Prevalence of CNV-neutral structural genomic rearrangements in MLH1, MSH2, and PMS2 not detectable in routine NGS diagnostics.
Fam Cancer
; 19(2): 161-167, 2020 04.
Article
in En
| MEDLINE
| ID: mdl-32002723
ABSTRACT
Routine diagnostics for colorectal cancer patients suspected of having Lynch-Syndrome (LS) currently uses Next-Generation-Sequencing (NGS) of targeted regions within the DNA mismatch repair (MMR) genes. This analysis can reliably detect nucleotide alterations and copy-number variations (CNVs); however, CNV-neutral rearrangements comprising gene inversions or large intronic insertions remain undetected because their breakpoints are usually not covered. As several founder mutations exist for LS, we established PCR-based screening methods for five known rearrangements in MLH1, MSH2, or PMS2, and investigated their prevalence in 98 German patients with suspicion of LS without a causative germline variant or CNV detectable in the four MMR genes. We found no recurrence of CNV-neutral structural rearrangements previously described Neither for two inversions in MLH1 (exon 1 and exon 16-19) within 33 MLH1-deficient patients, nor for two inversions in MSH2 (exon 1-7 and exon 2-6) within 48 MSH2-deficient patients. The PMS2 insertion in intron 7 was detected in one of 17 PMS2-deficient patients. None of the four genomic inversions constitutes a founder event within the German population, but we advise to test the rare cases with unsolved PMS2-deficiency upon the known insertion. As a next diagnostic step, tumour tissue of the unsolved patients should be sequenced for somatic variants, and germline analysis of additional genes with an overlapping clinical phenotype should be considered. Alternatively, full-length cDNA analyses may detect concealed MMR-defects in cases with family history.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms, Hereditary Nonpolyposis
/
MutS Homolog 2 Protein
/
Sequence Inversion
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DNA Copy Number Variations
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High-Throughput Nucleotide Sequencing
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Mismatch Repair Endonuclease PMS2
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MutL Protein Homolog 1
Type of study:
Diagnostic_studies
/
Prevalence_studies
/
Risk_factors_studies
Limits:
Humans
Country/Region as subject:
Europa
Language:
En
Journal:
Fam Cancer
Journal subject:
NEOPLASIAS
Year:
2020
Document type:
Article
Affiliation country: