrome that causes renal cell carcinoma, hemangioblastoma, pheochromocytoma and other tumours. VHL is inherited in an autosomal dominant fashion with ∼20% de novo rate. Despite clear clinical criteria, variants of uncertain significance continue to be encountered in the interpretation of VHL variants. The lack of VHL variant and clinical phenotype data-sharing among clinicians and researchers to-date has created uncertainties about the best way to monitor and treat patients with certain VHL variants.

Epilepsy in NF1: Epidemiologic, Genetic, and Clinical Features. A Monocentric Retrospective Study in a Cohort of 784 Patients.

Simple SummaryNeurofibromatosis type 1 is a relatively frequent neurocutaneous and tumor predisposition syndrome, which has been associated with a variety of neurological manifestations, including an increased incidence of seizures. Epilepsy in NF1 has been investigated over time by a number of studies, but most of these works were performed on small samples and often suffered from selection biases. Our study aimed to provide additional epidemiologic, clinical, and molecular data to the literature by retrospectively analyzing a large cohort of consecutive unselected patients affected with NF1. Such data may provide a better insight into the matter to other authors and clinicians alike.An increased lifetime risk of epilepsy has been reported in neurofibromatosis type 1 (NF1) patients, ranging between 4% and 14%. To further analyze the correlation between NF1 and epilepsy, we retrospectively reviewed the epidemiologic, clinical, radiological, and molecular data of 784 unselected patients diagnosed with NF1 and referred to the neurofibromatosis outpatient clinics at the University Hospital of Padua. A crude prevalence of epilepsy of 4.7% was observed. In about 70% of cases, seizures arose in the context of neuroradiological findings, with the main predisposing factors being cerebral vasculopathies and hydrocephalus. In the absence of structural abnormalities, the prevalence of epilepsy was found to be 1.27%, which is approximately equal to the total prevalence in the general population. NF1 patients with seizures exhibit a higher incidence of intellectual disability and/or developmental delay, as well as of isolated learning disabilities. The comparison of causative NF1 mutations between the two groups did not reveal a specific genotype–phenotype correlation. Our data refine the current knowledge on epileptological manifestations in NF1 patients, arguing against the hypothesis that specific mechanisms, inherent to neurofibromin cellular function, might determine an increased risk of epilepsy in this condition.

Microsimulation Model for Evaluating the Cost-Effectiveness of Surveillance in BAP1 Pathogenic Variant Carriers.

Pathogenic BAP1 germline variants cause a tumor-predisposition syndrome (BAP1-TPDS) linked to uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma. Surveillance of carriers of pathogenic BAP1 variants provides an opportunity for early tumor detection; however, there are no evidence-based guidelines for management of BAP1-TPDS, nor health economic evaluation; this study aims to provide this evidence. We created a Markov microsimulation health state transition model of BAP1 germline carriers to predict if active surveillance for the four main tumors influences survival and improves associated economic costs with a time horizon of 100 years from the perspective of the healthcare system (N = 10,000). Model inputs were derived from data published by the BAP1 Interest Group Consortium and other studies. Management and healthcare costs were extracted from Australian costing schedules (final figures converted to US dollars [USD]), and outcomes compared for individuals receiving surveillance with those in a nonsurveillance arm. Robustness was evaluated on 10,000 iterations of a 100-sample random sampling of the model output. On average, surveillance of BAP1 carriers increased survival by 4.9 years at an additional cost of $6,197 USD for the healthcare system including surveillance costs ($1,265 USD per life year gained). The nonsurveillance arm had more diagnosed late tumors (62.8% v 10.7%) and a higher rate of BAP1-related deaths (50.2% v 35.4%; a 29.5% increase). The model was cost-effective under all sensitivity analyses. Our secondary robustness analysis estimated that 99.86% of 100-sample iterations were cost-effective and 19.67% of these were cost-saving. It is recommended that carriers of BAP1 germline variants are identified and undertake active surveillance, as this model suggests that this could improve survival and be cost-effective for the healthcare system.

Clinicians Practicing Obstetrics and Gynecology Are Uniquely Situated to Recognize DICER1 Syndrome.

Pediatric gynecologic malignancies are rare, present with diverse pathologic findings, and can be associated with genetic syndromes such as Peutz-Jeghers, Lynch, and Li-Fraumeni. DICER1 mutation is an emerging entity that has been demonstrated to cause a hereditary tumor predisposition syndrome. Previously, gynecologic manifestations of DICER1 syndrome have been described in single or small case reports with an array of pathologic findings. Here, we discuss pediatric and adolescent patients with gynecologic DICER1-associated tumors, outline the significance of DICER1, and suggest points of care where the syndrome may be diagnosed in the context of routine obstetric and gynecology practice. Patients presenting with a personal or family history suspicious for DICER1 syndrome should undergo both germline and somatic testing, as the presence of DICER1 mutations will have an impact on both treatment and surveillance strategies.

Targeted Therapies for the Neurofibromatoses.

Simple SummaryThe neurofibromatoses—neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis—are genetic tumor predisposition syndromes in which affected patients are at risk for the development of nerve-associated central and peripheral tumors. Patients often develop multiple tumors which can result in significant symptoms and morbidity. Treatment of the tumors associated with these disorders has evolved over the past decade, including significant work focused on inhibition of the signaling dysregulation and symptom minimization. This review outlines the most common tumor types associated with each of these syndromes and the current progress in therapeutic options.Over the past several years, management of the tumors associated with the neurofibromatoses has been recognized to often require approaches that are distinct from their spontaneous counterparts. Focus has shifted to therapy aimed at minimizing symptoms given the risks of persistent, multiple tumors and new tumor growth. In this review, we will highlight the translation of preclinical data to therapeutic trials for patients with neurofibromatosis, particularly neurofibromatosis type 1 and neurofibromatosis type 2. Successful inhibition of MEK for patients with neurofibromatosis type 1 and progressive optic pathway gliomas or plexiform neurofibromas has been a significant advancement in patient care. Similar success for the malignant NF1 tumors, such as high-grade gliomas and malignant peripheral nerve sheath tumors, has not yet been achieved; nor has significant progress been made for patients with either neurofibromatosis type 2 or schwannomatosis, although efforts are ongoing.

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak–Zhuang Syndrome

SummaryThe integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak–Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex’s Lemonade Stand Foundation.)

Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia

In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations. To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort. In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021. Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel. Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history. In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.

NIMG-09. DETECTION OF ASYMPTOMATIC MALIGNANT LESIONS BY [18F]FDG PET/MRI IN CHILDREN AND ADOLESCENTS WITH NEUROFIBROMATOSIS TYPE 1

Abstract BACKGROUND Plexiform neurofibromas (PN) are a hallmark feature of Neurofibromatosis type 1 (NF1). 10% of PN undergo malignant transformation. As malignant peripheral nerve sheath tumors are a leading cause of death in NF1-patients, early detection of malignancy is essential. 2-deoxy-2-[ 18F]fluoro-D-glucose [18F]FDG PET/CT imaging is used in patients with NF1 to judge malignant transformation. AIMS: The present study evaluated [18F]FDG PET/MRI in pediatric NF1 patients at high risk for MPNST and its utility as a possible screening tool for malignant transformation of yet asymptomatic lesions. METHODS Patients aged 0-25 with symptomatic and asymptomatic neurofibromas who underwent PET/MRI from 2014 to 2021 were included. Chart review of imaging data, clinical and histological findings was performed retrospectively. RESULTS 41 patients (18 female) with a median age at first PET/MRI of 16.87 years (6.21-24.41) were included. 40 lesions were operated as indicated by clinical (e.g. pain, rapid growth) or imaging findings. Based on histopathological analysis 7 lesions in 4 patients were categorized as malignant, 3 as atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP). 4/7 malignant and 2/3 ANNUBP lesions were asymptomatic (i.e. without rapid growth, pain, neurologic dysfunction). 5/7 symptomatic tumors were without significant FDG-PET and proven benign by histology. 18 lesions (2 symptomatic) in 9 patients that showed an increased uptake suspect of malignant transformation were histologically classified as benign. None of the patients died during follow-up, 1 symptomatic MPNST patient received postsurgical radio- and chemotherapy. CONCLUSION Our data indicate that malignant transformation of PN also occurs in asymptomatic patients. [18F]FDG PET/MRI is feasible in pediatric and adolescent patients with the tumor predisposition syndrome NF1 and is an alternative to PET/CT when assessing for malignancy thereby drastically reducing radiation exposure. Early detection through screening of high-risk NF1 patients with [18F]FDG PET/MRI could potentially increase overall survival by facilitating early curative resection.

Case Report: The Emerging Role of Ring Chromosome 22 in Phelan-McDermid Syndrome With Atypical Teratoid/Rhabdoid Tumor: The First Child Treated With Growth Hormone.

Atypical teratoid/rhabdoid tumors (AT/RTs) in the rhabdoid tumor predisposition syndromes are most often caused by germline mutations of the SMARCB1 gene located in chromosome 22q11.2. Although rarely, it can also result from the constitutional ring chromosome 22 (r22): during mitosis the ring chromosome may lead to an increased rate of somatic mutations, resulting in rhabdoid tumor predispositions when the tumor-suppressor gene SMARCB1 is involved. Individuals with r22 may present similar features as those with Phelan-McDermid syndrome (PMDS) due to 22q13.3 deletion, including the SHANK3 gene. Despite several reports on AT/RT in children with r22 and/or PMDS have been published, the role of constitutional r22 as new oncogenic mechanism for AT/RT is still under investigation. There is not a lot of data available on therapeutic and prognostic implications of r22 in AT/RT and PMDS. Herein, we present the first case of a child with constitutional r22, PMDS and AT/RT of the brain, who is a long term survivor and is been treated with growth hormone. We also describe an unexpected adverse reaction to midazolam.

The Gynecologist's Role in the Workup and Management of Patients with Leiomyomas Demonstrating Fumarate Hydratase Deficiency

Study Objective Fumarate hydratase (FH) tumor predisposition syndrome or hereditary leiomyomatosis renal cell cancer (HLRCC) is caused by an autosomal-dominant heterozygous mutation in the FH gene. It is characterized by uterine or cutaneous leiomyomas and renal tumors. Timely diagnosis of HLRCC allows for cancer surveillance. Yet, delays in diagnosis are common in patients with isolated uterine findings. Given that leiomyomas are the most common benign tumors in reproductive-aged women, gynecologists are in an opportunistic position to detect HLRCC earlier. In this series, we present three patients with FH-deficient leiomyomas, and review the gynecologist's unique role in screening, workup, and diagnosis of HLRCC. Design Case Series. Setting Academic institution. Patients or Participants Three patients. Interventions Surgery and genetic screening. Measurements and Main Results Case 1 A 33-year-old with heavy menstrual bleeding and an 18cm uterine lesion presents for abdominal myomectomy. Pathological evaluation was suggestive of FH-deficient leiomyoma, which was confirmed by immunohistochemistry (IHC). She was lost to follow up. Case 2 A 32-year-old with pelvic pain, infertility, and a submucosal fibroid presents for robotic myomectomy. Pathology and IHC confirmed a diagnosis of FH-deficient leiomyoma. Genetic testing for FH mutation was negative. Case 3 A 52-year-old with adenomyosis unresponsive to conservative management presents for hysterectomy. Pathological evaluation was suggestive of FH-deficient leiomyoma, however IHC did not support this diagnosis. Genetic testing was negative. Conclusion HLRCC presents with a variation of phenotypes ranging from leiomyomas to metastatic renal cell carcinoma. Our cases underscore the gynecologist's unique role in the diagnosis of HLRCC. The majority of uterine fibroids are not associated with an increased risk malignancy. FH-deficient leiomyomas can occur in both syndromic and sporadic settings. A thorough history can identify patients at risk. Characteristic histopathological features should prompt genetic evaluation. Management requires a multidisciplinary approach and surveillance can be offered to individuals with even a suspected diagnosis in whom an FH mutation has not been identified. Fumarate hydratase (FH) tumor predisposition syndrome or hereditary leiomyomatosis renal cell cancer (HLRCC) is caused by an autosomal-dominant heterozygous mutation in the FH gene. It is characterized by uterine or cutaneous leiomyomas and renal tumors. Timely diagnosis of HLRCC allows for cancer surveillance. Yet, delays in diagnosis are common in patients with isolated uterine findings. Given that leiomyomas are the most common benign tumors in reproductive-aged women, gynecologists are in an opportunistic position to detect HLRCC earlier. In this series, we present three patients with FH-deficient leiomyomas, and review the gynecologist's unique role in screening, workup, and diagnosis of HLRCC. Case Series. Academic institution. Three patients. Surgery and genetic screening. Case 1 A 33-year-old with heavy menstrual bleeding and an 18cm uterine lesion presents for abdominal myomectomy. Pathological evaluation was suggestive of FH-deficient leiomyoma, which was confirmed by immunohistochemistry (IHC). She was lost to follow up. Case 2 A 32-year-old with pelvic pain, infertility, and a submucosal fibroid presents for robotic myomectomy. Pathology and IHC confirmed a diagnosis of FH-deficient leiomyoma. Genetic testing for FH mutation was negative. Case 3 A 52-year-old with adenomyosis unresponsive to conservative management presents for hysterectomy. Pathological evaluation was suggestive of FH-deficient leiomyoma, however IHC did not support this diagnosis. Genetic testing was negative. HLRCC presents with a variation of phenotypes ranging from leiomyomas to metastatic renal cell carcinoma. Our cases underscore the gynecologist's unique role in the diagnosis of HLRCC. The majority of uterine fibroids are not associated with an increased risk malignancy. FH-deficient leiomyomas can occur in both syndromic and sporadic settings. A thorough history can identify patients at risk. Characteristic histopathological features should prompt genetic evaluation. Management requires a multidisciplinary approach and surveillance can be offered to individuals with even a suspected diagnosis in whom an FH mutation has not been identified.

Activation of Raf signalling in NF2-null Schwann cells leads to sustained proliferation; an investigation of a new and inducible model for human schwannoma

Abstract Aims The NF2 gene encodes the tumour suppressor Merlin, which is deleted in 100% of patients with the familial tumour predisposition syndrome neurofibromatosis type 2 but also in 70% of those who develop sporadic schwannomas. The Raf-TR mouse model uses a tamoxifen-inducible Raf-kinase/ oestrogen receptor fusion protein (Raf-TR) expressed in myelinating Schwann cells to mimic a nerve injury response in Schwann cell by activating Raf/MEK/ERK signalling in the absence of peripheral nerve injury. We will assess whether Raf/MEK/ERK activation on an NF2 null background leads to tumourigenesis within the vestibular nerves and dorsal root ganglia (DRGs), two tumour sites identified in the Periostin-Cre mouse model in which schwannoma formation is spontaneous, with a view to generating an inducible NF2 null schwannoma mouse model. Method Mice with a Schwann cell specific loss of Merlin were crossed with mice carrying a tamoxifen-inducible Raf-TR gene to generate Raf-TR+/-; P0-Cre+/-; NF2fl/fl (Cre+) mice which were NF2 null and compared to Raf-TR+/-; P0-Cre-/-; NF2fl/fl (Cre-) littermate controls. Mice were injected with tamoxifen or vehicle for five consecutive days and their vestibular nerves and dorsal root ganglia (DRGs) were analysed at various timepoints . An EdU proliferation assay was used to quantify the proliferation in the vestibular ganglia, as well as the DRGs. Rates of proliferation were compared to Cre- age-matched littermate controls treated with tamoxifen or vehicle. Results In the Periostin-Cre NF2 null schwannoma model, tumours form spontaneously in the DRGs and vestibular ganglia. In our new model, we see a clear increase in proliferation at 21 d post-injection in the NF2 null (Cre+) tamoxifen-treated mice compared to control (Cre-) tamoxifen-treated controls in both DRGs and vestibular ganglia. Cre- tamoxifen-treated mice do not show increased proliferation compared to Cre- vehicle controls. Taken together, this shows that activation of the Raf/MEK/ERK pathway in Schwann cells only causes a sustained proliferation response on an NF2 null background in the DRGs and vestibular ganglia. We are assessing later timepoints to further characterise tumour development in these mice. Conclusion Combining the Raf-TR mouse model to create a demyelinating phenotype with an NF2 null background leads to vastly increased rates of proliferation at the sites of schwannoma tumourigenesis within the peripheral nervous system: the DRGs and the vestibular ganglia. The high proliferation in the vestibular ganglia in particular is similar to the development of vestibular schwannomas in patients with Neurofibromatosis type 2. The new mouse model used in this study shows potential to be very useful as an inducible schwannoma tumour model, in which we can study the early events of tumour formation.

Somatic mosaics in hereditary tumor predisposition syndromes

Historically, it is estimated that 5–10% of cancer patients carry a causative genetic variant for a tumor predisposition syndrome. These conditions have high clinical relevance as they are actionable regarding risk-specific surveillance, predictive genetic testing, reproductive options, and – in some cases – risk reducing surgery or targeted therapy. Every individual is born with on average 0.5–1 exonic mosaic variants prevalent in single or multiple tissues. Depending on the tissues affected, mosaic conditions can abrogate the clinical phenotype of a tumor predisposition syndrome and can even go unrecognized, because it can be impossible or difficult to detect them with routine genetic testing in blood/leucocytes. On the other hand, it is estimated that at least 4% of presumed de novo variants are the result of low-level mosaicism (variant allele frequency <10%) in a parent, while around 7% are true mosaic variants with a higher variant allele frequency, which can sometimes be confused for heterozygous variants. Clonal hematopoiesis however can simulate a mosaic tumor predisposition in genetic diagnostics and has to be taken into account, especially for TP53 variants.Depending on the technique, variant allele frequencies of 2–3% can be detected for single nucleotide variants by next generation sequencing, copy number variants with variant allele frequencies of 5–30% can be detected by array-based technologies or MLPA.Mosaic tumor predisposition syndromes are more common than previously thought and may often remain undiagnosed. The clinical suspicion and diagnostic procedure for several cases with mosaic tumor predisposition syndromes are presented.

Expression profiling of circulating miRNA in the Neurofibromatosis type 1 and related cancers in a large NF1 Italian cohort

MiRNAs are short noncoding RNAs involved in regulating gene expression at post-transcriptional level. Several studies have suggested their role as biomarkers for various diseases. Its roles in mediating tumorigenesis remain largely unexplored in many disorders, including Neurofibromatosis type 1 (NF1, OMIM#162200), the most frequent autosomal dominant tumour predisposition syndrome, caused by loss-of-function mutations in the NF1 gene. The study aims to identify circulating miRNA profiling in the NF1 and NF1-related cancers and deregulated miRNA gene-target pathways associated to different NF1 phenotypes.

Neurofibromatosis type 1: Molecular spectrum of the NF1 mutations in a large cohort of adult Italian patients

Neurofibromatosis type I (NF1, OMIM #162200) is one of the most common genetic tumor predisposition syndrome, caused by loss of function mutations in the NF1 gene. To date, no clear genotype-phenotype correlation has been discerned in NF1. We aimed to investigate the molecular spectrum of NF1 gene and evaluated the genotype–phenotype correlations in a large cohort of adult Italian NF1 patients.

A Posterior-Anterior Cephalometric Study of Skull Symmetry in Patients With Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome. Bone findings make a significant contribution to the clinical diagnosis of NF1. It has been suggested that there are characteristic skeletal features of the NF1 patients' skull that cause a specific 'NF1 facies'. To test this thesis, skull examinations were carried out on NF1 patients. The posteroanterior (PA) cephalograms of 76 patients with NF1 were analyzed using defined measuring points. Patients with confirmed facial plexiform neurofibromas (PNF) were excluded from the study. A special interest of the investigation was the symmetry of the measuring points defined as the distance to the median sagittal plane. NF1 patients have a slightly larger distance to the Z-plane than controls at the zygomatic arch and mastoid measurement points (p=0.027 and 0.028, respectively). In contrast, the distances of the juga and antegonion measurement points from the horizontal reference plane are larger in the control group (p=0.002 and 0.480, respectively). The transverse development of the midface at the level of the zygomatic arch showed no differences from the control group (p=0.841). The transverse diameter of the skull at the mastoid and juga measurement points is smaller in the NF1 group compared to the control group (p=0.010 and 0.002, respectively). There is a statistically significant left-right (LR) asymmetry of the distances to the median sagittal plane in favor of the left side in the patient group (p=0.002 to 0.037). However, the numerical deviations from the control group are small overall. Considering the natural, biological deviations of cephalometric measurements of the individual from idealized geometric norms, the facial skeleton of NF1 patients is symmetrically developed. It is unlikely that the calculated LR asymmetry of the patients has a visible effect. In comparison to cephalometric values of a normal population, no characteristic facial skeleton of the NF1 patient in the PA projection of the skull can be derived from these findings. Clear asymmetries of the facial skeleton should give rise to further diagnosis to clarify the suspicion of facial PNF.

Neurofibromatosis: Molecular Pathogenesis and Natural Compounds as Potential Treatments.

The neurofibromatosis syndromes, including NF1, NF2, and schwannomatosis, are tumor suppressor syndromes characterized by multiple nervous system tumors, particularly Schwann cell neoplasms. NF-related tumors are mainly treated by surgery, and some of them have been treated by but are refractory to conventional chemotherapy. Recent advances in molecular genetics and genomics alongside the development of multiple animal models have provided a better understanding of NF tumor biology and facilitated target identification and therapeutic evaluation. Many targeted therapies have been evaluated in preclinical models and patients with limited success. One major advance is the FDA approval of the MEK inhibitor selumetinib for the treatment of NF1-associated plexiform neurofibroma. Due to their anti-neoplastic, antioxidant, and anti-inflammatory properties, selected natural compounds could be useful as a primary therapy or as an adjuvant therapy prior to or following surgery and/or radiation for patients with tumor predisposition syndromes, as patients often take them as dietary supplements and for health enhancement purposes. Here we review the natural compounds that have been evaluated in NF models. Some have demonstrated potent anti-tumor effects and may become viable treatments in the future.

Uterine leiomyomatosis in adolescents and young adults (AYAs) may represent a narrow phenotypic variant of FH tumour predisposition syndrome

FH Tumour Predisposition Syndrome, also known as Hereditary Leiomyomatosis and renal cell cancer (HLRCC), or Reed Syndrome, is an autosomal dominant condition clinically characterized by multiple cutaneous leiomyomas, multiple early-onset uterine leiomyomas and early-onset renal cell cancer. Here we report a young female with FH Tumour Predisposition Syndrome with no clinical features except early-onset uterine leiomyomas. Whilst there is a significant history of uterine leiomyomas in her family, there is no history of cutaneous leiomyomas or renal cell cancer (RCC). Uterine leiomyomatosis in young adults may represent a narrow phenotypic variant of FH Tumour Predisposition Syndrome. It is important that young women who present with multiple leiomyomata or leiomyomata with atypical features are referred for molecular genetic testing.

P06.07 Germline mutation of SMARCE1 gene in a family with spinal meningiomas

Abstract BACKGROUND Meningioma is the most common benign primary intracranial tumor, arising from arachnoid cells of the meninges, but in 20% of cases displays aggressive behavior. Meningiomas are mainly sporadic and the familial forms are very rare. Meningioma account for a small subset (1–4%) of all pediatric brain tumors and may be associated with hereditary tumor predisposition syndrome caused by germline mutations of NF2, SMARCB1, SUFU, and SMARCE1 genes. MATERIAL AND METHODS We present a case of a 16-year-old girl with spinal clear cell meningiomas (CCMs) WHO II with a second spinal lesion identified during the follow-up. Considering the multiple lesions, we performed Whole Exome Sequencing (WES) on DNA from peripheral blood to search for an underlying CCMs tumor predisposition syndrome (#607174). RESULTS We identified a heterozygous frameshift variant c.439delA (p.Ser147fs) in SMARCE1, chromatin remodelling factor that acts as a tumor suppressor gene. Meningioma analysis by Sanger sequencing showed a loss of heterozygosity (LOH) of the wild-type allele. We identified the c.439delA in the constitutional DNA of the father and the sister but not in the mother. At the moment, the father is asymptomatic and the 14 years old sister showed two spinal lesions (meningiomas likely) at the first MRI. CONCLUSION We report a family study of hereditary tumor predisposition syndrome to CCMs with SMARCE1 mutation in which are present two asymptomatic carriers with different ages and gender. The asymptomatic carriers will undergo neurological examination and MRI of the brain and spine, according to a screening protocol. The incomplete penetrance phenomenon is known in SMARCE1-related families with CCMs and it is probably due to the interaction of SMARCE1 with yet unidentified genes.

366P The genetic landscape of tumor predisposition syndromes in Chinese patients with glioma

Tumorigenesis is generally driven by a combination of inherited genetic alterations and acquired somatic cell mutations. Glioma usually manifests sporadically, while certain tumors are now known to be associated with tumor predisposition syndromes. The spectrum of syndromes that have glioma manifestations includes neurofibromatosis types 1 and 2, tuberous sclerosis complex, Li-Fraumeni syndrome, Cowden syndrome, Turcot syndrome. A comprehensive understanding of the genetics and molecular pathogenesis of glioma is critical in improving clinical care and promoting the development of molecularly targeted therapeutics.