In a groundbreaking study poised to reshape colorectal cancer diagnostics, researchers highlight the urgent need for supplemental testing to precisely identify certain high-risk patients. This new evidence, published in BMC Cancer, uncovers critical gaps in the current diagnostic process that could inadvertently omit patients with high microsatellite instability (MSI-H) and Lynch syndrome (LS), both pivotal in guiding effective therapeutic decisions and genetic counseling.
Microsatellite instability is a hallmark of defective DNA mismatch repair, serving as a crucial biomarker in colorectal cancer (CRC) for tailoring immunotherapy and screening for hereditary cancer syndromes such as Lynch syndrome. Immunohistochemistry (IHC) for mismatch repair (MMR) proteins and polymerase chain reaction (PCR)-based MSI testing remain the standard modalities for assessing MSI status. However, this new investigation into 2,910 colorectal cancer patients reveals a discordance rate of 3.2% between these two methodologies — a discrepancy that carries profound clinical implications.
The study delineates two distinct discordant groups: one comprising patients who were proficient in mismatch repair by IHC but showed MSI-H by PCR (pMMR&MSI-H), and the other with deficient MMR by IHC but microsatellite stable (MSS) by PCR (dMMR&MSS). Within this spectrum, patients categorized as pMMR&MSI-H stand out due to their risk of missed diagnoses, which could lead to suboptimal treatment and failure to identify underlying Lynch syndrome.
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One of the most striking findings is the prevalence of Lynch syndrome-associated germline mutations in over one-third (36.4%) of the pMMR&MSI-H group, compared to none in the dMMR&MSS discordant cohort. This highlights a significant oversight in identifying hereditary cancer risk when relying solely on MMR-IHC without confirmatory MSI-PCR in certain pMMR cases. Lynch syndrome, the most common hereditary colorectal cancer syndrome, elevates lifetime cancer risk, demanding precise and early identification for patient management and family screening.
Further molecular characterization revealed distinctive pathological features in the discordant pMMR&MSI-H patients. They were more likely to harbor right-sided colon tumors, display well-differentiated histology, and carry mutations in exon 20 of the PIK3CA gene — a genetic alteration previously implicated in oncogenic signaling and tumor progression. These molecular signatures differentiate them clearly from the consistent pMMR&MSS cohort, suggesting a unique biological subset that can be targeted for supplementary testing strategies.
Conversely, the dMMR&MSS discordant group presented with higher frequencies of rectal tumor location, advanced stage IV clinical presentation, and wild-type PIK3CA exon 20 status. This highlights divergent tumor biology and reinforces the complexity underlying MSI and MMR assessment discrepancies, shaping clinical approaches accordingly.
The study’s core recommendation encourages a supplemental MSI-PCR test for all pMMR colorectal cancer patients with tumors located in the right colon or those harboring PIK3CA exon 20 mutations. Implementing this approach could identify approximately 65.1% of patients who were initially misclassified by IHC, thereby bridging the diagnostic gap significantly.
The implications of this finding are manifold. Accurate and early detection of MSI-H status ensures that eligible patients receive immune checkpoint inhibitors, which have dramatically improved outcomes in mismatch repair-deficient tumors. Simultaneously, uncovering Lynch syndrome through confirmatory testing enables cascade testing in families, facilitating preventative strategies and surveillance for multiple cancers.
Upon identification of MSI-H status by this enhanced protocol, the authors advocate subsequent next-generation sequencing (NGS) to detect Lynch syndrome-associated germline mutations comprehensively. This two-tiered testing paradigm aligns with precision oncology principles, optimizing patient care through genetic precision and avoiding the risks associated with misdiagnosis.
This study’s extensive cohort of nearly 3,000 patients lends robust validity to its conclusions. By integrating molecular pathology with advanced genetic screening techniques, it crafts a pragmatic roadmap to minimize false negatives that could otherwise compromise therapeutic decisions and familial risk assessments.
Moreover, the research underscores the heterogeneity within colorectal cancer, particularly the complexity of pMMR tumors exhibiting MSI-H status by PCR, which defies the classical concordance expected between MMR-IHC and MSI testing. This insight challenges the existing reliance on a single diagnostic modality and propels the oncology community to adopt a more nuanced evaluation algorithm.
From a translational perspective, identifying PIK3CA exon 20 mutations as a marker enriches the predictive power of molecular testing, inching closer to tailored surveillance and management strategies. This molecular clue serves as a beacon to flag patients who might evade detection through routine IHC screening, thus serving as a guide for targeted MSI-PCR testing.
Clinicians are urged to reconsider diagnostic workflows, particularly for right-sided colon cancer patients, where discordance rates suggest a heightened risk of MSI-H misclassification. Integrating this dual-testing approach promises to refine patient stratification, facilitating timely immunotherapy and germline mutation discovery with consequential benefits for patient and family outcomes.
This revelation also spotlights the essential role of multidisciplinary collaboration, where pathologists, molecular biologists, and clinical oncologists synchronize efforts for precise diagnosis. The insights gained here not only affect initial testing paradigms but also influence surveillance protocols, genetic counseling pathways, and therapeutic planning.
As immunotherapy continues to revolutionize colorectal cancer treatment, this study drives home the necessity of precision in identifying MSI status unequivocally. The downstream effect of misclassification spans missed immunotherapy eligibility, overlooked hereditary cancer diagnosis, and the loss of opportunities for preventive interventions in relatives.
The strategic recommendation to supplement routine MMR-IHC with MSI-PCR testing in a defined patient subset encapsulates a shift toward meticulous molecular diagnostics. This transition acknowledges the limitations and variability inherent in histopathological assessments, advocating for a layered approach that leverages molecular insights to safeguard clinical decision-making.
Future research pathways inspired by these findings may explore the mechanistic underpinnings of discordance, potential targeted therapies for pMMR&MSI-H patients, and the cost-benefit implications of widespread MSI-PCR supplementation. Ongoing refinement of diagnostic tools aligned with tumor biology stands to elevate outcomes on a population scale.
In sum, this meticulous study challenges prevailing diagnostic doctrines and charts a clear, actionable course to mitigate the risk of misdiagnosing critical MSI-H colorectal cancer cases and Lynch syndrome. By harmonizing histological evaluation with molecular testing, it paves the way for enhanced personalized medicine strategies that promise to transform colorectal cancer care for the better.
Subject of Research: Improving diagnostic accuracy for microsatellite instability (MSI) and Lynch syndrome in colorectal cancer patients with proficient mismatch repair (pMMR).
Article Title: Certain pMMR colorectal cancer patients should undergo additional MSI-PCR testing to reduce the risk of misdiagnosing MSI-H and Lynch syndrome.
Article References: Huang, J., Xu, L., Cai, Y. et al. Certain pMMR colorectal cancer patients should undergo additional MSI-PCR testing to reduce the risk of misdiagnosing MSI-H and Lynch syndrome. BMC Cancer 25, 1103 (2025). https://doi.org/10.1186/s12885-025-14484-3
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14484-3
Tags: clinical implications of MSI statuscolorectal cancer patient management strategiesdiscrepancies in cancer diagnosticshereditary cancer syndrome screeninghigh-risk colorectal cancer patientsIHC vs. PCR MSI testingimmunotherapy tailoring for CRCLynch syndrome genetic counselingmicrosatellite instability testing importancemismatch repair protein assessmentpMMR colorectal cancer diagnosticssupplemental MSI testing necessity
