High-sensitivity microsatellite instability assessment for the detection of mismatch repair defects in normal tissue of biallelic germline mismatch repair mutation carriers.
Adolescent
Adult
Brain Neoplasms
/ blood
Child
Child, Preschool
Colorectal Neoplasms
/ blood
Colorectal Neoplasms, Hereditary Nonpolyposis
/ blood
DNA Mismatch Repair
/ genetics
DNA-Binding Proteins
/ genetics
Female
Germ-Line Mutation
/ genetics
Heterozygote
High-Throughput Nucleotide Sequencing
Humans
Infant
Male
Microsatellite Instability
MutS Homolog 2 Protein
/ genetics
Neoplastic Syndromes, Hereditary
/ blood
Young Adult
constitutional mismatch repair deficiency
highly sensitive methodologies
lynch syndrome
microsatellite instability
next generation sequencing
Journal
Journal of medical genetics
ISSN: 1468-6244
Titre abrégé: J Med Genet
Pays: England
ID NLM: 2985087R
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
07
05
2019
revised:
16
07
2019
accepted:
16
07
2019
pubmed:
9
9
2019
medline:
5
2
2021
entrez:
9
9
2019
Statut:
ppublish
Résumé
Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.
Identifiants
pubmed: 31494577
pii: jmedgenet-2019-106272
doi: 10.1136/jmedgenet-2019-106272
pmc: PMC7146943
doi:
Substances chimiques
DNA-Binding Proteins
0
G-T mismatch-binding protein
0
MSH2 protein, human
EC 3.6.1.3
MutS Homolog 2 Protein
EC 3.6.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
269-273Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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