| Title: |
Metastatic Odyssey: Decoding the Genomic Journey from Primary Colorectal Cancer to Disseminated Disease |
| Authors: |
Taxiarchis Konstantinos Nikolouzakis; John Souglakos; Epameinondas Evangelos Kantidakis; Katerina Achilleos; Troye van Staden; Emmanuel Chrysos |
| Source: |
Cancers ; Volume 18 ; Issue 7 ; Pages: 1062 |
| Publisher Information: |
Multidisciplinary Digital Publishing Institute |
| Publication Year: |
2026 |
| Collection: |
MDPI Open Access Publishing |
| Subject Terms: |
colorectal cancer; metastasis; genomics; circulating tumor DNA; organotropism; tumor microenvironment |
| Description: |
Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early—before clinical detection—challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories—from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity—with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition. |
| Document Type: |
text |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://dx.doi.org/10.3390/cancers18071062 |
| DOI: |
10.3390/cancers18071062 |
| Availability: |
https://doi.org/10.3390/cancers18071062 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.42D8B661 |
| Database: |
BASE |