Proteogenomic Characterization of Early Intrahepatic Recurrence after Curative-Intent Treatment of Colorectal Liver Metastases

Clinical and pathological factors are insufficient to accurately identify patients at risk of early recurrence after curative-intent treatment of colorectal liver metastases (CRLM). This study aimed to identify candidate prognostic proteogenomic biomarkers for early intrahepatic recurrence after curative-intent resection of CRLM. Patients diagnosed with intrahepatic recurrence within 6 months of liver resection were categorized as the “early recurrence” group, while those who achieved a recurrence-free status for 10 years were designated as “durable remission”. Comprehensive genomic and proteomic profiling of fresh frozen samples from these prognostically distinct groups was performed using the TruSight Oncology 500 assay and label-free data-dependent acquisition liquid chromatography–mass spectrometry. Genetic alterations were identified in 117 of the 523 profiled genes in patients with early recurrence. The most common somatic mutations linked to early recurrence were TP53 (88%), APC (71%), KRAS (38%), and SMAD4 (21%). SMAD4 alterations were absent in samples from patients with a durable remission. Calponin-2, versican core protein, glutathione peroxidase 3, fibulin-5, and amyloid-β precursor protein were upregulated more than 2-fold in early recurrence. Exploratory analysis of these proteogenomic biomarkers suggests that SMAD4, calponin-2, and glutathione peroxidase 3 may have the potential to predict early recurrence, enabling improved prognostication and precision oncology in CRLM.