Molecular characteristics of Chinese colorectal cancer patients with microsatellite instability

Introduction

Colorectal cancer (CRC) ranks as the third most frequent malignant tumor worldwide, with China having the second-highest incidence rate after lung cancer, while its mortality rate falls fourth in both the Eastern and Western parts of the world (1,2). In recent years, the development of molecular diagnoses has significantly advanced CRC treatment, specifically in immunotherapy. Building on this, the KEYNOTE-177 study in 2020 established programmed cell death protein-1 (PD-1) inhibitors as first-line therapy for late-stage CRC with DNA mismatch repair (dMMR)/microsatellite instability-High (MSI-H), further promoting MSI-H CRC research. The term MSI refers to the phenomenon where tandem-repeated DNA sequences called microsatellites (MS) consisting of a maximum of six nucleotides of the human genome change their length due to faulty dMMR, which inadequately restores missing or inserted sequences (3). Although various studies indicate different rates, MSI incidence rates among CRC patients are varying and range from 6.3% to 20.3% (4,5).

Apart from MSI-H, programmed cell death ligand-1 (PD-L1) and tumor mutational burden (TMB) are also biomarkers related to immunotherapy. According to Kim et al. (6), PD-L1 expression in tumor and immune cells is related to the high methylation and immune-rich subtypes of MSI-H CRC. Trabucco et al. (7) reported that MSI-H and TMB-H often co-occur in solid tumors, but the presence of TMB-H does not always imply the presence of MSI-H. Currently, there is scarce and conflicting data on the role of Epstein-Barr virus (EBV) and homologous recombination deficiency (HRD) in CRC. Thus, it is crucial to investigate the correlation between EBV, HRD, and MSI-H in CRC (8). Some studies have identified variations in gene mutations in patients with microsatellite stable tumors (MSS) and MSI-H phenotypes of CRC (4,7,9,10); however, there is a potential risk for bias due to the limited studies conducted among Chinese populations. Therefore, this research undertook a comprehensive exploratory analysis of Chinese patients with CRC of this type using a large sample size. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-169/rc).

Methods

This study retrospectively collected sample data from 14,239 CRC patients who underwent next generation sequencing (NGS) at Shanghai 3D Medicines Inc. between 2017 and 2022. The laboratory holds certification from CAP, CLIA, and ISO. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Affiliated Hospital of Guizhou Medical University. The requirement for written informed consent was waived by the ethics committee because of the retrospective nature of the study and the use of de-identified data. NGS results were coupled with relevant clinical data including age and gender.

Sample types and workflow

A total of 14,239 patients were included in this study. Among them, 12,892 cases were analyzed using tissue samples only, 1,294 cases using blood samples only, 48 cases had paired tissue and blood samples available for sequencing, and the sample type was unavailable for 5 cases.

The overall workflow included DNA extraction, library preparation with unique molecular identifiers (UMIs), hybrid-capture enrichment using a customized NGS panel, sequencing on the NovaSeq 6000 platform, and downstream bioinformatic analyses for single nucleotide variation (SNV)/indel, CNV, gene fusion, MSI, TMB, and HRD, with key quality control (QC) metrics monitored throughout the process.

NGS testing method

The NGS method sequenced tissue or plasma samples from CRC patients and covered the entire exons and some introns of 500 or 100 selected MSI loci and 733 cancer-related genes (the full list was provided in Table S1). A pathologist assessed the tumor cell content of all specimens to ensure ≥20%. The captured DNA library underwent 100bp paired-end sequencing on the NovaSeq 6000 platform (Illumina) as previously described (11). The average sequencing depth for tissue samples was ≥500×, for blood samples was ≥5,000×, and for prognostic and resistance-related genes was ≥30,000×. The sequencing data was analyzed to determine SNV, Indel, CNV, gene fusion, MSI status, TMB, HRD score and EBV.

TMB testing method

The TMB testing method counted the synonymous and non-synonymous SNVs and indels in the coding region of the examined cells, excluding driver mutations. All SNVs and indels in the target gene coding region were considered, including missense, silent, premature translation termination, stop codon loss, in-frame, and out-of-frame mutations. For blood TMB (bTMB), known germline single nucleotide polymorphisms (SNPs) with population frequencies ≥0.015 in the dbSNP, 1000 Genomes, and ESP6500 databases were excluded (12).

MSI testing method

The MSI testing method calculated MSI status using an internally developed R script (12). Repeat length distributions at each MS locus were analyzed to evaluate locus instability. MSI analysis was performed using two sample sources: tumor tissue DNA and circulating tumor DNA (ctDNA) from plasma. For tissue samples, MSI was assessed using a panel covering 500 MS loci. For plasma samples, blood-based MSI (bMSI) refers to MSI detected from ctDNA derived from plasma. Plasma samples were processed as previously described (12), and DNA extracted from plasma was subjected to MSI analysis using a panel of 100 MS markers, with the workflow validated by tissue PCR as reported previously (12). MSI score or bMSI was defined as the percentage of unstable loci. Tissue samples with an MSI score ≥0.4 were classified as MSI-H, otherwise as MSS. Samples with bMSI scores ≥0.2 were classified as bMSI-H, otherwise as bMSS.

HRD testing method

This study developed the 3DMed-HRD algorithm to measure HRD as the sum of genomic heterozygosity loss (LOH), telomere allelic imbalance (TAI), and large segmental transitions (LST) (11). These SNPs are distributed throughout the human genome exceeding 10,000. An HRD score threshold of 30 was referenced where relevant for background interpretation (13).

Statistical analysis

Statistical analysis was conducted using SPSS 25. Continuous variables were expressed as a median with a range, while categorical and counting variables were presented with absolute values and percentages. The Pearson’s Chi-squared test was utilized for comparisons, with all tests being two-sided. In terms of statistical significance, P values less than 0.05 were observed as significant.

Results

The characteristics of MSI-H and MSS CRC patients

The study analyzed data from 14,239 patients with colon or rectal cancer (Table 1), with a prevalence of 62.9% and 37.1%, respectively. Among these patients, 7.15% had MSI-H colon cancer, a lower incidence rate than the 10–20% reported in the European and American populations. The incidence of MSI-H was higher in colon cancer than in rectal cancer (10% vs. 2.4%, P<0.05). No significant difference was found in the incidence of MSI-H between male and female patients (6.89% vs. 7.60%, P=0.10). The average age for CRC diagnosis was 59 years (10–94 years), while the onset of MSI-H patients was significantly lower than that of MSS patients (53 vs. 59 years, P<0.05), consistent with reports in the Chinese population (4). In primary lesions, metastases, and blood of CRC patients, the detection rates of MSI-H were 8.13%, 2.64%, and 4.29%, respectively (P<0.05). MSI-H detection was highest in primary lesions and lowest in metastases. Additionally, out of 8,360 patients, 6,975 and 6,339 were tested for HRD scores and EBV, resulting in an average TMB and HRD of 17.5 mutations/Mb and 12.8, respectively. The TMB of MSI-H patients was significantly higher than that of MSS patients (92.28 vs. 12.07 mutations/Mb, P<0.05), while the HRD score was lower (4.53 vs. 13.5, P<0.05). EBV positivity rate among CRC patients was 0.4% (27 cases), with no EBV-positive MSI-H cases detected. In summary, the study indicates that MSI-H incidence is relatively low in the Chinese population and is associated with high TMB and low HRD scores, showing significant differences between MSI-H and MSS in age, tumor location, and sample type.

Molecular characteristics of MSI-H versus MSS patients with CRC

There was a significant difference in the frequency of somatic mutations between MSI-H and MSS subtypes, as indicated by the frequency rates of several genetically important biomarkers in Figure 1. The most commonly mutated genes in CRC included APC (69.34%), TP53 (66.49%), KRAS (49.88%), and PIK3CA (16.63%), among others, such as BRAF (6.39%), NRAS (3.83%), GNAS (3.32%), ERBB2 (5.23%), BRCA2 (3.42%), and BRCA1 (1.34%). The positivity rate of KRAS was consistent in both MSI-H and MSS subtypes (50.27% vs. 49.86%, P=0.781). Frequencies of TGFBR2 (43.93% vs. 0.71%), PIK3CA (41.63% vs. 14.67%, P<0.05), BRAF (11.04% vs. 0.89%, P<0.05), and ERBB2 (10.38% vs. 4.83%, P<0.05) were significantly higher in the MSI-H group compared to MSS, while the positivity rates of APC (51.26% vs. 70.76%, P<0.05), TP53 (27.76% vs. 69.54%, P<0.05), and NRAS (1.86% vs. 3.98%, P<0.05) were higher in MSS. Additionally, we observed changes in the dMMR system, such as in ARID1A (48.31% vs. 4.61%, P<0.05), MSH6 (37.27% vs. 0.97%), MLH3 (37.05% vs. 0.27%), BRCA2 (28.63% vs. 1.44%), ATR (23.39% vs. 1.101%), MLH1 (20.77% vs. 0.31%), MLH3 (14.32% vs. 0.43%), and BRCA1 (8.31% vs. 0.80%), likely due to the known association between dMMR and MSI. Furthermore, our analysis showed that KRAS mutations usually occurred with lower rates of NRAS mutations, and that KRAS and BRAF p.V600E mutations were incompatible but could coexist with other BRAF mutations. Overall, except for APC and TP53 mutations, MSI-H exhibits a higher frequency of mutations in various genes.

Figure 1 Mutation frequency in MSI-H/MSS patients with colorectal cancer. MSI, microsatellite instability; MSI-H, MSI-High; MSS, microsatellite stable tumors.

We examined the relationship between TMB in different types of CRC and the MSI status. Our analysis showed a significant difference between MSI-H and MSS subtypes. The mean TMB in primary lesions, metastatic lesions, and blood of MSI-H CRC were 93.58 vs. 81.51 vs. 82.54, respectively (P=0.41), while in MSS, the mean TMB in primary lesions, metastatic lesions, and blood were 12.35 vs. 8.638 vs. 11.26, respectively (P=0.03), with higher TMB in primary lesions than in metastatic lesions (Figure 2A,2B). Similarly, the TMB in primary and metastatic lesions of MSI-H CRC was higher than that in MSS (93.58 vs. 12.35, P<0.001; 81.51 vs. 8.638, P<0.001), while there was no significant difference in TMB between MSI-H and MSS in blood (82.54 vs. 93.58, P=0.29) (Figure 2C-2F).

Figure 2 Relationship between MSI-H and TMB in different colorectal cancer samples. ****, P<0.0001. EBV, Epstein-Barr virus; MSI, microsatellite instability; MSI-H, MSI-High; MSS, microsatellite stable tumors; TMB, tumor mutational burden.

Furthermore, we scrutinized the correlation between 16 homologous recombination repair (HRR) pathway genes and HRD and found that the HRD score in the wild-type group of HRR genes was remarkably greater than that in the mutated group (13.53 vs. 9.82, P<0.001). There was no significant association between the mutation status of HRR genes and HRD scores in both the MSS and MSI-H groups (13.61 vs. 14.22, P=0.19; 4.128 vs. 4.569, P=0.54) as presented in Figure 3A-3C. Figure 3D,3E manifests that the HRD scores were sparser in both the HRR mutation group and MSS group. The positivity rate of EBV in CRC was 0.4% (27 cases), and no occurrence was reported in MSI-H as represented in Figure 3F.

Figure 3 Relationship between MSI-H and HRD EBV in colorectal cancer. ****, P<0.0001. EBV, Epstein-Barr virus; HRD, homologous recombination deficiency; HRR, homologous recombination repair; m, mutated-type; MSI, microsatellite instability; MSI-H, MSI-High; w, wild-type.

Discussion

MSI-H CRC is a population that is an appropriate target for immunotherapy. Typically, the MSI-H phenotype is more prevalent in colon cancer than rectal cancer. The MSI-H detection rate of 7.15%, which is lower than in Europe and America (15%) (5), but similar to the reported MSI frequency in the eastern region of China (6.31%) (4) and the 7.6% dMMR incidence reported by Li Liang’s team in CRC (14). Our findings indicate that the detection rate of MSI-H in primary tumors, blood, and metastatic tumors varies. Furthermore, the incidence rate of MSI-H in metastatic tumors is significantly lower than that in primary tumors and blood samples. Previous studies have also drawn this conclusion, suggesting that this may be related to the biological characteristics of MSI-H tumors (15). The detection rates obtained from different regions, populations, sample types, and detection methods vary. Our study has a wider sampling range, and thus, the detected MSI frequency may better reflect the general characteristics of the Chinese population.

The frequency of other gene mutations, such as KRAS, BRAF, and NRAS, is consistent with previous reports in CRC overall, encompassing both Eastern and Western cohorts [40–50% for KRAS (16), 5.4–6.7% for BRAF (17), and 3.8% for NRAS (18)]. Notably, in Western cohorts specifically enriched for MSI-H CRCs, reported mutation frequencies range from 12–20% for KRAS and 16–52% for BRAF (19). MSI-H presents significantly higher mutation rates in the PIK3CA, BRAF, ERBB2, and DDR genes; however, the APC, TP53, and NRAS mutation rates are lower. Sally E. Trabucco’s research revealed that some gene mutations were remarkably enriched in MSI-H or MSS tumors and were linked to pathways in these tumors (7). After analyzing the mutation status of RAS and BRAF, we found that KRAS and BRAF p.V600E mutations were mutually exclusive, which was consistent with previous reports (4), but BRAF other site mutations could coexist. Furthermore, our research showed that MSI-H patients are younger than MSS patients, which can serve as a diagnostic reference for physicians.

TMB is a significant autonomous biomarker for immunotherapy. Studies demonstrate that TMB exhibits a strong correlation with the objective response rate (ORR) of anti-PD-1/PD-L1 therapy in solid tumor patients (20,21). Schrock et al. (22) and Kabbarah’s team (23) reported median TMB values of 46.1 and 52 Mut/Mb, respectively, for MSI-H colon cancer patients, compared to 3.5 and 6 Mut/Mb, respectively, for MSS patients. Our research revealed significantly higher median TMB values of 80 Mut/Mb for MSI-H patients and 6.7 Mut/Mb for MSS patients. Our TMB data for MSI-H colon cancer patients are evidently high and may be attributed to differences in the tested populations. MSI-H patients exhibit higher TMB values than MSS patients, both in primary and metastatic lesions, and the trend is not significant due to fewer blood samples tested for MSI-H. In the MSI-H type, the TMB values tested in different sample types showed no significant difference, while in the MSS type, the TMB of primary lesions was higher than that of metastases. Puccini et al. (15) reported that TMB-H and MSI-H are more easily observed in primary tumors than in distant metastases. Tumor heterogeneity may exist in different samples, and TMB detection in blood can overcome this problem. However, whether blood TMB analysis is more advantageous than tissue TMB analysis requires prospective trials to verify.

Patients with HRD-positive malignant tumors, such as ovarian and breast cancer, have demonstrated high sensitivity to chemotherapy with platinum and PARP inhibitors. The role of HRD score in the context of CRC is not well understood. Methods for determining HRD include the detection of BRCA1/2 or HRR mutations and the identification of HRD gene scars in the cell genome. International reports on PARP inhibitor therapy in ovarian cancer primarily use genomic scars to identify HRD. Our research data demonstrate a median HRD score of 12.8, and the score is significantly lower in the MSI-H group than in the MSS group. Previous studies have shown that the HRD subgroup in MSS/proficient mismatch repair (pMMR) CRC patients exhibits unique molecular and prognostic features, with HRD genes being more commonly found in MSI-H/dMMR tumors than in MSS/pMMR tumors (24). For HRR-related gene pathogenic mutation detection, a study showed that ARID1A was the most common mutation gene in CRC, followed by BRCA2, BRCA1, ATM, etc. Our research data are consistent with the study results. However, a high frequency of HRR variation was observed in MSI-H, but the HRD score was lower. HRR is a gene detected at the cause level, while HRD score is identified at the result level; these two are not entirely equivalent. It has been reported that approximately 36% of HRD-positive tumors do not harbor pathogenic mutations in HRR genes, suggesting that HRR mutation status alone is insufficient to predict the presence of HRD (25). Further research is necessary to establish whether the combination of HRR and HRD scores better guides PARP inhibitor therapy.

EBV infection is related to the occurrence and development of various tumors such as nasopharyngeal carcinoma, gastric cancer, and lymphoma, but there is limited research data on its association with CRC. Previous studies have reported that EBV infection exhibits an association with the pathologic and clinical outcomes of CRC and might facilitate the progression of CRC (26). We have investigated the prevalence of EBV positivity in our cohort and observed a rate of 0.4%, which is substantially lower in comparison to the broad range of EBV positivity rates (1.4–46%: PCR and IHC) reported in earlier studies (8). Nevertheless, certain studies have displayed minimal or no EBV expression in invasive CRC (27,28). EBV positivity and MSI-H may be mutually exclusive, and further exploration is needed to understand the relationship between MSI-H and EBV in CRC.

This is one of the largest sample size studies investigating the molecular differences between MSI-H and MSS subtypes in Chinese CRC patients. Compared to MSS, MSI-H has distinct molecular features. Furthermore, TMB-H is more common in MSI-H, while HRD scores are lower in MSI-H phenotypes, and EBV has a lower incidence rate in CRC.

However, this study has some limitations; its retrospective study design may have resulted in implicit selection bias, and heterogeneity of sample types (primary, metastatic, and plasma), potential sensitivity differences between tissue- and plasma-based testing, and limited clinical annotation may have further influenced the analyses. In addition, systematic matched germline MMR testing was not available in this cohort, precluding definitive classification of MSI-H tumors as Lynch syndrome–associated or sporadic (29). Future prospective studies integrating paired germline sequencing with epigenetic and clinical data are warranted.

Considering that targeted therapies for most genomic alterations in CRC remain inadequate, a comprehensive understanding of MSI-H’s molecular characteristics as an immunotherapeutic biomarker may present opportunities for precision treatment of CRC in the future.

Conclusions

In conclusion, MSI-H CRC in the Chinese population exhibits distinct clinicopathological and molecular characteristics compared with MSS tumors, including differences in mutation profiles, TMB, HRD scores, and EBV status. Our findings provide a comprehensive overview of the molecular landscape of MSI-H CRC in a large Chinese cohort and further support the clinical significance of MSI as a biomarker for precision treatment and immunotherapy. Future prospective studies integrating germline, epigenetic, and clinical outcome data are needed to further refine the molecular classification and therapeutic management of MSI-H CRC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-169/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-169/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-169/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2025-1-169/coif). D.F. is an employee of 3D Medicines Inc. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Affiliated Hospital of Guizhou Medical University. The requirement for written informed consent was waived by the ethics committee because of the retrospective nature of the study and the use of de-identified data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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