Germline and Tumor Sequencing as a Diagnostic Tool To Resolve Suspected Lynch Syndrome.
Adult
Aged
Brain Neoplasms
/ diagnosis
Colorectal Neoplasms
/ diagnosis
Colorectal Neoplasms, Hereditary Nonpolyposis
/ diagnosis
Computational Biology
/ methods
Female
Germ-Line Mutation
High-Throughput Nucleotide Sequencing
/ methods
Humans
Male
Middle Aged
Neoplasms
/ diagnosis
Neoplastic Syndromes, Hereditary
/ diagnosis
Pedigree
Reproducibility of Results
Exome Sequencing
Whole Genome Sequencing
Young Adult
Journal
The Journal of molecular diagnostics : JMD
ISSN: 1943-7811
Titre abrégé: J Mol Diagn
Pays: United States
ID NLM: 100893612
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
07
05
2020
revised:
13
11
2020
accepted:
15
12
2020
pubmed:
1
1
2021
medline:
31
3
2022
entrez:
31
12
2020
Statut:
ppublish
Résumé
Patients in whom mismatch repair (MMR)-deficient cancer develops in the absence of pathogenic variants of germline MMR genes or somatic hypermethylation of the MLH1 gene promoter are classified as having suspected Lynch syndrome (SLS). Germline whole-genome sequencing (WGS) and targeted and genome-wide tumor sequencing were applied to identify the underlying cause of tumor MMR deficiency in SLS. Germline WGS was performed on samples from 14 cancer-affected patients with SLS, including two sets of first-degree relatives. MMR genes were assessed for germline pathogenic variants, including complex structural rearrangements and noncoding variants. Tumor tissue was assessed for somatic MMR gene mutations using targeted, whole-exome sequencing or WGS. Germline WGS identified pathogenic MMR variants in 3 of the 14 cases (21.4%), including a 9.5-megabase inversion disrupting MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8 of 11 tumors tested (72.7%). In a second mother-daughter pair, a somatic cause of tumor MMR deficiency was supported by the presence of double somatic MSH2 mutations in their respective tumors. More than 70% of SLS cases had double somatic MMR mutations in the absence of germline pathogenic variants in the MMR or other DNA repair-related genes on WGS, and, therefore, were confidently assigned a noninherited cause of tumor MMR deficiency.
Identifiants
pubmed: 33383211
pii: S1525-1578(20)30610-3
doi: 10.1016/j.jmoldx.2020.12.003
pmc: PMC7927277
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
358-371Subventions
Organisme : NCI NIH HHS
ID : U01 CA097735
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA097735
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA167551
Pays : United States
Informations de copyright
Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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