Bayesian modeling for genetic anticipation in presence of mutational heterogeneity: a case study in Lynch syndrome.
Philip S. Boonstra,Bhramar Mukherjee,Jeremy M. G. Taylor,Mef Nilbert,Victor Moreno,Stephen B. Gruber +5 more
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TLDR
A Bayesian approach is posit to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO, and a model predicts family‐level anticipation effects that are potentially useful in genetic counseling clinics for high‐risk families.Abstract:
Summary Genetic anticipation, described by earlier age of onset (AOO) and more aggressive symptoms in successive generations, is a phenomenon noted in certain hereditary diseases Its extent may vary between families and/or between mutation subtypes known to be associated with the disease phenotype In this article, we posit a Bayesian approach to infer genetic anticipation under flexible random effects models for censored data that capture the effect of successive generations on AOO Primary interest lies in the random effects Misspecifying the distribution of random effects may result in incorrect inferential conclusions We compare the fit of four-candidate random effects distributions via Bayesian model fit diagnostics A related statistical issue here is isolating the confounding effect of changes in secular trends, screening, and medical practices that may affect time to disease detection across birth cohorts Using historic cancer registry data, we borrow from relative survival analysis methods to adjust for changes in age-specific incidence across birth cohorts Our motivating case study comes from a Danish cancer register of 124 families with mutations in mismatch repair (MMR) genes known to cause hereditary nonpolyposis colorectal cancer, also called Lynch syndrome (LS) We find evidence for a decrease in AOO between generations in this article Our model predicts family-level anticipation effects that are potentially useful in genetic counseling clinics for high-risk familiesread more
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Genetic predisposition to colorectal cancer: Where we stand and future perspectives
TL;DR: A comprehensive review of the genetically characterized and uncharacterized hereditary CRC syndromes and of low- and moderate-penetrance loci and variants identified through genome-wide association studies and candidate-gene approaches is performed.
Journal ArticleDOI
Telomere length and genetic anticipation in Lynch syndrome.
Nuria Seguí,Marta Pineda,Elisabet Guinó,Ester Borras,Matilde Navarro,Fernando Bellido,Victor Moreno,Conxi Lázaro,Ignacio Blanco,Gabriel Capellá,Laura Valle +10 more
TL;DR: It is suggested that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations, and the anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families was not explained by telomeres shortening.
Journal ArticleDOI
Genetic anticipation in Swedish Lynch syndrome families
Jenny von Salomé,Philip S. Boonstra,Masoud Karimi,Gustav Silander,Marie Stenmark-Askmalm,Marie Stenmark-Askmalm,Samuel Gebre-Medhin,Christos Aravidis,Mef Nilbert,Mef Nilbert,Annika Lindblom,Kristina Lagerstedt-Robinson +11 more
TL;DR: Whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990–2013 is determined.
Dissertation
Estudi de variants de significat desconegut en la síndrome de Lynch
TL;DR: Tambe et al. as discussed by the authors propose an algoritme d'estudi de variants that permeti integrar i prioritzar les diferents tecniques fin a la caracteritzacio funcional.
Dissertation
Estudio de la longitud telomérica e identificación de nuevos genes causales en el cáncer colorrectal hereditario no polipósico
TL;DR: Hemos estudiado el gen en 103 familias CCRf-X pero no se han identificado cambios relevantes that afecten the actividad enzimatica, desestimando a GALNT12 como un gen de alta penetrancia para CCR.
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