28 research outputs found
Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency
Background & aims: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood.Methods: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120
7 depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000
7 depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls.Results: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor.Conclusions: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk
Immunohistochemical assessment of individual tumor cells in lymph nodes of patients with non-small-cell lung cancer.
Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy
Metabolic characterization of breast tumors with positron emission tomography using F-18 fluorodeoxyglucose.
Idiopathische Amyloidose des Steinmarders: Nachweis der Amyloidfibrillen-Proteine im Gewebeschnitt mit der Immunperoxidase-Methode
Detection of fungal DNA in Aspergillus PCR-negative tissue biopsy samples from immunocompromised hematological patients using DNA microarray technology improves diagnosis of invasive fungal infections (IFI)
Activating mutations in the MAPâkinase pathway define nonâossifying fibroma of bone
Nonâossifying fibroma (NOF), which occasionally results in pathologic fracture, is considered the most common benign and selfâlimiting lesion of the growing skeleton. By DNA sequencing we have identified hotspot KRAS, FGFR1 and NF1 mutations in 48 of 59 patients (81.4%) with NOF, at allele frequencies ranging from 0.04 to 0.61. Our findings define NOF as a genetically driven neoplasm caused in most cases by activated MAPâkinase signalling. Interestingly, this driving force either diminishes over time or at least is not sufficient to prevent autonomous regression and resolution. Beyond its contribution to a better understanding of the molecular pathogenesis of NOF, this study adds another benign lesion to the spectrum of KRASâ and MAPâkinase signallingâdriven tumours