Genetic differences between primary colorectal cancer and its paired synchronous and metachronous metastases

As the second most deadly cancerous disease worldwide, colorectal cancer (CRC) stands in the center of scientific interest in hope to develop novel approaches for precise diagnostics and prognosis determination. Metastatic disease remains the main cause of CRC mortality. To investigate the underlying genetic differences between CRC patients with synchronous and metachronous liver metastases, we performed whole-exome sequencing of 210 patient samples using formalin-fixed paraffin-embedded samples from primary tumors and the paired liver metastatic tissue. The analyses included types and levels of mutations and copy number variation. APC and TP53 were the most commonly mutated genes in all samples with differing frequency between primary CRC (both 50%) and its metachronous metastasis (both 64%). While MPDZ gene mutations were restricted to primary tumors that developed metachronous metastases only, mutations in VCAN, MTCL1, MDN1, SHROOM2, SPEG, and GLI2 were more prevalent in primary tumors giving rise to synchronous metastases. FBN1 mutations were unique to synchronous liver metastatic tissue. Analysis of genetic interactions revealed different associations between mutated genes in patients with tumors of different chronicity, including driver genes such as TP53, which was associated with APC in synchronous patients, while in primary tumors with metachronous metastases it co-occurs with mutations in NBPF11 and PRAMEF15, respectively. The results suggest that distinct tumor progression pathways account for different chronicity outcomes further affecting patients' survival. However, larger studies are needed incorporating transcriptomic and epigenomic data to shed further light on the mechanistic chain from mutations to downstream gene expression regulation.