Germline mismatch repair gene variants analyzed by universal sequencing in Japanese cancer patients.
Adolescent
Adult
Aged
Aged, 80 and over
Child
Colorectal Neoplasms, Hereditary Nonpolyposis
/ genetics
DNA Mismatch Repair
DNA-Binding Proteins
/ genetics
Female
Germ-Line Mutation
High-Throughput Nucleotide Sequencing
/ methods
Humans
Japan
Male
Microsatellite Instability
Middle Aged
Mismatch Repair Endonuclease PMS2
/ genetics
MutL Protein Homolog 1
/ genetics
MutS Homolog 2 Protein
/ genetics
Proto-Oncogene Proteins B-raf
/ genetics
Sequence Analysis, DNA
Young Adult
Lynch syndrome
exome sequencing
mismatch repair gene
next generation sequencing
pathogenicity
variant of uncertain significance
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
05
02
2019
revised:
25
06
2019
accepted:
04
07
2019
pubmed:
7
8
2019
medline:
22
8
2020
entrez:
7
8
2019
Statut:
ppublish
Résumé
Lynch syndrome (LS) is the commonest inherited cancer syndrome caused by pathogenic variants of germline DNA mismatch repair (g.MMR) genes. Genome-wide sequencing is now increasingly applied for tumor characterization, but not for g.MMR. The aim of this study was to evaluate the incidence and pathogenicity of g.MMR variants in Japanese cancer patients. Four g.MMR genes (MLH1, MSH2, MSH6, and PMS2) were analyzed by next generation sequencing in 1058 cancer patients (614 male, 444 female; mean age 65.6 years) without past diagnosis of LS. The g.MMR variant pathogenicity was classified based on the ClinVar 2015 database. Tumor MMR immunohistochemistry, microsatellite instability (MSI), and BRAF sequencing were also investigated in specific cases. Overall, 46 g.MMR variants were detected in 167 (15.8%) patients, 17 likely benign variants in 119 patients, 24 variants of uncertain significance (VUSs) in 68 patients, two likely pathogenic variants in two patients, and three pathogenic variants in three (0.3%) patients. The three pathogenic variants included two colorectal cancers with MLH1 loss and high MSI and one endometrial cancer with MSH6 loss and microsatellite stability. Two likely pathogenic variants were shifted to VUSs by ClinVar (2018). One colon cancer with a likely benign variant demonstrated MLH1 loss and BRAF mutation, but other nonpathogenic variants showed sustained MMR and microsatellite stability. Universal sequencing of g.MMR genes demonstrated sundry benign variants, but only a small proportion of cancer patients had pathogenic variants. Pathogenicity evaluation using the ClinVar database agreed with MSI, MMR immunohistochemistry, and BRAF sequencing.
Sections du résumé
BACKGROUND
BACKGROUND
Lynch syndrome (LS) is the commonest inherited cancer syndrome caused by pathogenic variants of germline DNA mismatch repair (g.MMR) genes. Genome-wide sequencing is now increasingly applied for tumor characterization, but not for g.MMR. The aim of this study was to evaluate the incidence and pathogenicity of g.MMR variants in Japanese cancer patients.
METHODS
METHODS
Four g.MMR genes (MLH1, MSH2, MSH6, and PMS2) were analyzed by next generation sequencing in 1058 cancer patients (614 male, 444 female; mean age 65.6 years) without past diagnosis of LS. The g.MMR variant pathogenicity was classified based on the ClinVar 2015 database. Tumor MMR immunohistochemistry, microsatellite instability (MSI), and BRAF sequencing were also investigated in specific cases.
RESULTS
RESULTS
Overall, 46 g.MMR variants were detected in 167 (15.8%) patients, 17 likely benign variants in 119 patients, 24 variants of uncertain significance (VUSs) in 68 patients, two likely pathogenic variants in two patients, and three pathogenic variants in three (0.3%) patients. The three pathogenic variants included two colorectal cancers with MLH1 loss and high MSI and one endometrial cancer with MSH6 loss and microsatellite stability. Two likely pathogenic variants were shifted to VUSs by ClinVar (2018). One colon cancer with a likely benign variant demonstrated MLH1 loss and BRAF mutation, but other nonpathogenic variants showed sustained MMR and microsatellite stability.
CONCLUSIONS
CONCLUSIONS
Universal sequencing of g.MMR genes demonstrated sundry benign variants, but only a small proportion of cancer patients had pathogenic variants. Pathogenicity evaluation using the ClinVar database agreed with MSI, MMR immunohistochemistry, and BRAF sequencing.
Identifiants
pubmed: 31386297
doi: 10.1002/cam4.2432
pmc: PMC6745857
doi:
Substances chimiques
DNA-Binding Proteins
0
G-T mismatch-binding protein
0
MLH1 protein, human
0
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
PMS2 protein, human
EC 3.6.1.-
MSH2 protein, human
EC 3.6.1.3
Mismatch Repair Endonuclease PMS2
EC 3.6.1.3
MutL Protein Homolog 1
EC 3.6.1.3
MutS Homolog 2 Protein
EC 3.6.1.3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5534-5543Subventions
Organisme : Shizuoka prefecture
Informations de copyright
© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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