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Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients
- Source :
- PLoS One (print), 11(6):e0157381. Public Library of Science, PLoS ONE, 11(6). PUBLIC LIBRARY SCIENCE, PLOS ONE, 11(6):e0157381. Public Library of Science, PLoS ONE, Vol 11, Iss 6, p e0157381 (2016), PLoS ONE [E], 11(6). Public Library of Science, PLoS ONE
- Publication Year :
- 2016
-
Abstract
- BACKGROUND AND AIMS: Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. METHODS: Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. RESULTS: Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). CONCLUSIONS: This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.
- Subjects :
- 0301 basic medicine
lcsh:Medicine
DNA Mismatch Repair
Biochemistry
Germline
White Blood Cells
Database and Informatics Methods
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
Leukocytes
DNA sequencing
Genome Sequencing
lcsh:Science
Medicine(all)
Genetics
DNA methylation
Multidisciplinary
Agricultural and Biological Sciences(all)
integumentary system
Genomics
Middle Aged
Genomic Databases
Chromatin
Colon/metabolism
Lynch syndrome
Nucleic acids
Gene Expression Regulation, Neoplastic
Oncology
030220 oncology & carcinogenesis
Leukocytes/metabolism
Cohort studies
Epigenetics
DNA mismatch repair
Cellular Types
DNA modification
Colorectal Neoplasms
MutL Protein Homolog 1
Sequence Analysis
Transcriptome Analysis
Chromatin modification
Research Article
Chromosome biology
Next-Generation Sequencing
Cell biology
Colon
Sequence analysis
Immune Cells
Immunology
Rectum/metabolism
Sequence Databases
Biology
Research and Analysis Methods
MLH1
03 medical and health sciences
Germline mutation
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
Journal Article
medicine
Humans
Molecular Biology Techniques
Sequencing Techniques
Molecular Biology
Gene
DNA sequence analysis
Germ-Line Mutation
Colorectal Cancer
Blood Cells
Biology and life sciences
MutL Protein Homolog 1/genetics
Biochemistry, Genetics and Molecular Biology(all)
lcsh:R
Rectum
Cancers and Neoplasms
Computational Biology
DNA
Genome Analysis
medicine.disease
Colorectal Neoplasms, Hereditary Nonpolyposis
Colorectal Neoplasms/genetics
digestive system diseases
Biological Databases
030104 developmental biology
lcsh:Q
Gene expression
Genetics and Molecular Biology(all)
Subjects
Details
- ISSN :
- 19326203
- Database :
- OpenAIRE
- Journal :
- PLoS One (print), 11(6):e0157381. Public Library of Science, PLoS ONE, 11(6). PUBLIC LIBRARY SCIENCE, PLOS ONE, 11(6):e0157381. Public Library of Science, PLoS ONE, Vol 11, Iss 6, p e0157381 (2016), PLoS ONE [E], 11(6). Public Library of Science, PLoS ONE
- Accession number :
- edsair.doi.dedup.....e0855c047394f34887630bd5c7c85338