Lymph Node Metastases in Colon Cancer are Polyclonal

Purpose:  Recent studies have highlighted the existence of sub-clones in tumors. Lymph nodes are generally the first location of metastasis for most solid epithelial tumors including colorectal cancer (CRC). We sought to understand the genetic origin of lymph node metastasis in CRC by evaluating the relationship between CRC tumor sub-clones present in primary tumors and lymph nodes. Experimental Design:  A total of 33 samples from seven CRC's, including two or three spatially disparate regions from each primary tumor and one to four matched lymph nodes for each tumor, underwent next-generation whole-exome DNA sequencing, Affymetrix OncoScan SNP arrays, and targeted deep confirmatory sequencing. We performed mapping between SNPs and copy number events from the primary tumor and matched lymph node samples, allowing us to profile heterogeneity and the mutational origin of LN metastases. The computational method PyClone was used to define sub-clones within each tumor. The method Citup was subsequently used to infer phylogenetic relationships among sub-clones. Results:  We found there was substantial heterogeneity in mutations and copy number changes among all samples from any given patient. For each patient, the primary tumor regions and matched lymph node metastases were each polyclonal and the clonal populations differed from one lymph node to another. In some patients, the cancer cell populations in a given lymph node originated from multiple distinct regions of a tumor. Conclusions: Our data support a model of lymph node metastatic spread in colorectal cancer whereby metastases originate from multiple waves of seeding from the primary tumor over time.

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