Journal
ONCOTARGET
Volume 6, Issue 26, Pages 22179-22190Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4246
Keywords
colorectal cancer; exome sequencing; liver metastasis; RNA sequencing; somatic mutation
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Funding
- National Research Foundation of Korea - Ministry of Science, ICT, and Future Planning [NRF-2012M3A9D1054670, NRF-2014M3C9A3068554]
- KRIBB Research Initiative
- Asan Institute for Life Sciences [2014-69]
- National Research Foundation [2013R1A2A1A03070986]
- Ministry of Science, ICT, and Future Planning
- Korea Health 21 RD Project [HI06C0868, HI13C1750]
- Center for Development and Commercialization of Anti-Cancer Therapeutics [HI10C2014]
- Ministry of Health and Welfare, Republic of Korea
- National Research Foundation of Korea [2012M3A9D1054670] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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To characterize the mutation profiles of colorectal cancer (CRC) primary tumors (PTs) and liver metastases (CLMs), we performed both whole-exome and RNA sequencing. Ten significantly mutated genes, including BMI1, CARD11, and NRG1, were found in 34 CRCs with CLMs. We defined three mutation classes (Class 1 to 3) based on the absence or presence of mutations during liver metastasis. Most mutations were classified into Class 1 (shared between PTs and CLMs), suggesting the common clonal origin of PTs and CLMs. Class 1 was more strongly associated with the clinical characteristics of advanced cancer and was more frequently superimposed with chromosomal deletions in CLMs than Class 2 (PT-specific). The integration of exome and RNA sequencing revealed that variant-allele frequencies (VAFs) of mutations in the transcriptome tended to have stronger functional implications than those in the exome. For instance, VAFs of the TP53 and APC mutations in the transcriptome significantly correlated with the expression level of their target genes. Additionally, mutations with high functional impact were enriched with high VAFs in the CLM transcriptomes. We identified 11 mutation-associated splicing events in the CRC transcriptomes. Thus, the integration of the exome and the transcriptome may elucidate the underlying molecular events responsible for CLMs.
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