Cover Image

Frameshift mutations in peripheral blood as a biomarker for surveillance of Lynch syndrome

Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes, which lead to high microsatellite instability and frameshift mutations at coding mononucleotide repeats in the genome. Recurrent frameshift mutations in these regions are thought...

Full description

Saved in:
Bibliographic Details
Main Authors: Song, Yurong (Author) , Loomans-Kropp, Holli (Author) , Baugher, Ryan N (Author) , Somerville, Brandon (Author) , Baxter, Shaneen S (Author) , Kerr, Travis D (Author) , Plona, Teri M (Author) , Mellott, Stephanie D (Author) , Young, Todd B (Author) , Lawhorn, Heidi E (Author) , Wei, Lei (Author) , Hu, Qiang (Author) , Liu, Song (Author) , Hutson, Alan D. (Author) , Pinto, Ligia (Author) , Potter, John D (Author) , Sei, Shizuko (Author) , Gelincik, Ozkan (Author) , Lipkin, Steven M (Author) , Gebert, Johannes (Author) , Kloor, Matthias (Author) , Shoemaker, Robert H (Author)
Format: Article (Journal)
Language:English
Published: June 2024
In: Journal of the National Cancer Institute
Year: 2024, Volume: 116, Issue: 6, Pages: 957-965
ISSN:1460-2105
DOI:10.1093/jnci/djae060
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1093/jnci/djae060
Get full text
Author Notes:Yurong Song, Holli Loomans-Kropp, Ryan N Baugher, Brandon Somerville, Shaneen S Baxter, Travis D Kerr, Teri M Plona, Stephanie D Mellott, Todd B Young, Heidi E Lawhorn, Lei Wei, Qiang Hu, Song Liu, Alan Hutson, Ligia Pinto, John D Potter, Shizuko Sei, Ozkan Gelincik, Steven M Lipkin, Johannes Gebert, Matthias Kloor, Robert H Shoemaker
Description
Summary:Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair genes, which lead to high microsatellite instability and frameshift mutations at coding mononucleotide repeats in the genome. Recurrent frameshift mutations in these regions are thought to play a central role in the increased risk of various cancers, but no biomarkers are currently available for the surveillance of high microsatellite instability-associated cancers.A frameshift mutation-based biomarker panel was developed and validated by targeted next-generation sequencing of supernatant DNA from cultured high microsatellite instability colorectal cancer cells. This panel supported selection of 122 frameshift mutation targets as potential biomarkers. This biomarker panel was then tested using matched tumor, adjacent normal tissue, and buffy coat samples (53 samples) and blood-derived cell-free DNA (cfDNA) (38 samples) obtained from 45 high microsatellite instability and mismatch repair-deficient patients. We also sequenced cfDNA from 84 healthy participants to assess background noise.Recurrent frameshift mutations at coding mononucleotide repeats were detectable not only in tumors but also in cfDNA from high microsatellite instability and mismatch repair-deficient patients, including a Lynch syndrome carrier, with a varying range of target detection (up to 85.2%), whereas they were virtually undetectable in healthy participants. Receiver operating characteristic curve analysis showed high sensitivity and specificity (area under the curve = 0.94) of the investigated panel.We demonstrated that frameshift mutations can be detected in cfDNA from high microsatellite instability and mismatch repair-deficient patients and asymptomatic carriers. The 122-target frameshift mutation panel described here has promise as a tool for improved surveillance of high microsatellite instability and mismatch repair-deficient patients, with the potential to reduce the frequency of invasive screening methods for this high-cancer-risk cohort.
Item Description:Online veröffentlicht am 11. März 2024
Gesehen am 23.09.2024
Physical Description:Online Resource
ISSN:1460-2105
DOI:10.1093/jnci/djae060

Similar Items