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Simple Summary We have analyzed a panel of 88 pediatric medulloblastoma tumors for exon 3 mutations from the CTNNB1 gene and identified eight missense point-mutations and one in-frame deletion. We describe and functionally characterize a novel CTNNB1 in-frame deletion (c.109-111del, pSer37del, ΔS37) found in a pediatric patient with a classic medulloblastoma, WNT-activated grade IV (WHO 2016). To the best of our knowledge, this mutation has not been previously reported in medulloblastoma, and it is uncertain its role in the disease development and progression. Our analysis discloses gain-of-function properties for the new ΔS37 β-catenin variant. Abstract Medulloblastoma is the primary malignant tumor of the Central Nervous System (CNS) most common in pediatrics. We present here, the histological, molecular, and functional analysis of a cohort of 88 pediatric medulloblastoma tumor samples. The WNT-activated subgroup comprised 10% of our cohort, and all WNT-activated patients had exon 3 CTNNB1 mutations and were immunostained for nuclear β-catenin. One novel heterozygous CTNNB1 mutation was found, which resulted in the deletion of β-catenin Ser37 residue (ΔS37). The ΔS37 β-catenin variant ectopically expressed in U2OS human osteosarcoma cells displayed higher protein expression levels than wild-type β-catenin, and functional analysis disclosed gain-of-function properties in terms of elevated TCF/LEF transcriptional activity in cells. Our results suggest that the stabilization and nuclear accumulation of ΔS37 β-catenin contributed to early medulloblastoma tumorigenesis.

Inherited platelet disorders are a heterogeneous group of rare diseases, caused by inherited defects in platelet production and/or function. Their genetic diagnosis would benefit clinical care, prognosis and preventative treatments. Until recently, this diagnosis has usually been performed via Sanger sequencing of a limited number of candidate genes. High-throughput sequencing is revolutionizing the genetic diagnosis of diseases, including bleeding disorders. We have designed a novel high-throughput sequencing platform to investigate the unknown molecular pathology in a cohort of 82 patients with inherited platelet disorders. Thirty-four (41.5%) patients presented with a phenotype strongly indicative of a particular type of platelet disorder. The other patients had clinical bleeding indicative of platelet dysfunction, but with no identifiable features. The high-throughput sequencing test enabled a molecular diagnosis in 70% of these patients. This sensitivity increased to 90% among patients suspected of having a defined platelet disorder. We found 57 different candidate variants in 28 genes, of which 70% had not previously been described. Following consensus guidelines, we qualified 68.4% and 26.3% of the candidate variants as being pathogenic and likely pathogenic, respectively. In addition to establishing definitive diagnoses of well-known inherited platelet disorders, high-throughput sequencing also identified rarer disorders such as sitosterolemia, filamin and actinin deficiencies, and G protein-coupled receptor defects. This included disease-causing variants in DIAPH1 (n=2) and RASGRP2 (n=3). Our study reinforces the feasibility of introducing high-throughput sequencing technology into the mainstream laboratory for the genetic diagnostic practice in inherited platelet disorders., This study was supported by research grants from the Gerencia Regional de Salud (GRS 1370/A/16), ISCIII & Feder (PI14/01956), CIBERER CB15/00055, Fundación Séneca (19873/GERM/15) and Sociedad Española de Trombosis y Hemostasia (SETH). SPW holds a British Heart Foundation chair.

The aim of this study is to describe childhood cancer incidence and survival in Castilla y Leon (Spain) for the period 2003 to 2014 and to explore differences between rural and urban areas.We made a cohort study in the childhood population of our region for the period of years referred before. Age-adjusted incidence rates to the world standard population (ASRw) were calculated by direct method, and their comparisons were made using incidence rate rations. Survival proportions were calculated by Kaplan-Meier method and their comparisons with log-rank test. The median childhood population less than 15 years old was 296,776 children. A total of 615 cases were recorded from the population-based Childhood Cancer Registry, including all malignant and benign tumors of the central nervous system.Age-standardized incidence rates for all cancers were 176.6 per million. Leukemia incidence rates were highest in rural areas (51.08/million) than in urban areas (33.65/million; P = .018), and by age groups; these differences only remained at age 0 to 4 years with higher rural leukemia incidence (67.13/million) than in urban areas (39.32/million; P = .05). There were no statistically significant differences between rural and urban areas for lymphomas, central nervous system, and all other malignant solid tumors grouped. The 5-year overall survival rate for all patients was 84%, similar to other developed countries, with greater survival in rural areas (88%) compared with urban areas (80%; P = .033). The analysis by tumor groups showed a greater survival rate in rural areas for all the groups, although these differences only reached statistical significance in the group of leukemias, with a survival rate of 90% for rural areas compared with 76% for urban areas (P = .01). Analyzing survival rate by age groups in leukemias only significant survival differences at 10 to 14 years were encountered.We found a higher incidence of leukemia in girls, mainly in rural areas, and also a better survival rate in children diagnosed with leukemia belonging to this population area. Future studies that analyze these facts in similar populations can help us clarify what genetic, epigenetic and environmental factors influence our population and are responsible for these findings.