Abstract
Liver is the most common site where metastatic lesions of colorectal cancer (CRC) arise. Although researches have shown mutations in driver genes, copy number variations (CNV) and alterations in relevant signaling pathways promoted the tumor evolution and immune escape during colorectal liver metastasis (CLM), the underlying mechanism remains largely elusive. Tumor and matched metastatic tissues were collected from 16 patients diagnosed with colorectal cancer and subjected to whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for studying colorectal cancer clonal evolution and immune escape during CLM. Shared somatic mutations between primary and metastatic tissues with a commonly observed subclonal-clonal (S-C) changing pattern indicated a common clonal origin between two lesions. The recurrent mutations with S-C changing pattern included those in KRAS, SYNE1, CACNA1H, PCLO, FBXL2, and DNAH11. The main CNV events underwent clonal-clonal evolution (20q amplification (amp), 17p deletion (del), 18q del and 8p del), subclonal-clonal evolution (8q amp, 13q amp, 8p del) and metastasis-specific evolution (8q amp) during the process of CLM. In addition, we revealed a potential mechanism of tumor cell immune escape by analyzing human leukocytes antigens (HLA) related clonal neoantigens and immune cell components in CLM. Our study proposed a novel liver metastasis-related evolutionary process in colorectal cancer and emphasized the theory of neo-immune escape in colorectal liver metastasis.
Highlights
The colorectal liver metastasis (CLM) is a multistep and complex process during which tumor cells develop aggressive phenotypic features, and intensely interact with the host immune microenvironment [1]
Somatic mutations and indels in CLM We examined the mutational burdens in 15 pairs of colorectal primary tumors and matched liver metastases and observed 24,590 somatic single nucleotide variations and 9996 small insertions and deletions (Indels) in those samples
The mutations in liver metastases were enriched in extracellular matrix (ECM), collagen and MET related pathways, which were closely associated with down-stream KRAS-MEK/ERK and PI3K-MTOR signaling pathways (Supplementary Fig. S1B, C)
Summary
The colorectal liver metastasis (CLM) is a multistep and complex process during which tumor cells develop aggressive phenotypic features, and intensely interact with the host immune microenvironment [1]. 33–50% patients with colorectal cancer (CRC) progressed to CLM [2, 3], which is the major cause of CRC-related deaths. Yoshikuni et al analyzed the sequencing data of 1460 patients who underwent CLM resection, and found that multiple somatic mutations in RAS, TP53, and SMAD4 were related with worse prognosis [4]. Hu et al identified the surrogates of metastasis in a cohort enrolling 2751 samples of CRC and suggested that in ~81% patients, tumor cells were commonly disseminated for metastases as early as when the tumor was clinically undetectable (typically,
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