Colorectal Adenocarcinoma

This study investigates predictive biomarkers for immune checkpoint inhibitor (ICI) response in metastatic urothelial carcinoma. Researchers found that ICI responders exhibited higher tumor mutational burden (TMB) and enriched mutations in genes such as PIK3CA. Functional in vitro and in vivo studies demonstrated that PIK3CA mutations enhance tumor immunogenicity by activating the IRF1-NLRC5-MHC-I axis, thereby improving antigen presentation and CD8+ T-cell cytotoxic response. These findings suggest that PIK3CA mutation could serve as a biomarker to predict ICI sensitivity and represents a novel immune-modulating mechanism.

This real-world study analyzed the genomic landscape of GNAQ and GNA11 mutations in 5,416 patients with metastatic solid tumors. It revealed that these mutations, while known in uveal melanoma, are also present in other cancers such as colorectal, melanoma, and gastric cancer. An immunogenic subgroup, characterized by non-hotspot mutations and high TMB or MSI, was identified and associated with potential benefit from immune checkpoint inhibitors. Canonical hotspot mutations, conversely, were predominant in TMB-low/MSS tumors. These findings highlight the importance of differentiating driver mutations from bystander mutations to guide therapeutic strategies.

The COSMOS-CRC study investigated the diagnostic performance of a blood-based cell-free DNA (cfDNA) test for colorectal cancer (CRC) and advanced precancerous lesions (APLs). This multimodal assay was applied to 451 patients with histologically confirmed CRC or APLs. It demonstrated an overall sensitivity of 87.9% for CRC, with stage-specific sensitivities of 71.2% for stage I and 97.4% for stages II-IV. Notably, for T1 CRC patients, the test achieved 100% sensitivity for detecting lymph node metastasis (LNM). The findings suggest that this cfDNA test could enhance risk stratification and potentially reduce unnecessary radical surgeries in T1 CRC management.

This study developed a functional precision oncology platform using patient-derived organoids (PDOs) and xenografts (PDOXs) from BRAFV600E-mutant colorectal cancer (CRC). The platform faithfully recapitulated tumor heterogeneity and drug responses. Researchers discovered that RNF43 mutations predict enhanced sensitivity to the encorafenib-cetuximab combination and increase tumor immunogenicity. These findings provide a mechanistic rationale for combining targeted therapies with immunotherapy in this aggressive CRC subtype.

This pooled analysis of two phase II clinical trials, MEDITREME and METIMMOX, investigated the efficacy of first-line chemoimmunotherapy in patients with microsatellite stable (MSS) metastatic colorectal cancer. The findings revealed a significant improvement in median overall survival for the chemoimmunotherapy group compared to chemotherapy alone. Additionally, higher complete response rates were observed with the combination therapy. The study also suggests that baseline CD8+ T-cell infiltration could serve as a predictive biomarker to identify patients most likely to benefit from this treatment approach.

This prospective observational study assessed the utility of circulating tumor DNA (ctDNA) for mutational profiling and dynamic monitoring in 33 patients with metastatic colorectal cancer receiving palliative chemotherapy. ctDNA was detected in most patients at baseline, revealing frequent mutations in APC, TP53, KRAS, and PIK3CA. Good concordance was observed between plasma ctDNA profiles and tissue data. Longitudinal analysis showed the emergence of acquired mutations, particularly RAS mutations under anti-EGFR therapy, and correlated high ctDNA levels with shorter overall survival. These findings highlight ctDNA's potential to guide personalized treatment strategies and monitor resistance.

This study investigated the utility of urinary extracellular vesicles (EVs) as a liquid biopsy source for colorectal cancer (CRC). Urinary EVs demonstrated superior purity and DNA quality compared to plasma and urinary cell-free samples. Detecting RAS/BRAF mutations in urinary EV-DNA after curative surgery allowed for minimal residual disease (MRD) identification. MRD positivity was strongly associated with an increased risk of recurrence and inferior overall survival. These findings suggest that urinary EV-DNA is a promising tool for postoperative monitoring and risk stratification in CRC patients.

This study compared the efficiency of bisulfite and enzymatic DNA methylation conversion methods for analyzing colorectal cancer (CRC) biomarkers. Researchers quantified methylation levels of BCAT1, IKZF1, and SEPTIN9 in paired tumor and normal tissues from 24 CRC patients. Results indicated that bisulfite conversion led to significantly higher methylation levels for IKZF1 and SEPTIN9 in tumor tissues compared to enzymatic conversion. This potential overestimation by the bisulfite method could impact the specificity of methylation biomarkers.

This study developed a novel immune classification for colorectal cancer (CRC) through integrative multi-omics analysis. By utilizing gene expression, mutation, and methylation profiles from two large CRC cohorts, three distinct clusters (MotifCC) were identified, each with unique molecular and immune characteristics. Cluster1, featuring high WNT pathway activation, exhibited the worst prognosis and a tumor-promoting microenvironment, suggesting benefit from a combination of immunotherapy and WNT-targeted treatment. Cluster2, with low immune infiltration and high glycolysis intensity, might respond to metabolism inhibitors, while Cluster3, characterized by high gene methylation, high tumor mutation burden, and microsatellite instability, showed a better response to immunotherapy. This classification provides valuable insights for understanding CRC heterogeneity and tailoring immunotherapy strategies.

This study investigated the prevalence and characteristics of germline mutations in 1094 Chinese colorectal cancer (CRC) patients using a 53-gene hereditary cancer panel. Pathogenic/likely pathogenic (P/LP) germline mutations were identified in 9.3% of patients, with mismatch repair (MMR) genes being the most frequently affected. Chinese patients showed lower frequencies of MUTYH and APC mutations but higher rates of MMR mutations compared to Western populations. Patients harboring germline P/LP mutations had significantly better progression-free survival, and a notable proportion of carriers lacked family history or were diagnosed after age 65. These findings highlight the need for population-specific genetic testing and screening strategies tailored for Asian populations.

This study demonstrates that MEK1/2 inhibitors, targeting the Ras-MAPK pathway, induce AXIN1 protein loss in colorectal cancer cell lines and patient-derived organoids. Unlike GSK3 inhibitors, this loss is not attributed to altered AXIN1 protein stability or post-translational modifications, nor to a significant reduction in its transcript levels. Analyses revealed that MEK1/2 inhibitors reduce global protein synthesis via an mTOR-associated pathway, an effect sufficient to cause AXIN1 loss. Co-treatment with tankyrase inhibitors was shown to partially prevent this AXIN1 reduction.

This meta-analysis assessed the efficacy and safety of single-agent versus dual immunotherapy for metastatic colorectal cancer (mCRC) with DNA mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). PD-1/PD-L1 monotherapy significantly improved objective response rate (ORR) compared to chemotherapy, demonstrating a favorable safety profile. Dual immunotherapy (nivolumab plus ipilimumab) showed a superior ORR over monotherapy, but with increased toxicity. Benefits in progression-free survival (PFS) and overall survival (OS) were not consistently statistically significant across trials.

This study developed a prognostic model for colorectal cancer (CRC) using 101 machine learning algorithms based on immune-related genes. Analyzing CRC patient data, the Ridge regression model demonstrated the best performance, generating an immune-related gene risk score (IRGRS) significantly associated with lower survival rates. The IRGRS was identified as an independent prognostic factor and correlated with immune cell infiltration and stromal activity. This score could also predict response to immune checkpoint inhibitors and sensitivity to certain chemotherapies.