Uncovering a mammalian neural-specific poly(A) binding protein with unique properties.

The mRNA 3' poly(A) tail plays a critical role in regulating both mRNA translation and turnover. It is bound by the cytoplasmic poly(A) binding protein (PABPC), an evolutionarily conserved protein that can interact with translation factors and mRNA decay machineries to regulate gene expression. Mammalian PABPC1, the prototypical PABPC, is expressed in most tissues and interacts with eukaryotic translation initiation factor 4G (eIF4G) to stimulate translation in specific contexts. In this study, we uncovered a new mammalian PABPC, which we named neural PABP (neuPABP), as it is predominantly expressed in the brain. neuPABP maintains a unique architecture as compared with other PABPCs, containing only two RNA recognition motifs (RRMs) and maintaining a unique N-terminal domain of unknown function. neuPABP expression is activated in neurons as they mature during synaptogenesis, where neuPABP localizes to the soma and postsynaptic densities. neuPABP interacts with the noncoding RNA BC1, as well as mRNAs coding for ribosomal and mitochondrial proteins. However, in contrast to PABPC1, neuPABP does not associate with actively translating mRNAs in the brain. In keeping with this, we show that neuPABP has evolved such that it does not bind eIF4G and as a result fails to support protein synthesis in vitro. Taken together, these results indicate that mammals have expanded their PABPC repertoire in the brain and propose that neuPABP may support the translational repression of select mRNAs.

Understanding the Burden of Colorectal Adenomas in Patients Younger Than 50 Years: A Large Single-Center Retrospective Cohort Study.

BACKGROUND: Colorectal cancer is increasing in young adults. Our understanding of the adenoma-carcinoma sequence in young patients aged <50 years is lacking. The yield obtained by lowering the age of screening colonoscopy remains unclear. OBJECTIVE: The goal of this study was to understand the burden and histology of colorectal polyps in young adults and to explore predictors of adenoma detection in this population. DESIGN: This is a retrospective cohort study. SETTING: Colonoscopies were performed at a single university-affiliated tertiary care center. PATIENTS: This study included adults aged <50 years who underwent a colonoscopy between 2014 and 2019. Patients with inflammatory bowel disease and genetic disorders were excluded. MAIN OUTCOME MEASURES: Adenoma detection rates were analyzed according to age. Predictors of adenoma detection were investigated by multiple logistic regression. RESULTS: A total of 4475 patients were analyzed. The mean age was 40.2 ± 8.0 years, 56.4% were female, and the mean BMI was 26.3 ± 5.5 kg/m2. A family history of colorectal cancer was reported in 23.8% of patients. The overall polyp and adenoma detection rates were 22% and 14%. The majority of polyps were adenomatous (58.9% of all polypectomies) and located in the left colon or rectum (61.4%). The detection rates of adenomas, advanced neoplasias, and adenocarcinomas were highest in patients aged 45 to 49 (19.3%, 4.8%, and 1.3%). On multivariate analysis, variables independently associated with adenoma detection included age (OR 1.08, 95% CI, 1.06-1.1), female sex (OR 1.80, 95% CI, 1.44-2.27), BMI (OR 1.01, 95% CI, 1.01-1.05), and having undergone a diagnostic colonoscopy (OR 1.81, 95% CI, 1.44-2.29). On subgroup analysis of patients aged 45 to 49, the same variables remained associated with adenoma detection except for age. LIMITATIONS: The study was limited due to the retrospective nature with heterogenous data. CONCLUSIONS: Adenoma detection in young adults aged 45 to 49 approaches the current adenoma detection of older adults. Predictors of adenoma detection in these young adults are female gender and BMI, which may help guide colorectal cancer screening guidelines in the future. See Video Abstract at http://links.lww.com/DCR/B843. COMPRENDER DE LA CARGA DE LOS ADENOMAS COLORRECTALES EN PACIENTES AOS UN ESTUDIO DE COHORTE RETROSPECTIVO DE UN SOLO CENTRO: ANTECEDENTES:El cáncer colorrectal está aumentando en adultos jóvenes. No se conoce la secuencia adenoma-carcinoma en pacientes jóvenes <50 años. El rendimiento obtenido al reducir la edad de la colonoscopia de detección sigue sin estar claro.OBJETIVO:Comprender la carga y la histología de los pólipos colorrectales en adultos jóvenes y explorar los predictores de detección de adenomas en esta población.DISEÑO:Estudio de cohorte retrospectivo.AJUSTE:Las colonoscopias se realizaron en un único centro de atención terciario afiliado a la universidad.PACIENTES:Adultos jóvenes <50 años que se sometieron a una colonoscopia entre 2014-2019. Se excluyeron los pacientes con enfermedad inflamatoria intestinal y trastornos genéticos.PRINCIPALES MEDIDAS DE RESULTADO:Se analizaron las tasas de detección de adenomas según la edad. Los predictores de la detección de adenomas se investigaron mediante regresión logística múltiple.RESULTADOS:Se analizaron 4475 pacientes. La edad media fue de 40,2 ± 8,0 años, el 56,4% eran mujeres y el IMC medio fue de 26,3 ± 5,5 kg / m2. Se informó de antecedentes familiares de cáncer colorrectal en el 23,8% de los pacientes. Las tasas generales de detección de pólipos y adenomas fueron del 22% y el 14%, respectivamente. La mayoría de los pólipos eran adenomatosos (58,9% de todas las polipectomías) y estaban localizados en colon izquierdo o recto (61,4%). Las tasas de detección de adenomas, neoplasias avanzadas y adenocarcinomas fueron más altas en pacientes de 45 a 49 años (19,3%, 4,8% y 1,3%, respectivamente). En el análisis multivariado, las variables asociadas de forma independiente con la detección de adenomas incluyeron: edad (OR 1.08; IC del 95%: 1,06-1,1), sexo femenino (OR 1,80; IC del 95%: 1,44-2,27), IMC (OR 1,01; IC del 95%: 1,01-1,05)) y haber sido sometido a una colonoscopia diagnóstica (OR 1,81; IC 95% 1,44-2,29). En el análisis de subgrupos de pacientes de 45 a 49 años, las mismas variables permanecieron asociadas con la detección de adenomas, excepto la edad.LIMITACIONES:Carácter retrospectivo con datos heterogéneos.CONCLUSIONES:La detección de adenomas en adultos jóvenes de 45 a 49 años se acerca a la detección actual de adenomas en adultos mayores. Los predictores de la detección de adenomas en estos adultos jóvenes son el sexo femenino y el IMC, que pueden ayudar a guiar las pautas de detección del cáncer colorrectal en el futuro. Consulte Video Resumen en http://links.lww.com/DCR/B843. (Traducción-Dr. Hagerman).

DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis.

BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.