Abstract
BackgroundColorectal cancer (CRC) is a major cancer type whose mechanism of metastasis remains elusive.MethodsIn this study, we characterised the evolutionary pattern of metastatic CRC (mCRC) by analysing bulk and single-cell exome sequencing data of primary and metastatic tumours from 7 CRC patients with liver metastases. Here, 7 CRC patients were analysed by bulk whole-exome sequencing (WES); 4 of these were also analysed using single-cell sequencing.ResultsDespite low genomic divergence between paired primary and metastatic cancers in the bulk data, single-cell WES (scWES) data revealed rare mutations and defined two separate cell populations, indicative of the diverse evolutionary trajectories between primary and metastatic tumour cells. We further identified 24 metastatic cell-specific-mutated genes and validated their functions in cell migration capacity.ConclusionsIn summary, scWES revealed rare mutations that failed to be detected by bulk WES. These rare mutations better define the distinct genomic profiles of primary and metastatic tumour cell clones.
Highlights
Colorectal cancer (CRC) is a major cancer type whose mechanism of metastasis remains elusive
A total of 24 bulk whole-exome sequencing (WES) and 321 single-cell whole-exome sequencing (scWES) samples were sequenced on the Illumina platform, with high-quality data (Methods, Additional file 1: Table S1), which included single-cell and bulk sample pairs from four patients: CRC4, CRC5, CRC6, and CRC7 (Fig. 1B)
Similar to the results we found in the subclone analysis of CRC5, all tumour cell clones shared a large number of Single-nucleotide variant (SNV), including those in some well-known CRC driver genes, such as TP53 and MAPK6 (Fig. 5A)
Summary
Colorectal cancer (CRC) is a major cancer type whose mechanism of metastasis remains elusive. Distant metastasis occurs in approximately 20% of newly diagnosed CRC patients [3] and is one of the major causes of patient death and a poor prognosis. The mechanism of Single-cell sequencing methods have emerged as powerful tools to resolve ITH and trace clonal lineages. With advances in experimental protocols and computational methods, it has become possible to identify genome-wide single-cell somatic mutation profiles [9, 10] and estimate the evolution of cell lineages [11,12,13,14]. Leung et al reported a ‘late-dissemination model’ through single-cell lineage tracing from primary and liver mCRC samples based on a panel of 1000 cancer genes [10]. The limited number of genes in panel sequencing methods may restrict the evolutionary model of CRC metastasis
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