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30.01.2020 | Original Article

Prevalence of CNV-neutral structural genomic rearrangements in MLH1, MSH2, and PMS2 not detectable in routine NGS diagnostics

verfasst von: Monika Morak, Verena Steinke-Lange, Trisari Massdorf, Anna Benet-Pages, Melanie Locher, Andreas Laner, Katrin Kayser, Stefan Aretz, Elke Holinski-Feder

Erschienen in: Familial Cancer | Ausgabe 2/2020

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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.

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Titel: Prevalence of CNV-neutral structural genomic rearrangements in MLH1, MSH2, and PMS2 not detectable in routine NGS diagnostics
verfasst von: Monika Morak
Verena Steinke-Lange
Trisari Massdorf
Anna Benet-Pages
Melanie Locher
Andreas Laner
Katrin Kayser
Stefan Aretz
Elke Holinski-Feder
Publikationsdatum: 30.01.2020
Verlag: Springer Netherlands
Erschienen in: Familial Cancer / Ausgabe 2/2020
Print ISSN: 1389-9600
Elektronische ISSN: 1573-7292
DOI: https://doi.org/10.1007/s10689-020-00159-4

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25.04.2024 | Nierenkarzinom | Nachrichten

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Prevalence of CNV-neutral structural genomic rearrangements in MLH1, MSH2, and PMS2 not detectable in routine NGS diagnostics

Abstract

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