Integrated genomic and transcriptomic profiling of driver–pathway relationships in colorectal cancer.

Abstract

e15723 Background: Relationships between DNA driver alterations and downstream transcriptional pathway activation in colorectal cancer (CRC) are not well defined in routine specimens. We assessed driver–pathway concordance using paired DNA and transcriptome profiling. Methods: Tumors from 192 CRC patients (male = 85; female = 107) were profiled by a 517-gene DNA panel and AmpliSeq tissue transcriptome. Pathogenic/likely pathogenic SNV/indels defined driver status. A priori driver–pathway associations based on established CRC biology ( APC →WNT/β-catenin; RAS/RAF→MAPK; PIK3CA →PI3K/AKT/mTOR; SMAD4 →TGF-β/EMT) were evaluated. Pathway activity scores were computed as the average log 2 fold-change of curated pathway marker genes (scores calculated when ≥4 marker genes were available). Mutant vs wild-type groups were compared using Mann–Whitney; Δmedian with bootstrap 95% CI; BH-FDR across a priori tests. Multivariable linear regression adjusted for age, sex, and AJCC stage. Results: Median age was 55 years (IQR 44–63). AJCC stage was IV in 122/192 (63.5%) and unknown in 58/192 (30.2%); adenocarcinoma comprised 166/192 (86.5%). Frequent drivers were TP53 152/192 (79.2%), APC 109/192 (56.8%), KRAS 102/192 (53.1%), BRAF 20/192 (10.4%), PIK3CA 28/192 (14.6%), and SMAD4 30/192 (15.6%); RAS/RAF alterations occurred in 128/192 (66.7%). APC -mutant tumors showed higher WNT/β-catenin activation (evaluable n = 139; Δmedian +0.66, 95% CI +0.15 to +1.40; p = 0.0059; FDR = 0.029), remaining significant after adjustment (β = +0.74, 95% CI +0.04 to +1.44; p = 0.039). SMAD4 -mutant tumors showed lower TGF-β signaling (evaluable n = 159; Δmedian −0.87, 95% CI −1.94 to −0.30; p = 0.0116; FDR = 0.029), also significant after adjustment (β = −1.10, 95% CI −2.12 to −0.08; p = 0.036). RAS/RAF→MAPK and PIK3CA →PI3K/AKT/mTOR were not significant (FDR > 0.05). Conclusions: In routine CRC specimens, paired genomic and transcriptomic profiling demonstrated biologically coherent driver–pathway concordance for APC /WNT activation and SMAD4 /TGF-β signaling. Integrated multi-omics provides pathway-contextual interpretation alongside DNA comprehensive genomic profiling and may support molecular stratification in translational CRC studies.