The usefulness of comprehensive genome profiling test in screening of Lynch syndrome independent of the conventional clinical screening or microsatellite instability tests

Sep 23, 2026

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Lynch syndrome (LS) is a hereditary cancer predisposition caused by germline pathogenic variants in DNA mismatch repair genes, commonly screened using microsatellite instability (MSI) testing and immunohistochemistry. Comprehensive genomic profiling (CGP) was applied to 1583 patients (Jan 2020–Apr 2024), detecting MMR-gene PGPVs in 19; confirmatory testing identified LS in eight overall, including cases missed by conventional screening. The study highlights that MMR pathogenic variants may not align with high MSI prediction scores in TCGA.

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CategoryHealthcare

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Introduction

Lynch syndrome and conventional screening

Role of CGP and limitations of MSI/MMR criteria

[www.nature.com/jhg](www.nature.com/jhg) ARTICLE OPEN The usefulness of comprehensive genome proﬁling test in screening of Lynch syndrome independent of the conventional clinical screening or microsatellite instability tests Mizuki Yamaguchi 1, Shintaro Akabane 1 ✉ , Hiroaki Niitsu2, Hikaru Nakahara2, Asuka Toshida2, Tetsuya Mochizuki 1, Takuya Yano1, Yoshihiro Saeki1, Hiroshi Okuda1, Manabu Shimomura1, Kazuhiro Sentani3, Kiwamu Akagi4, Hideki Ohdan1 and Takao Hinoi 2 © The Author(s) 2025 | | | | | --- | --- | --- | | | Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline pathogenic variants of DNA mismatch repair (MMR) genes. To diagnose LS, the microsatellite instability (MSI) test or immunohistochemistry of MMR enzymes is used as a conventional clinical screening method for all patients with colorectal and endometrial cancers. Recently, patients with advancedstage cancers have undergone comprehensive genomic proﬁling (CGP), which is useful not only for the detection of molecularly targeted personalized therapies, but also for the screening of hereditary cancer syndromes by determining presumed germline pathogenic variants (PGPVs) . Between January 2020 and April 2024, 1583 patients underwent CGP at our institute. PGPVs in MMR genes were detected in 19 patients. Although one patient died prior to the disclosure of the results and eight patients declined conﬁrmatory genetic testing, the remaining ten patients underwent conﬁrmatory genetic tests, of whom six were found to have a hereditary origin. Two additional patients were diagnosed with LS using tumor-normal paired CGP. Eventually, a total of eight patients were diagnosed with LS. Herein, we describe two patients with microsatellite-stable cancer who could not be diagnosed using conventional clinical screening or MSI testing. Furthermore, we showed that pathogenic variants of MMR genes do not always correlate with high MSI prediction scores in several cancer types in The Cancer Genome Atlas (TCGA) dataset analysis. These ﬁndings highlight the usefulness of CGP as a screening tool to identify individuals with possible LS, especially when conventional | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | criteria and MSI/MMR testing fail. | | | | | | | | | | | | Journal of Human Genetics (2025) 70:385–393; [https://doi.org/10.1038/s10038-025-01345-x](https://doi.org/10.1038/s10038-025-01345-x) | | | | | | INTRODUCTION In a genome, there are a number of short repeats of DNA sequences consisting of 1–6 nucleotides, which are referred to as microsatellite regions [1, 2] . During DNA replication, insertions and deletions of these repeated nucleotides in microsatellite regions occur frequently and are repaired by several mismatch repair enzymes [3] . Most microsatellite regions are found in introns, but they also exist in the exons of certain tumor suppressors and DNA repair genes [2] . Therefore, a deﬁciency in the mismatch repair (MMR) mechanism causes a frameshift of these coding regions in numerous loci in parallel, resulting in carcinogenesis with microsatellite instability (MSI-H) [3] . Lynch syndrome (LS) is oneof the most prevalent hereditary cancer predisposition syndromes caused by germline pathogenic variants of MMR genes, including MLH1, MSH2, MSH6, PMS2, and, rarely, EPCAM [4, 5] . Owing to the presence of a germline loss-of-function variant in LS, the loss of one MMR allele is sufﬁcient to cause MMR deﬁciency and carcinogenesis in multiple organs [6, 7] . Youth patients with LShave a signiﬁcantly increased risk of developing colorectal and endometrial cancers. The risk of other cancers, including ovarian, gastric, small intestinal, pancreatobiliary, upper tract urothelial, brain, and skin cancers, has also increased. Additionally, evidence suggests a potential association between breast, bladder, and pro

FAQs

What is Lynch syndrome (LS) and how is it typically screened?

LS is a hereditary cancer predisposition caused by germline pathogenic variants in DNA mismatch repair genes. Conventional screening relies on microsatellite instability (MSI) testing or immunohistochemistry of MMR enzymes for colorectal and endometrial cancers.

How was comprehensive genomic profiling (CGP) used in the study?

CGP was performed on 1583 patients between January 2020 and April 2024 to detect presumed germline pathogenic variants (PGPVs) relevant to hereditary cancer syndromes, including LS.

Why can CGP identify LS cases that conventional MSI/MMR screening misses?

The study describes microsatellite-stable cancers that were not diagnosable using conventional clinical screening or MSI testing. It also shows MMR pathogenic variants do not always correlate with high MSI prediction scores in TCGA, supporting CGP as an alternative screening tool.

Sep 23, 2026

Uploaded by Pentious