Gastric cancer, known for its molecular complexity, has consistently challenged clinicians and researchers attempting to tailor more effective therapies. A striking feature influencing treatment response is microsatellite instability (MSI), a genetic signature with significant implications for the efficacy of immune checkpoint inhibitors. However, the routine clinical assessment of MSI status remains riddled with obstacles due to the intricate behavior of mismatch repair (MMR) protein expression within tumor tissues. Recent work published in BMC Cancer by Zhong et al. unveils a deeper understanding of the heterogeneity in MMR protein expression and its clinical consequences, potentially redefining diagnostic and therapeutic strategies in gastric cancer.
Traditionally, MMR protein status is screened via immunohistochemical (IHC) staining for proteins such as MLH1, MSH2, MSH6, and PMS2. These proteins play essential roles in DNA repair through the recognition and excision of mismatched bases during DNA replication. When defective, the resultant failure to maintain genomic integrity leads to MSI, a hallmark of certain cancer subtypes marked by frequent insertion or deletion mutations in repetitive DNA sequences. Identifying MSI is critical because tumors exhibiting high MSI (MSI-H) often respond robustly to immune checkpoint blockade, a treatment revolutionizing cancer care in the last decade.
However, the IHC evaluation of MMR proteins in gastric cancer is confounded by intratumoral heterogeneity—where areas within the same tumor display varying levels or patterns of protein expression. This variability can manifest as a (sub)clonal staining pattern, where clusters of tumor cells retain protein expression while adjacent groups lose it, complicating the binary interpretation of proficient versus deficient MMR status. Zhong et al.’s study confronts this challenge by meticulously examining a large cohort of gastric cancer samples, revealing how such heterogeneity impacts MSI diagnosis.
The study examined 1,049 gastric adenocarcinoma cases collected from the First Affiliated Hospital of Zhejiang University School of Medicine over six years. Among these, seven cases displayed marked heterogeneous MMR protein staining characterized by abrupt loss of staining juxtaposed with retained areas within the same tumor specimen. Previous paradigm may have classified these heterogeneous cases as MMR proficient (pMMR) due to dominant intact staining regions, potentially missing MSI-H tumors. To address this, the team employed tumor microdissection, isolating the staining-lost regions for precise molecular MSI testing.
Remarkably, the microdissected tumor areas with lost MMR staining consistently demonstrated MSI-H status despite the overarching categorization as pMMR by conventional IHC. This breakthrough highlights how disregarding intratumoral heterogeneity could lead to underdiagnosis of MSI-H tumors, depriving patients of optimized immunotherapies. The work advocates for integrative diagnostic strategies that combine detailed IHC pattern analysis with targeted molecular assays to safeguard against false negatives.
Beyond technical diagnostic implications, Zhong et al. further interrogated the relationship between MSI status and clinical-pathological features in a carefully selected cohort of 107 patients. Their data revealed a spectrum of distinct characteristics associated with MSI-H tumors in gastric cancer. These tumors more commonly occurred in older patients, predominantly localized to the distal stomach, and were histologically classified as intestinal-type adenocarcinomas. Strikingly, these MSI-H tumors also exhibited a reduced incidence of lymphatic metastasis and perineural invasion, as well as lower clinical staging.
While these clinicopathological features align with findings in other cancers with MSI, the study underscored the prognostic nuances in gastric cancer. Although no significant difference in 45-month disease-free survival was observed between MSI and microsatellite stable (MSS) groups, multivariate analysis noted patient age and pTNM stage as robust prognostic factors influencing progression-free survival. This indicates that MSI status, though pivotal in guiding immunotherapy decisions, may not alone dictate clinical outcomes, warranting a holistic appraisal of patient and tumor characteristics.
The implications of this research ripple into the clinical realm. Accurate MSI detection directly informs therapeutic approaches, particularly the use of immune checkpoint inhibitors, which have transformed the treatment landscape for many MSI-H malignancies. As such, meticulous characterization and reporting of MMR protein staining heterogeneity should become a standard practice. This nuanced approach ensures that patients receive precise diagnoses and the benefit of emerging personalized immunotherapy regimens.
Zhong et al. also emphasize the utility of quantifying the extent of heterogeneous staining rather than relying solely on present/absent dichotomies. Advanced image analysis and pathologist training are called upon to improve interpretation fidelity and reproducibility across institutions. The study thus bridges molecular pathology with clinical oncology, laying the groundwork for an integrated diagnostic framework that can capture the diverse biology of gastric cancer.
Future efforts will undoubtedly build on these insights, investigating the genetic underpinnings driving MMR heterogeneity and exploring whether therapeutic responses differ between homogeneous and heterogeneous MSI-H tumors. Additionally, refining biopsy sampling protocols to capture representative tumor regions could mitigate diagnostic pitfalls inherent in intratumoral variability.
In conclusion, the work by Zhong and colleagues marks a seminal advance in our understanding of mismatch repair protein expression variability in gastric cancer. By revealing the hidden MSI-H status within tumors masked by heterogeneous MMR IHC patterns, the study advocates for a paradigm shift in pathological assessment and personalized oncology. Such findings not only refine diagnostic precision but also potentiate tailored immunotherapy strategies, heralding a new era in gastric cancer management.
With gastric cancer remaining a leading cause of cancer mortality worldwide, insights into molecular heterogeneity and its clinical ramifications are critical. This study exemplifies how rigorous translational research can uncover concealed tumor complexities and steer precision medicine forward. As immunotherapy continues its ascendancy, ensuring that diagnostic tools match molecular intricacies will be paramount to improving survival and quality of life for gastric cancer patients globally.
The future beckons an era where pathology reports encompass detailed characterization of MMR protein expression patterns, MSI status confirmed by molecular methods, and integrated clinical prognostic modeling. Zhong et al.’s work is a clarion call to the oncology community: embrace complexity within gastric tumors to unlock the full potential of immune-based therapies and ultimately transform patient care in this challenging malignancy.
Subject of Research: Heterogeneity of mismatch repair protein expression and its clinical and prognostic implications in gastric cancer, with a focus on microsatellite instability status.
Article Title: Deciphering mismatch repair protein expression variability in gastric cancer: clinical and prognostic implications.
Article References:
Zhong, F., Zhang, M., Xu, L. et al. Deciphering mismatch repair protein expression variability in gastric cancer: clinical and prognostic implications. BMC Cancer 25, 1699 (2025). https://doi.org/10.1186/s12885-025-14857-8
Image Credits: Scienmag.com
DOI: 10.1186/s12885-025-14857-8 (Published 04 November 2025)
