Schistosoma Infection, KRAS Mutation Status, and Prognosis of Colorectal Cancer
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Among the various factors associated with CRC, infections caused by pathogens with carcinogenic potential, such as Schistosoma, have been increasingly recognized as contributors to the disease’s development. The kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated genes in CRC patients, playing a critical role in determining therapeutic strategies. This study aims to explore the relationship between Schistosoma infection, KRAS mutation status, and the prognosis of CRC, providing insights into the underlying mechanisms and clinical implications.
The study enrolled 489 CRC patients diagnosed at Union Hospital, Tongji Medical College of Huazhong University of Science and Technology between January 1, 2010, and June 31, 2019. These patients were categorized into two groups: schistosomal CRC (SCRC, n=30) and non-schistosomal CRC (NSCRC, n=459). The diagnosis of CRC was confirmed pathologically, with the degree of differentiation and histological type described according to the American Joint Committee on Cancer criteria. Schistosoma infection was confirmed by the presence of intact or calcified eggs, active granulomas, or adult worms in the tissue samples. Patients with metastatic disease or unconfirmed tumor information were excluded from the study.
Clinical data collected for each patient included sex, age, year of diagnosis, cancer stage, histological type, tumor differentiation, primary tumor site, primary tumor size, chemotherapy, radiotherapy, KRAS mutation status, survival time, and survival status. KRAS mutation status was verified using quantitative polymerase chain reaction (qPCR). The study was approved by the Medical Ethics Committee of Union Hospital, and all statistical analyses were performed using SPSS software (version 26.0).
The baseline characteristics of the CRC patients were analyzed, and Kaplan-Meier survival analysis revealed that SCRC patients had significantly worse overall survival (OS) and disease-free survival (DFS) compared to NSCRC patients. The mean survival time (MST) for OS in SCRC patients was 51.9 months (95% confidence interval [CI]: 43.0–60.7), compared to 65.3 months (95% CI: 62.9–67.6) in NSCRC patients. Similarly, the MST for DFS in SCRC patients was 51.5 months (95% CI: 42.4–60.6), compared to 63.1 months (95% CI: 60.7–65.6) in NSCRC patients. These findings indicate that Schistosoma infection is associated with a poorer prognosis in CRC patients.
Univariate and multivariate Cox regression analyses further supported these results. Schistosoma infection was identified as an independent risk factor for OS in CRC patients. Specifically, the hazard ratio (HR) for OS in SCRC patients compared to NSCRC patients was 2.689 (95% CI: 1.416–5.108) in univariate analysis and 2.507 (95% CI: 1.275–4.932) in multivariate analysis. For DFS, Schistosoma infection was a risk factor in univariate analysis (HR: 2.062; 95% CI: 1.098–3.873), but this association was not statistically significant in multivariate analysis (HR: 1.849; 95% CI: 0.956–3.575).
The study also investigated the relationship between Schistosoma infection and KRAS mutation status. While there was no significant difference in the overall KRAS mutation rate between SCRC and NSCRC patients (63.3% vs. 48.8%), a detailed analysis of specific mutation sites revealed a notable distinction. Patients with SCRC were more likely to have KRASG12S/D mutations compared to NSCRC patients (43.3% vs. 18.1%). Due to limitations in the qPCR detection kit, which combined primers for G12S and G12D mutations, the exact mutation site could not be distinguished initially. To address this, the study expanded its analysis using next-generation sequencing on an additional 230 CRC patients. After propensity score matching (PSM) at a 1:4 ratio, the results showed that the KRASG12D mutation rate was significantly higher in SCRC patients compared to NSCRC patients (4/8 vs. 3/32). Notably, the KRASG12S mutation was absent in both groups.
Despite the higher prevalence of KRASG12D mutations in SCRC patients, the study found no association between KRAS mutations and OS or DFS in CRC patients. This aligns with previous research indicating that KRAS mutations are not independent predictors of survival in CRC. The findings suggest that the poor prognosis associated with Schistosoma infection may not be directly driven by KRAS mutations.
The study’s strengths include its large sample size, comprehensive clinical and pathological data, and the use of PSM to control for confounding factors. The diagnostic accuracy was ensured through rigorous review by experienced pathologists. This research provides valuable insights into the association between Schistosoma infection and KRAS mutations in CRC, highlighting the need for further investigation into the mechanisms underlying this relationship.
In conclusion, this study demonstrates that Schistosoma infection is associated with a worse prognosis in CRC patients, as evidenced by poorer OS and DFS. Additionally, SCRC patients exhibit a higher rate of KRASG12D mutations, which may limit their treatment options due to the lack of effective inhibitors for this specific mutation. The findings underscore the importance of preventing and treating schistosomiasis to improve outcomes for CRC patients. Future research should focus on elucidating the mechanisms linking Schistosoma infection to KRASG12D mutations and exploring potential therapeutic strategies for this subset of patients.
doi.org/10.1097/CM9.0000000000002905
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