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

Autor:	Song Y; Vaccine, Immunity and Cancer Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Loomans-Kropp H; Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.; Now at Department of Internal Medicine, The Ohio State University, Columbus, OH, USA., Baugher RN; Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Somerville B; Vaccine, Immunity and Cancer Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Baxter SS; Vaccine, Immunity and Cancer Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Kerr TD; Vaccine, Immunity and Cancer Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Plona TM; Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Mellott SD; Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Young TB; Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Lawhorn HE; Molecular Diagnostics Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Wei L; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Hu Q; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Liu S; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Hutson A; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA., Pinto L; Vaccine, Immunity and Cancer Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Potter JD; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Research Centre for Hauora and Health, Massey University, Wellington, New Zealand.; School of Public Health, University of Washington, Seattle, WA, USA., Sei S; Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA., Gelincik O; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Lipkin SM; Department of Medicine, Weill Cornell Medicine, New York, NY, USA., Gebert J; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany., Kloor M; Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany., Shoemaker RH; Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
Jazyk:	angličtina
Zdroj:	Journal of the National Cancer Institute [J Natl Cancer Inst] 2024 Jun 07; Vol. 116 (6), pp. 957-965.
DOI:	10.1093/jnci/djae060
Abstrakt:	Background: 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. Methods: 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. Results: 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. Conclusions: 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. (Published by Oxford University Press 2024.)
Databáze:	MEDLINE
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