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.