The complexity of screening PMS2 in DNA isolated from formalin-fixed paraffin-embedded material.
Adult
Aged
Aged, 80 and over
Colorectal Neoplasms
/ genetics
DNA
/ chemistry
DNA Fragmentation
DNA Polymerase II
/ genetics
DNA Polymerase III
/ genetics
Female
Formaldehyde
/ chemistry
Genetic Testing
/ methods
Humans
Male
Middle Aged
Mismatch Repair Endonuclease PMS2
/ genetics
Mutation
Paraffin Embedding
/ methods
Poly-ADP-Ribose Binding Proteins
/ genetics
Pseudogenes
Sensitivity and Specificity
Sequence Analysis, DNA
/ methods
Tissue Fixation
/ methods
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
25
09
2018
accepted:
27
09
2019
revised:
19
09
2019
pubmed:
17
10
2019
medline:
1
5
2021
entrez:
17
10
2019
Statut:
ppublish
Résumé
Germline variants in the DNA mismatch repair (MMR) gene PMS2 cause 1-14% of all Lynch Syndrome cancers. Correct variant analysis of PMS2 is complex due to the presence of multiple pseudogenes and the occurrence of gene conversion. The analysis complexity increases in highly fragmented DNA from formalin-fixed paraffin-embedded (FFPE) tissue. Here we describe a reliable approach to detect true PMS2 variants in fragmented DNA. A custom NGS panel designed for FFPE tissue was used targeting four MMR genes, POLE and POLD1. Amplicon design for PMS2 was based on the position of paralogous sequence variants (PSVs) that distinguish PMS2 from its pseudogenes. PMS2 variants in exons 1-11 can be correctly curated based on this information. For exons 12-15 this is less reliable as these undergo gene conversion. Using this method, we screened PMS2 variants in 125 MMR-deficient tumors. Of the 125 tumors tested, six were unexplained MMR-deficient tumors with solitary PMS2 protein expression loss. In these six tumors two unclassified variants (class 3) and five variants likely affecting function (class 4/5) were detected in PMS2. One microsatellite unstable tumor with positive staining for all MMR proteins was found to carry a frameshift PMS2 variant (class 5). No class 4 or class 5 PMS2 variants were detected in tumors with other patterns of MMR protein expression loss.
Identifiants
pubmed: 31616036
doi: 10.1038/s41431-019-0527-x
pii: 10.1038/s41431-019-0527-x
pmc: PMC7028990
doi:
Substances chimiques
Poly-ADP-Ribose Binding Proteins
0
Formaldehyde
1HG84L3525
DNA
9007-49-2
POLD1 protein, human
EC 2.7.7.-
DNA Polymerase II
EC 2.7.7.7
DNA Polymerase III
EC 2.7.7.7
POLE protein, human
EC 2.7.7.7
PMS2 protein, human
EC 3.6.1.-
Mismatch Repair Endonuclease PMS2
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
333-338Subventions
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : UL2012-5542
Pays : International
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : UL2012-5542
Pays : International
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : UL2012-5542
Pays : International
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