Matched primary samples for metachronous liver metastases of colorectal cancer
In months to years after resection of their primary tumor, 10-15% of colorectal cancer patients develop metachronous metastases. While surgical removal of these metastases does prolong survival, outcomes vary markedly – from long-term remission of disease to early relapse within <12 months after surgery. To identify clinico-genomic determinants of relapse, we assembled metachronous liver metastases from 41 patients and their matched primary tumors, where available. Clinically, early relapse was associated with a greater number of liver metastases, and regional nodal involvement, consistent with a higher metastatic burden. Genomically, early relapsing metastases exhibited increased chromosomal instability and characteristic aneuploidy patterns, involving loss of 3p and 5q arms and gain of chr 16, while presence of multiple APC mutations was more likely in metastases with late or no relapse. Transcriptome analyses linked these aneuploidy patterns to gene-dosage effects and differential expression patterns related to metastatic progression. In matched primary tumors and metachronous metastases from the same patients, relapse-associated aneuploidy patterns were either acquired during metastatic evolution or pre-existed in primaries. Three independent cohorts (MSK MetTropism, HMF, TCGA), were used to corroborate these findings, revealing higher frequencies of 3p/5q loss and chr 16 gain in metastases versus primaries and survival differences linked to these genomic features. Collectively, our findings implicate chromosomal instability as a key mechanism in metachronous metastases and lay the foundation for clinical studies to evaluate the degree to which arm-level aneuploidy patterns can help personalize decisions in the long-term clinical management of colorectal cancer.