Proteogenomic\nCharacterization of Early Intrahepatic\nRecurrence after Curative-Intent Treatment of Colorectal Liver Metastases

Clinical and pathological factors are insufficient to\naccurately\nidentify patients at risk of early recurrence after curative-intent\ntreatment of colorectal liver metastases (CRLM). This study aimed\nto identify candidate prognostic proteogenomic biomarkers for early\nintrahepatic recurrence after curative-intent resection of CRLM. Patients\ndiagnosed with intrahepatic recurrence within 6 months of liver resection\nwere categorized as the “early recurrence” group, while\nthose who achieved a recurrence-free status for 10 years were designated\nas “durable remission”. Comprehensive genomic and proteomic\nprofiling of fresh frozen samples from these prognostically distinct\ngroups was performed using the TruSight Oncology 500 assay and label-free\ndata-dependent acquisition liquid chromatography–mass spectrometry.\nGenetic alterations were identified in 117 of the 523 profiled genes\nin patients with early recurrence. The most common somatic mutations\nlinked to early recurrence were <i>TP53</i> (88%), <i>APC</i> (71%), <i>KRAS</i> (38%), and <i>SMAD4</i> (21%). <i>SMAD4</i> alterations were absent in samples\nfrom patients with a durable remission. Calponin-2, versican core\nprotein, glutathione peroxidase 3, fibulin-5, and amyloid-β\nprecursor protein were upregulated more than 2-fold in early recurrence.\nExploratory analysis of these proteogenomic biomarkers suggests that <i>SMAD4</i>, calponin-2, and glutathione peroxidase 3 may have\nthe potential to predict early recurrence, enabling improved prognostication\nand precision oncology in CRLM.