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. 2024 Jun 7;116(6):957-965.
doi: 10.1093/jnci/djae060.

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

Yurong Song  1 , Holli Loomans-Kropp  2   3 , Ryan N Baugher  4 , Brandon Somerville  1 , Shaneen S Baxter  1 , Travis D Kerr  1 , Teri M Plona  4 , Stephanie D Mellott  4 , Todd B Young  4 , Heidi E Lawhorn  4 , Lei Wei  5 , Qiang Hu  5 , Song Liu  5 , Alan Hutson  5 , Ligia Pinto  1 , John D Potter  6   7   8 , Shizuko Sei  2 , Ozkan Gelincik  9 , Steven M Lipkin  9 , Johannes Gebert  10 , Matthias Kloor  10 , Robert H Shoemaker  2
Affiliations

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

Yurong Song et al. J Natl Cancer Inst. .

Erratum in

Abstract

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.

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Conflict of interest statement

The authors declared no conflict of interest.

Figures

Figure 1.
Figure 1.
Receiver operating characteristic curve analysis of frameshift mutation comparison between high microsatellite instability and mismatch repair-deficient patients and healthy participants. The receiver operating characteristic curve was generated by comparing the number of frameshift mutations detected between high microsatellite instability and Lynch syndrome patients and healthy participants. Pooled samples were excluded in this analysis. A) All 122 targets in the panel were included in the analysis. B, C, D) Receiver operating characteristic curve modeling analysis: By removing those targets, frameshift mutations were also detected in healthy participants (B, 66 targets), and by further removing those targets frameshift mutations were detected in ≤2 patients (C, 49 targets) or in ≤5 patients (D, 20 targets). AUC = area under the curve; CI = confidence interval.
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