KRAS and TP53 mutations are the two most common driver mutations in patients with lung adenocarcinoma (LUAD), and they appear to reduce latency and increase metastatic proclivity when a KRAS and TP53 co-mutation (KRAS/TP53-mut) occurs. However, the molecular mechanism involved is unclear. N⁶-methyladenosine (m⁶A), the most abundant RNA modification in mammal mRNAs, plays a critical role in tumorigenesis. Here, we used genomic and transcriptomic data and found that only LUAD patients with KRAS/TP53-mut, but not an individual mutation, appeared to exhibit poor overall survival when compared with patients without KRAS and TP53 mutation (wildtype). Subsequently, we analyzed the differential expression of the 15-m⁶A-related genes in LUAD with different mutations and found that YTHDF1 was the most upregulated in KRAS/TP53-mut patients and associated with their adverse prognosis. Bioinformatics and experimental evidence indicated that elevated YTHDF1 functionally promoted the translation of cyclin B1 mRNA in an m⁶A-dependent manner, thereby facilitating the tumor proliferation and poor prognosis of LUAD with KRAS/TP53-mut. Furthermore, the concurrent increase in YTHDF1 and cyclin B1 was confirmed by immunohistochemistry staining in patients with co-occurring KRAS/TP53 mutations. YTHDF1 was correlated with an unfavorable clinical stage and tumor size. Collectively, we identified and confirmed a novel “YTHDF1–m⁶A–cyclin B1 translation” axis as an essential molecular pathway for the prognosis of KRAS/TP53-mut LUAD.

MicroRNA-92a (miR-92a) may serve as a novel promising biomarker in multiple cancers, including colorectal cancer (CRC); however, the diagnostic accuracy and the underlying molecular mechanism of miR-92a in CRC is poorly understood. We first carried out meta-analysis and found that serum/plasma miR-92a yield better diagnostic efficacy when compared to stool samples and CRC tissues, and this finding was validated by our independent study through stool sample. Multiple bioinformatics assay indicated that miR-92a expression was positively correlated with heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) expression and closely related with the clinical characteristics of CRC. Experimental evidence showed that knockdown of HNRNPA2B1 could significantly decrease miR-92a expression and secretion in RKO cells. HNRNPA2B1 mediated miR-92a via m6A RNA modification. These findings indicate that HNRNPA2B1-m6A RNA modification-derived MicroRNA-92a upregulation and section from the local CRC acts a candidate noninvasive serum biomarker in colorectal cancer. Our study provides a novel insight into miR-92a mechanisms in relation to both expression and secretion for CRC diagnosis.

Serum tumor markers play a critical role in the early screening, treatment monitoring, and prognostic assessment of malignant tumors, yet poor comparability across different measurement systems frequently undermines their clinical value. We evaluated the comparability of carbohydrate antigen 19‐9 (CA19‐9) and carbohydrate antigen 15‐3 (CA15‐3) across seven contemporary measurement systems—Abbott Alinity I, Autobio A2000PLUS, Beckman Access Dxl 800, Mindray CL6000i, Roche Cobas E801, Snibe Maglumi X8, and Sysmex HISCL‐5000 using 464 native serum samples for CA19‐9 and 499 for CA15‐3. Spearman correlations were higher for CA15‑3 ( r : 0.927‒0.997) than for CA19‑9 ( r : 0.777‒0.985). With the all‐method median as a pragmatic comparator, Passing‒Bablok regression and difference plots were generated for each system. Against analytical performance specifications derived from biological variation, all systems except Abbott Alinity (22.5%) met the minimum bias criterion of ±21.6% for CA19‐9, whereas for CA15‐3 only Abbott Alinity (‒10.159%), Roche Cobas (13.01%), and Snibe Maglumi (−3.923%) fell within the minimum bias criterion of ±13.9%. CA19‐9 and CA15‐3 concentrations were recalibrated using three mathematical approaches: principal component analysis and two nonlinear regression models. After recalibration, the variability of CA19‐9 and CA15‐3 values decreased significantly. Our findings indicate that CA19‐9 and CA15‐3 results are not directly interchangeable across different systems, which poses a real‐world challenge for longitudinal patient follow‐up. However, mathematical models derived from individual patient serum samples can effectively reduce system‐related discrepancies, thereby enabling more consistent serial interpretations and supporting more informed clinical decisions in routine practice.

Genomic mutations in pancreatic ductal adenocarcinoma (PDAC) are hypothesized to drive poor prognosis and low response rates to targeted therapy through crosstalk among downstream regulatory networks. Here, we apply a causal inference-based approach, Mutation-Upstream-of-Metabolomic-Signature (MUMS), to show that prognostic serum metabolomic signatures can capture such crosstalk and reflect the collective impact of mutation-driven networks on tumor progression. We identify a panel of nine serum metabolites that predicts survival outcomes across multiple independent PDAC cohorts. MUMS analysis further identifies and functionally validates GRPEL1 as a tumor-promoting gene whose downstream metabolic signature converges with that of the mTOR/PI3K/Akt signaling pathway. Consistently, GRPEL1 sensitizes PDAC cells to proliferation arrest induced by mTOR inhibition. Together, our findings provide proof-of-concept evidence that serum metabolic signatures can reflect crosstalk within the tumor mutational landscape. These co-regulatory patterns offer a framework for uncovering new therapeutic targets and guiding the design of rational combination therapies.