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Background Bazex–Dupré–Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4-Mb interval on chromosome Xq25-q27.1. However, the genetic mechanism of BDCS remains an open question. Objectives To investigate the genetic aetiology and molecular mechanisms underlying BDCS. Methods We ascertained multiple individuals from eight unrelated families affected with BDCS (F1–F8). Whole-exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long-range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head–tail junctions. Hi-C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. Results In eight families with BDCS, we identified overlapping 18–135-kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi-C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. Conclusions Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic? Bazex–Dupré–Christol syndrome (BDCS) is a rare X-linked basal cell carcinoma susceptibility syndrome linked to an 11·4-Mb interval on chromosome Xq25-q27.1.Loss-of-function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add? BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1.The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene.ACTRT1 loss-of-function variants are unlikely to cause BDCS. What is the translational message? This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management.ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas.

Single-nucleotide variations (SNVs) (formerly single-nucleotide polymorphism [SNV]) influence genetic predisposition to endometrial cancer. We hypothesized that a polygenic risk score (PRS) comprising multiple SNVs may improve endometrial cancer risk prediction for targeted screening and prevention.We developed PRSs from SNVs identified from a systematic review of published studies and suggestive SNVs from the Endometrial Cancer Association Consortium. These were tested in an independent study of 555 surgically-confirmed endometrial cancer cases and 1202 geographically-matched controls from Manchester, United Kingdom and validated in 1676 cases and 116,960 controls from the UK Biobank (UKBB).Age and body mass index predicted endometrial cancer in both data sets (Manchester: area under the receiver operator curve [AUC] = 0.77, 95% CI = 0.74-0.80; UKBB: AUC = 0.74, 95% CI = 0.73-0.75). The AUC for PRS19, PRS24, and PRS72 were 0.58, 0.55, and 0.57 in the Manchester study and 0.56, 0.54, and 0.54 in UKBB, respectively. For PRS19, women in the third tertile had a 2.1-fold increased risk of endometrial cancer compared with those in the first tertile of the Manchester study (odds ratio = 2.08, 95% CI = 1.61-2.68, PAn endometrial cancer risk prediction model incorporating a PRS derived from multiple SNVs may help stratify women for screening and prevention strategies.

PURPOSE: Neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are genetically distinct tumor predisposition syndromes with overlapping phenotypes. We sought to update the diagnostic criteria for NF2 and SWN by incorporating recent advances in genetics, ophthalmology, neuropathology, and neuroimaging. METHODS: We used a multistep process, beginning with a Delphi method involving global disease experts and subsequently involving non-neurofibromatosis clinical experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing NF2 and SWN. These criteria incorporate mosaic forms of these conditions. In addition, we recommend updated nomenclature for these disorders to emphasize their phenotypic overlap and to minimize misdiagnosis with neurofibromatosis type 1. CONCLUSION: The updated criteria for NF2 and SWN incorporate clinical features and genetic testing, with a focus on using molecular data to differentiate the 2 conditions. It is likely that continued refinement of these new criteria will be necessary as investigators study the diagnostic properties of the revised criteria and identify new genes associated with SWN. In the revised nomenclature, the term "neurofibromatosis 2" has been retired to improve diagnostic specificity. ispartof: GENETICS IN MEDICINE vol:24 issue:9 pages:1967-1977 ispartof: location:United States status: published

Recent genetic sequencing studies in large series’ of predominantly childhood medulloblastoma have implicated loss-of-function, predominantly truncating, variants in the ELP1 and GPR161 genes in causation of the MBSHH subtype specifically. The latter association, along with a report of an index case with some features of Gorlin syndrome has led to speculation that GPR161 may also cause Gorlin syndrome. We show that these genes are associated with relatively low absolute risks of medulloblastoma from extrapolating lifetime risks in the general population and odds ratios from the population database gnomAD. The projected risks are around 1 in 270–430 for ELP1 and 1 in 1600–2500 for GPR161. These risks do not suggest the need for MRI screening in infants with ELP1 or GPR161 variants as this is not currently recommended for PTCH1 where the risks are equivalent or higher. We also screened 27 PTCH1/SUFU pathogenic variant-negative patients with Gorlin syndrome for GPR161 and found no suspicious variants. Given the population frequencies of 0.0962% for GPR161 and 0.0687% for ELP1, neither of these genes can be a cause of Gorlin syndrome with an unexplained population frequency far lower at 0.0021%.

Missense variants in the NF2 gene result in variable NF2 disease presentation. Clinical classification of missense variants often represents a challenge, due to lack of evidence for pathogenicity and function. This study provides a summary of NF2 missense variants, with variant classifications based on currently available evidence. NF2 missense variants were collated from pathology-associated databases and existing literature. Association for Clinical Genomic Sciences Best Practice Guidelines (2020) were followed in the application of evidence for variant interpretation and classification. The majority of NF2 missense variants remain classified as variants of uncertain significance. However, NF2 missense variants identified in gnomAD occurred at a consistent rate across the gene, while variants compiled from pathology-associated databases displayed differing rates of variation by exon of NF2. The highest rate of NF2 disease-associated variants was observed in exon 7, while lower rates were observed toward the C-terminus of the NF2 protein, merlin. Further phenotypic information associated with variants, alongside variant-specific functional analysis, is necessary for more definitive variant interpretation. Our data identified differences in frequency of NF2 missense variants by exon between gnomAD population data and NF2 disease-associated variants, suggesting a potential genotype-phenotype correlation; further work is necessary to substantiate this.

Vestibular schwannomas are benign nerve sheath tumours that arise on the vestibulocochlear nerves. Vestibular schwannomas are known to occur in the context of tumour predisposition syndromes NF2-related and LZTR1-related schwannomatosis. However, the majority of vestibular schwannomas present sporadically without identification of germline pathogenic variants.To identify novel genetic associations with risk of vestibular schwannoma development, we conducted a genome-wide association study in a cohort of 911 sporadic vestibular schwannoma cases collated from the neurofibromatosis type 2 genetic testing service in the north-west of England, UK and 5500 control samples from the UK Biobank resource. One risk locus reached genome-wide significance in our association analysis (9p21.3, rs1556516, P = 1.47 × 10−13, odds ratio = 0.67, allele frequency = 0.52).9p21.3 is a genome-wide association study association hotspot, and a number of genes are localized to this region, notably CDKN2B-AS1 and CDKN2A/B, also referred to as the INK4 locus. Dysregulation of gene products within the INK4 locus have been associated with multiple pathologies and the genes in this region have been observed to directly impact the expression of one another. Recurrent associations of the INK4 locus with components of well-described oncogenic pathways provides compelling evidence that the 9p21.3 region is truly associated with risk of vestibular schwannoma tumorigenesis.

BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case-control study of 3,767 cases and 2,043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3-444.2; P=0.0001). The risk was highest for women with EOC (OR=140.8; 95% CI 23.5-1723.0; PT was associated with smaller risks for BC/EOC (OR=5.4; 95%CI 2.4-12.7; P=0.0003), EOC (OR=5.9; 95% CI 1.3-23.0; p=0.0550), and BC (OR=5.3; 95%CI 2.3-12.9; P=0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant-negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant-negative missense variants may confer higher risks than their loss-of-function counterparts.

A number of case/family reports have proposed PTCH2 as a putative Gorlin Syndrome (GS) gene, but evidence to support this is lacking. We assessed our cohort of 21 PTCH1/SUFU negative GS families for PTCH2 variants and assessed current evidence from reported cases/families and population data. In our PTCH1/SUFU variant negative GS cohort (25% of total), no pathogenic or likely pathogenic PTCH2 variants were identified. In addition, none of the previously published PTCH2 variants in GS families/cases could be considered pathogenic or likely pathogenic using current guidelines. The absence of clear pathogenic variants in GS families and the high frequency of Loss-of-function (LoF) variants in the general population, including the presence of homozygous LoF variants without a clinical phenotype, mean that it is untenable that PTCH2 is a GS gene. PTCH2 should not be included in panels for genetic diagnosis of GS.

PURPOSE To investigate the contribution of PALB2 pathogenic gene variants (PGVs, PALB2_PGV) and the CHEK2 c.1100delC (CHEK2_1100delC) PGV to familial breast and ovarian cancer, and PALB2_PGV associated breast cancer pathology. METHODS Outcomes of germline PALB2_PGV and CHEK2_1100delC testing were recorded in 3,127 women with histologically confirmed diagnoses of invasive breast cancer, carcinoma in situ, or epithelial nonmucinous ovarian cancer, and 1,567 female controls. Breast cancer pathology was recorded in PALB2_PGV cases from extended families. RESULTS Thirty-five PALB2 and 44 CHEK2_1100delC PGVs were detected in patients (odds ratio [OR] PALB2 breast-ovarian = 5.90 [95% CI: 1.92-18.36], CHEK2 breast-ovarian = 4.46 [95% CI: 1.86-10.46], PALB2 breast = 6.16 [95% CI: 1.98-19.21], CHEK2 breast = 4.89 [95% CI: 2.01-11.34]). Grade 3 ER-positive HER2-negative, grade 3 and triple negative (TN) tumors were enriched in cases with PALB2 PGVs compared with all breast cancers known to our service (respectively: 15/43, 254/1,843, P = 0.0005; 28/37, 562/1,381, P = 0.0001; 12/43, 204/1,639, P

Schwannomatosis comprises a group of hereditary tumor predisposition syndromes characterized by, usually benign, multiple nerve sheath tumors, which frequently cause severe pain that does not typically respond to drug treatments. The most common schwannomatosis-associated gene is NF2, but SMARCB1 and LZTR1 are also associated. There are still many cases in which no pathogenic variants (PVs) have been identified, suggesting the existence of as yet unidentified genetic risk factors. In this study, we performed extended genetic screening of 75 unrelated schwannomatosis patients without identified germline PVs in NF2, LZTR1, or SMARCB1. Screening of the coding region of DGCR8, COQ6, CDKN2A, and CDKN2B was carried out, based on previous reports that point to these genes as potential candidate genes for schwannomatosis. Deletions or duplications in CDKN2A, CDKN2B, and adjacent chromosome 9 region were assessed by multiplex ligation-dependent probe amplification analysis. Sequencing analysis of a patient with multiple schwannomas and melanomas identified a novel duplication in the coding region of CDKN2A, disrupting both p14ARF and p16INK4a. Our results suggest that none of these genes are major contributors to schwannomatosis risk but the possibility remains that they may have a role in more complex mechanisms for tumor predisposition.

Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required.

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

Meningiomas are the most common primary brain tumor and their incidence and prevalence is increasing. This review summarizes current evidence regarding the embryogenesis of the human meninges in the context of meningioma pathogenesis and anatomical distribution. Though not mutually exclusive, chromosomal instability and pathogenic variants affecting the long arm of chromosome 22 (22q) result in meningiomas in neural-crest cell-derived meninges, while variants affecting Hedgehog signaling, PI3K signaling,TRAF7,KLF4, andPOLR2Aresult in meningiomas in the mesodermal-derived meninges of the midline and paramedian anterior, central, and ventral posterior skull base. Current evidence regarding the common pathways for genetic pathogenesis and the anatomical distribution of meningiomas is presented alongside existing understanding of the embryological origins for the meninges prior to proposing next steps for this work.

Schwannomatosis is a rare tumor predisposition syndrome that causes multiple schwannomas. Germline loss-of-function (LoF) LZTR1 variants were only recently identified as disease-causing, so relatively few variants have been identified in patients. In addition, many LoF variants exist in Genome Aggregation Database (gnomAD) in people who do not have clinical symptoms of schwannomatosis. These factors, and the incomplete penetrance seen in this condition, hinder definitive interpretation of the clinical significance of novel LoF variants identified in schwannomatosis patients. We collated published LOF LZTR1 variants identified in schwannomatosis patients and classified them according to current American College of Medical Genetics and Genomics/Association for Molecular Pathology/Association of Clinical Genomic Science guidelines. Subsequently, pathogenic/likely pathogenic schwannomatosis-associated LoF variants were compared with LoF LZTR1 variants reported in gnomAD data. Using current classification guidelines, 64/71 LoF LZTR1 variants reported in schwannomatosis patients in the literature were classified as pathogenic/likely pathogenic, and their frequency in probands 64/359 (17.8%) was significantly higher than the frequency of potential LoF variants identified in the general population (0.36%; p < 0.0001). The majority of published classifications of schwannomatosis-associated LoF variants are robust. However, the high frequency of LoF LZTR1 variants in the general population suggests that LZTR1 variants confer a reduced risk of schwannomas compared to germline NF2 and SMARCB1 pathogenic variants, making classification of novel variants challenging.

PURPOSE: Epithelial ovarian cancer (EOC) is associated with pathogenic variants (PVs) in homologous recombination and/or mismatch repair genes. We aimed to review the testing of women with familial EOC at our center.METHODS: Women with familial EOC (≥2 EOC in family, including index case) referred to our center between 1993 and 2021 were included. Genetic testing (BRCA/Lynch syndrome screening, exome sequencing, panel testing, 100,000 Genome Project, and NIHR BioResource genome sequencing) and clinical demographic, diagnosis, and survival data were reviewed.RESULTS: Of 277, 128 (46.2%) women were BRCA heterozygotes (BRCA1: 89, BRCA2: 39). The detection rate in BRCA-negative women was 21.8%; the most commonly affected gene was BRIP1 (5.9%). The non-BRCA detection rate was significantly higher in families with 2 affected members with EOC only (22.4%) than the families with ≥3 (11.1%) affected members (odds ratio = 9.9, 95% CI = 1.6-105.2, P = .0075). Overall, 112 different PVs in 12 homologous recombination/mismatch repair genes were detected in 150 of 277 (54.2%) unrelated women.CONCLUSION: This is the largest report of women with familial EOC undergoing wider testing to date. One-fifth of BRCA-negative women were heterozygous for a PV in a potentially actionable gene. Wider genetic testing of women with familial EOC is essential to optimize their treatment and prevention of disease in family members.

Clear cell meningioma (CCM) is a rare variant of meningioma. In recent years, an association between cranial and spinal CCMs and germline loss of function mutations in the SMARCE1 gene (SWI/SNF chromatin remodeling complex subunit gene) has been discovered. We report a family with an incidental large spinal clear cell meningioma in a young adult following reflex screening for a germline loss of function pathogenic variant (PV) in the SMARCE1 gene. The index patient's mother and maternal grandfather were both also tested positive presymptomatically for SMARCE1. His mother developed intracranial and spinal meningiomas and his maternal grandfather developed a spinal CCM 4 years following a clear spinal MRI scan which required surgical excision. In this report we particularly emphasize the importance of genetic counseling and screening in siblings, parents and offspring of patients who are diagnosed with intracranial or spinal CCM in the context of SMARCE1 PVs. We recommend brain and spine Imaging screening of asymptomatic SMARCE1 PV carriers at least every 3 years, even if the baseline scan did not show any tumors.

PURPOSE: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).METHODS: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.RESULTS: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma CONCLUSION: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

BackgroundBazex-Dupré-Christol syndrome (BDCS; MIM301845) is a rare X-linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11.4 Mb interval on chromosome Xq25-27.1. However, the genetic mechanism of BDCS remains an open question.MethodsTo investigate the genetic etiology of BDCS, we ascertained eight families with individuals affected with BDCS (F1-F8). Whole exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease-causing variants within the linkage region. Array-comparative genomic hybridization and quantitative PCR were used to explore copy number variations (CNV) in BDCS families, followed by long-range gap-PCR and Sanger sequencing to amplify duplication junction and define the precise head-tail junctions, respectively. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from BDCS patients and sporadic BCCs to detect the expression of corresponding genes. The ACTRT1 variant (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with allele frequency calculator.ResultsIn eight BDCS families, we identified overlapping 18-135kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. We detected ARHGAP36 expression near the control hair follicular stem cells compartment, and found increased ARHGAP36 levels in hair follicles in telogen, BCCs and trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted ACTRT1 variants maximum tolerated minor allele frequency in control populations to be orders of magnitude higher than expected for a high-penetrant ultra-rare disorder, suggesting loss-of-function of ACTRT1 is unlikely to cause BDCS.ConclusionsOur data support the pathogenicity of intergenic duplications at Xq26.1, most likely leading to dysregulation of ARHGAP36, establish BDCS as a genomic disorder, and provide a potential therapeutic target for both inherited and sporadic BCCs.

Neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis are a group of autosomal dominant disorders that predispose to the development of nerve sheath tumors. Pathogenic variants (PVs) that cause NF1 and NF2 are located in the NF1 and NF2 loci, respectively. To date, most variants associated with schwannomatosis have been identified in the SMARCB1 and LZTR1 genes, and a missense variant in the DGCR8 gene was recently reported to predispose to schwannomas. In spite of the high detection rate for PVs in NF1 and NF2 (over 90% of non-mosaic germline variants can be identified by routine genetic screening) underlying PVs for a proportion of clinical cases remain undetected. A higher proportion of non-NF2 schwannomatosis cases have no detected PV, with PVs currently only identified in around 70%–86% of familial cases and 30%–40% of non-NF2 sporadic schwannomatosis cases. A number of variants of uncertain significance have been observed for each disorder, many of them located in noncoding, regulatory, or intergenic regions. Here we summarize noncoding variants in this group of genes and discuss their established or potential role in the pathogenesis of NF1, NF2, and schwannomatosis.

Background A vestibular schwannoma (VS) is a relatively rare, benign tumour of the eighth cranial nerve, often involving alterations to the gene NF2. Previous mathematical models of schwannoma incidence have not attempted to account for alterations in specific genes, and could not distinguish between nonsense mutations and loss of heterozygosity (LOH). Methods Here, we present a mechanistic approach to modelling initiation and malignant transformation in schwannoma. Each parameter is associated with a specific gene or mechanism operative in Schwann cells, and can be determined by combining incidence data with empirical frequencies of pathogenic variants and LOH. Results This results in new estimates for the base-pair mutation rate u = 4.48 × 10−10 and the rate of LOH = 2.03 × 10−6/yr in Schwann cells. In addition to new parameter estimates, we extend the approach to estimate the risk of both spontaneous and radiation-induced malignant transformation. Discussion We conclude that radiotherapy is likely to have a negligible excess risk of malignancy for sporadic VS, with a possible exception of rapidly growing tumours.

BackgroundBilateral vestibular schwannomas (VS) are pathognomonic of Neurofibromatosis type 2 (NF2), but the diagnostic criteria also include unilateral vestibular schwannomas (UVS) in combination with multiple meningiomas (MM) and other schwannomas, as well as MM without VS. ObjectiveTo investigate the diagnostic value of these criteria and establish the presence of other genetic conditions in patients presenting in this manner.Methods The (BLINDED FOR REVIEW) NF2 database was accessed to obtain information on patients presenting with a UVS and MM or ≥2 non-intradermal schwannomas (NIDS). We gathered data on patients diagnosed with NF2 due to MM without VS, and on patients presenting with MM without meeting NF2 criteria. Analysis was performed for pathogenic variants (PV) in NF2, SMARCE1, SMARCB1 and LZTR1.Results 131/131 patients presenting with a UVS and MM had a non-refuted diagnosis of NF2 after molecular studies, in comparison with 85/96 patients presenting with UVS and ≥2 NIDS (p=ConclusionPatients presenting with UVS and MM are significantly more likely to have a non-refuted diagnosis of NF2 than patients presenting with UVS and ≥2 NIDS, but significantly less likely to develop bilateral VS. 7% of those presenting with MM without meeting NF2 criteria had PV in SMARCE1, and 5% had mosaic NF2.

PURPOSE: By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS: We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS: We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION: The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS. ispartof: GENETICS IN MEDICINE vol:23 issue:8 pages:1506-1513 ispartof: location:United States status: published

Whilst panel testing of an extended group of genes including BRCA1/2 is commonplace, these studies have not been subdivided by histiotype or by a priori BRCA1/2 probability. Patients with a breast cancer diagnosis undergoing extended panel testing were assessed for frequency of actionable variants in breast cancer genes other than BRCA1/2 by histiotype and Manchester score (MS) to reflect a priori BRCA1/2 likelihood. Rates were adjusted by prior testing for BRCA1/2 in an extended series. 95/1398 (6.3%) who underwent panel testing were found to be positive for actionable non-BRCA1/2 breast/ovarian cancer genes (ATM, BARD1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, TP53). As expected, PALB2, CHEK2 and ATM were predominant with 80-(5.3%). The highest rate occurred in Grade-3 ER+/HER2− breast cancers-(9.6%). Rates of non-BRCA actionable genes was fairly constant over all likelihoods of BRCA1/2 but adjusted rates were three times higher with MS &lt, 9 (BRCA1/2 = 1.5%, other = 4.7%), but was only 1.6% compared to 79.3% with MS ≥ 40. Although rates of detection of non-BRCA actionable genes are relatively constant across BRCA1/2 likelihoods this disguises an overall adjusted low frequency in high-likelihood families which have been heavily pre-tested for BRCA1/2. Any loss of detection sensitivity for BRCA1/2 actionable variants in breast cancer panels should lead to bespoke BRCA1/2 testing being conducted first.

Purpose: We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods: Two large databases of individuals fulfilling NF2 criteria (n=1361) and those tested for NF2 variants with criteria short of diagnosis (n=1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the Positive Predictive Value (PPV) with regard to definite diagnosis.Results: There was no evidence for usefulness of old criteria ‘glioma’ or ‘neurofibroma’. ‘Ependymoma’ had 100% PPV and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced PPV(80%). Siblings as a first-degree-relative, without an affected parent, had 0% PPV. All three individuals with unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with unilateral VS plus ≥2 non-dermal schwannomas reduced PPV to 67%.Conclusion: The present study has confirmed important deficiencies in NF2 diagnostic criteria. The term ‘glioma’ should be dropped and replaced by ‘ependymoma’. Similarly ‘neurofibroma’ should be removed. Dropping ‘sibling’ from first-degree-relatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

A 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes of anorexia and vomiting. Examination revealed right torticollis and Horner’s syndrome, and a large abdominal mass arising from the pelvis. Magnetic resonance and positron emission tomography imaging revealed A) a 14cm heterogeneous enhancing mass, abutting the left kidney with standardised uptake value max=2.9, B) a large heterogeneous enhancing pelvic mass C) mesenteric adenopathy standardised uptake value max=10.3 and D) 6cm right lung apex mass standardised uptake value max=4.3.Computerised tomography-guided biopsy of lesion A was reported as neurofibroma with occasional atypia, lesion B a benign uterine leiomyoma and lesion C follicular Lymphoma world health organisation Grade 2.Although she had been given the diagnosis of Neurofibromatosis Type-1 (NF1) 25-years previously following removal of an intradural extramedullary schwannoma she had no cutaneous stigmata of NF1. Genetic analysis of blood lymphocyte DNA identified a pathogenic variant in SMARCB1 confirming a diagnosis of schwannomatosis..Following 6-months chemotherapy for lymphoma, surgery was performed to remove lesion A. Histology revealed a malignant peripheral nerve sheath tumour with areas of low and high-grade change. An incidental, well-differentiated small bowel neuroendocrine carcinoma was also excised. Close surveillance continues with no recurrence after six years. This case study describes a novel finding of three separate synchronous primary malignancies in a patient with schwannomatosis and a proven SMARCB1 pathogenic variant.

SMARCE1 loss destabilizes the canonical BAF complex and increases the formation of BRD9-containing non-canonical (ncBAF) complexes. SMARCE1-deficient cells, which are a model for clear cell meningioma, are sensitive to ncBAF complex inhibition.Mammalian SWI/SNF (mSWI/SNF) ATP-dependent chromatin remodeling complexes establish and maintain chromatin accessibility and gene expression, and are frequently perturbed in cancer. Clear cell meningioma (CCM), an aggressive tumor of the central nervous system, is uniformly driven by loss of SMARCE1, an integral subunit of the mSWI/SNF core. Here, we identify a structural role for SMARCE1 in selectively stabilizing the canonical BAF (cBAF) complex core-ATPase module interaction. In CCM, cBAF complexes fail to stabilize on chromatin, reducing enhancer accessibility, and residual core module components increase the formation of BRD9-containing non-canonical BAF (ncBAF) complexes. Combined attenuation of cBAF function and increased ncBAF complex activity generates the CCM-specific gene expression signature, which is distinct from that of NF2-mutated meningiomas. Importantly, SMARCE1-deficient cells exhibit heightened sensitivity to small-molecule inhibition of ncBAF complexes. These data inform the function of a previously elusive SWI/SNF subunit and suggest potential therapeutic approaches for intractable SMARCE1-deficient CCM tumors.

Purpose The LZTR1 gene has been associated with schwannomatosis tumor predisposition and is located in a region that is deleted in the great majority (89%) of patients with 22q11.2 deletion syndrome (22q11.2DS). Since it is known that approximately 1 in 500 people in the general population will develop a sporadic schwannoma and there are no reports of the occurrence of schwannoma in 22q11.2DS, we investigated whether whole-gene deletion of LZTR1 occurs in schwannomatosis and assessed the risk of schwannoma in 22q11.2DS. Methods We assessed the genetic testing results for LZTR1-associated schwannomatosis and the clinical phenotypes of patients with 22q11.2DS. Results There were no reports of schwannoma in over 1,500 patients with 22q11.2DS. In addition, no patients meeting clinical diagnostic criteria for schwannomatosis had a whole-gene deletion in LZTR1. Only 1 patient in 110 with an apparently sporadic vestibular schwannoma had a constitutional whole-gene deletion of LZTR1. Conclusion People with a large 22q11.2 deletion may have a reduced risk of developing a schwannoma compared to the general population.

Correction to: Nature Communications https://doi.org/10.1038/s41467-019-10717-9, published online 27 May 2020.The original version of this Article omitted from the Genome Aggregation Database consortium the member Marquis P. Vawter, from the Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA, USA. Additionally, the following was added to the Author Contributions: ‘All authors listed under The Genome Aggregation Database Consortium contributed to the generation of the primary data incorporated into the gnomAD resource’. This has been corrected in both the PDF and HTML versions of the Article.

Individuals vary in their innate behaviors, even when they have the same genome and have been reared in the same environment. The extent of individuality in plastic behaviors, like learning, is less well characterized. Also unknown is the extent to which intragenotypic differences in learning generalize: if an individual performs well in one assay, will it perform well in other assays? We investigated this using the fruit fly Drosophila melanogaster, an organism long-used to study the mechanistic basis of learning and memory. We found that isogenic flies, reared in identical lab conditions, and subject to classical conditioning that associated odorants with electric shock, exhibit clear individuality in their learning responses. Flies that performed well when an odor was paired with shock tended to perform well when other odors were paired with shock, or when the original odor was paired with bitter taste. Thus, individuality in learning performance appears to be prominent in isogenic animals reared identically, and individual differences in learning performance generalize across stimulus modalities. Establishing these results in flies opens up the possibility of studying the genetic and neural circuit basis of individual differences in learning in a highly suitable model organism.

Purpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

Background Limited data exist on the disease course of neurofibromatosis type 2 (NF2) to guide clinical trial design. Methods A prospective database of patients meeting NF2 diagnostic criteria, reviewed between 1990 and 2020, was evaluated. Follow-up to first vestibular schwannoma (VS) intervention and death was assessed by univariate analysis and stratified by age at onset, era referred, and inheritance type. Interventions for NF2-related tumors were assessed. Cox regression was performed to determine the relationship between individual factors from time of diagnosis to NF2-related death. Results Three hundred and fifty-three patients were evaluated. During 4643.1 follow-up years from diagnosis to censoring, 60 patients (17.0%) died. The annual mean number of patients undergoing VS surgery or radiotherapy declined, from 4.66 and 1.65, respectively, per 100 NF2 patients in 1990-1999 to 2.11 and 1.01 in 2010-2020, as the number receiving bevacizumab increased (2.51 per 100 NF2 patients in 2010-2020). Five patients stopped bevacizumab to remove growing meningioma or spinal schwannoma. 153/353 (43.3%) had at least one neurosurgical intervention/radiation treatment within 5 years of diagnosis. Patients asymptomatic at diagnosis had longer time to intervention and better survival compared to those presenting with symptoms. Those symptomatically presenting 40 years had poorer overall survival than those presenting at 26-39 years (P = .03 and P = .02, respectively) but those presenting between 16 and 39 had shorter time to VS intervention. Individuals with de novo constitutional variants had worse survival than those with de novo mosaic or inherited disease (P = .004). Conclusion Understanding disease course improves prognostication, allowing for better-informed decisions about care.

Funder: national institute of health research, INTRODUCTION: Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case-control studies, meta-analyses and genome-wide association studies to identify genomic variants that may be associated with endometrial cancer risk. METHODS: We searched MEDLINE, Embase and CINAHL from 2007 to 2019 without restrictions. We followed PRISMA 2009 guidelines. The search yielded 3015 hits in total. Following duplicate exclusion, 2674 abstracts were screened and 453 full-texts evaluated based on our pre-defined screening criteria. 149 articles were eligible for inclusion. RESULTS: We found that single nucleotide polymorphisms (SNPs) in HNF1B, KLF, EIF2AK, CYP19A1, SOX4 and MYC were strongly associated with incident endometrial cancer. Nineteen variants were reported with genome-wide significance and a further five with suggestive significance. No convincing evidence was found for the widely studied MDM2 variant rs2279744. Publication bias and false discovery rates were noted throughout the literature. CONCLUSION: Endometrial cancer risk may be influenced by SNPs in genes involved in cell survival, oestrogen metabolism and transcriptional control. Larger cohorts are needed to identify more variants with genome-wide significance.

ObjectivesCases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis.MethodsCases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups.ResultsAge at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants.ConclusionsUndiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1-associated VS tumourigenesis.

Early age at diagnosis of breast cancer is a known risk factor for hereditary predisposition and some studies show a high risk of contralateral breast cancer in BRCA1 carriers diagnosed at very young ages. However, little is published on the risk of TP53 carriers. 397 women with breast cancer diagnosed BRCA1, BRCA2, and TP53 genes was carried out alongside tests for copy number for PV on all referred women. Rates of contralateral breast cancer were censored at death, last assessment, or risk-reducing mastectomy. In total, 47 TP53, 218 BRCA1, and 132 BRCA2 PV carriers were identified with breast cancer diagnosed aged 35 years and under, as well as a representative sample of 261 not known to carry a PV in BRCA1, BRCA2, and TP53. Annual rates of contralateral breast cancer (and percentage of synchronous breast cancers) were TP53: 7.03% (4.3%), BRCA1: 3.57% (1.8%), and BRCA2: 2.63% (1.5%). In non-PV carriers, contralateral rates in isolated presumed/tested non-carrier cases with no family history were 0.56%, and for those with a family history, 0.69%. Contralateral breast cancer rates are substantial in TP53, BRCA1, and BRCA2 PV carriers diagnosed with breast cancer aged 35 and under. Women need to be advised to help make informed decisions on contralateral mastectomy, guided by life expectancy from their index tumor.

Objectives/hypothesis Unilateral vestibular schwannoma (VS) occurs with a lifetime risk of around 1 in 1,000 and is due to inactivation of the NF2 gene, either somatically or from a constitutional mutation. It has been postulated that familial occurrence of unilateral VS occurs more frequently than by chance, but no causal mechanism has been confirmed. Study design Retrospective database analysis. Methods The likelihood of chance occurrence of unilateral VS, or occurring in the context of neurofibromatosis type 2 (NF2), was assessed using national UK audit data and data from the national NF2 database. Families with familial unilateral VS (occurrence in first- and second-degree relatives) were assessed for constitutional NF2 and LZTR1 genetic variants, and where possible the tumor was also analyzed. Results Approximately 1,000 cases of unilateral VS occurred annually in the United Kingdom between 2013 and 2016. Of these, 2.5 may be expected to have a first-degree relative who had previously developed a unilateral VS. The likelihood of this occurring in NF2 was considered to be as low as 0.05 annually. None of 28 families with familial unilateral VS had a constitutional NF2 intragenic variant, and in nine cases where the VS was analyzed, both mutational events in NF2 were identified and excluded from the germline. Only three variants of uncertain significance were found in LZTR1. Conclusions Familial occurrence of unilateral VS is very unlikely to be due to a constitutional NF2 or definitely pathogenic LZTR1 variant. The occurrence of unilateral VS in two or more first-degree relatives is likely due to chance. This phenomenon may well increase in clinical practice with increasing use of cranial magnetic resonance imaging in older patients. Level of evidence 2b Laryngoscope, 129:967-973, 2019.

ObjectivesSchwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2.MethodsSchwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available.ResultsRegional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004).ConclusionsWithin the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

In families with multiple affected individuals with early-onset breast/ovarian cancer pathogenic variants in BRCA1 or BRCA2 are identified in approximately 20% of the cases. Extensive efforts have been made to identify additional highly penetrant breast cancer genes or alternative mutational mechanisms affecting BRCA1 and BRCA2 to explain the missing heritability. It has been proposed that part of the missing heritability may be explained by gene silencing due to promoter methylation of cancer associated genes, as described in colorectal cancer (MLH1 and MSH2). Here, for the first time, we report two independent families with multiple individuals affected by breast and ovarian cancer with transgenerational promoter methylation of BRCA1. RNA analysis of BRCA1 in the germline of breast/ovarian families, previously found to be BRCA1/2 mutation negative by Sanger sequencing and copy number analysis, identified two families with allelic loss of expression. To investigate the mechanism of transcriptional silencing, a total of 14 affected and unaffected family members from these two families were tested for BRCA1 promoter methylation by pyrosequencing in blood, buccal, and hair follicle cells. Allele specific methylation was determined by clonal bisulphite sequencing. BRCA1 promoter methylation in all three germ layers was present in 11 of 14 family members. Of the 7 women with promoter methylation five were affected with grade 3 breast/high grade serous ovarian cancer. The four males with BRCA1 promoter methylation had no history of cancer. Methylation levels were ˜50%, consistent with the silencing of one allele detected in RNA in these family members. Clonal bisulphite sequencing of an affected family member of each family confirmed that the alternative allele was specifically methylated. Interestingly, in both families the methylation pattern of the BRCA1 promoter segregated with the same novel heterozygous variant in the 5'UTR of BRCA1. These results indicate a novel mechanism for familial breast/ovarian cancer, caused by epigenetic silencing of one allele by transgenerational hypermethylation of the BRCA1 promoter, secondary to a variant in cis of BRCA1. We propose that methylation analyses are indicated in all families affected by early onset breast/ovarian cancer where standard mutation screening of BRCA1/2 has not identified a causative variant. Citation Format: van Veen EM, Smith MJ, Byers HJ, Wallace AJ, Lalloo FI, Newman WG, Evans DGR. Transgenerational epigenetic silencing of BRCA1 due to a germline variant unmasks a new mechanism for familial breast and ovarian cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD1-05.

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome, is a rare multisystemic autosomal dominant disorder typically presenting with cutaneous basal cell carcinomas, multiple keratocysts, and skeletal anomalies. NBCCS is caused by heterozygous mutations in the PTCH1 gene in chromosome 9q22, in the PTCH2 gene in 1p34, or the SUFU gene in 10q24.32. Here, we report on an 18-month-old boy presenting with medulloblastoma, frontal bossing, and multiple skeletal anomalies and his father who has basal cell carcinomas, palmar pits, macrocephaly, bifid ribs, calcification of falx cerebri, and a history of surgery for odontogenic keratocyst. These clinical findings were compatible with the diagnosis of NBCCS, and a novel mutation, c.1249delC; p.Gln417Lysfs*15, was found in PTCH1 causing a premature stop codon.

Grade II/III meningiomas have increased rates of recurrence with no approved medical therapies. The historical progression-free survival at 6 months (PFS-6) is 25% with rates >35% declared of interest for drug development. NF2 gene inactivation occurs in about half of meningiomas. Based on our studies showing mTORC1 and mTORC2/SGK1 pathway activation in NF2-deficient meningiomas and the paradoxical activation of the mTORC2/AKT pathway, we hypothesized that mTORC1/mTORC2 inhibitors would be active in meningiomas. We studied the effect of vistusertib in patients with progressive/recurrent grade II/III meningiomas (NCT03071874). Vistusertib was administered orally at 125mg twice daily on two consecutive days each week. MRIs were obtained every 56 days. Tumor size was defined as the largest cross-sectional area. Progression was defined as ≥ 25% increase in the sum of products of all measurable lesions over smallest sum observed. The primary endpoint was PFS-6. Secondary endpoints included toxicity, radiographic response, and correlative studies including immunohistochemistry for mTORC1/2 pathway activation and genetic biomarkers. Twenty-eight patients (13 female, median age 58 years, median KPS 80%) were enrolled. Median tumor size was 4.4cm; 71% were grade II and 50% harbored pathogenic NF2 variants. Four patients discontinued treatment voluntarily and 1 each withdrew for intercurrent illness and non-compliance. PFS-6 is 47% (CI, 26%-65%) and OS-12 is 72% (95%CI, 48%-86%). PFS but not OS was shorter for patients with grade 3 meningiomas; there was no difference in PFS/OS between genetic groups. Adverse events at least possibly related to vistusertib with frequency >10% include nausea, fatigue, hypophosphatemia, diarrhea, anorexia, dry mouth, hypertriglyceridemia, hypertension, vomiting, increased ALT, constipation, and weight loss. Vistusertib treatment was associated with a PFS-6 rate exceeding the target of 35% for recurrent high-grade meningioma. Adverse events were tolerable in this patient population. These data support the continued development of mTORC1/2 inhibitors in this setting.

BACKGROUND Little is known about cancer risk associated with pathogenic germline SUFU variants. METHODS Data of all previously published and 25 still unpublished patients with a pathogenic germline SUFU mutation were compiled. RESULTS 124 patients in 67 families were identified, most of them ascertained after the occurrence of a medulloblastoma (MB) or as part of Gorlin syndrome cohorts. Overall, 30 patients were healthy carriers and 94 patients developed a total of 129 tumors (up to 4 tumors/patient): 68 MBs, always as first tumor (median age at diagnosis: 1.5yr [0.1–5]), 22 patients with at least 1 basal cell carcinoma (BCC) (median 10/patient) (median age at first BCC: 43yr, [17–52]), 15 meningiomas (median age 43yr, [13–72]), 7 ovarian stromal/fibrous tumors (median age 12yr [5–34]), and 17 other tumors including 5 sarcomas (median age: 50yr [7–79]). Median age at last follow-up was 30yr. Nineteen patients died, including 11 from MB. Second malignancies were diagnosed in 21 patients including 13 in MB survivors. Mutations were inherited in 58/66 (88%) of cases in which inheritance could be tested and de novo in 8. In 6/67 families (9%), >2 children were diagnosed with a MB. CONCLUSION In this large cohort of germline SUFU mutation carriers, MB in infants is the most frequent tumor but the spectrum also includes typical Gorlin syndrome tumors (BCC, meningiomas, and ovarian stromal/fibrous tumors) either as first tumors or as second malignancies. This broad tumor spectrum and the high risk of second malignancies justify the implementation of specific cancer surveillance programs.

Background Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype–phenotype correlations in GS. Methods We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1–61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation. Results Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants (p=0.03). Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004). Conclusion We propose that the clinical heterogeneity of GS can in part be explained by the underlying or SUFU variant.