Journal
CELL RESEARCH
Volume 24, Issue 6, Pages 701-712Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2014.43
Keywords
single-cell sequencing; colon cancer; SLC12A5; biclonal; oncogene
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Funding
- National Basic Research Program of China (973 program) [2011CB809202, 2011CB809203]
- Hi-Tech Research and Development Program of China (863 program) [2009AA022707]
- Theme-based Research Scheme of the Hong Kong Research Grants Council [T12-403-11]
- Shenzhen Municipal Government of China [ZYC201005250020A]
- Key Laboratory project Supported by Shenzhen City [CXB200903110066A, CXB201108250096A]
- Shenzhen Key Laboratory of Gene Bank for National Life Science
- Innovative Research Team Project of GuangDong
- GuangDong Enterprise Key Laboratory of Human Disease Genomics
- Intramural Research Program of the National Institutes of Health
- National Cancer Institute
- Center for Cancer Research
- Cancer Genome Project, Scheme B CUHK
- Danish Natural Science Research Council for the Ole Romer grant
- Shenzhen Municipal Government and the Local Government of Yantian District of Shenzhen
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Single-cell sequencing is a powerful tool for delineating clonal relationship and identifying key driver genes for personalized cancer management. Here we performed single-cell sequencing analysis of a case of colon cancer. Population genetics analyses identified two independent clones in tumor cell population. The major tumor clone harbored APC and TP53 mutations as early oncogenic events, whereas the minor clone contained preponderant CDC27 and PABPC1 mutations. The absence of APC and TP53 mutations in the minor clone supports that these two clones were derived from two cellular origins. Examination of somatic mutation allele frequency spectra of additional 21 whole-tissue exome-sequenced cases revealed the heterogeneity of clonal origins in colon cancer. Next, we identified a mutated gene SLC12A5 that showed a high frequency of mutation at the single-cell level but exhibited low prevalence at the population level. Functional characterization of mutant SLC12A5 revealed its potential oncogenic effect in colon cancer. Our study provides the first exome-wide evidence at single-cell level supporting that colon cancer could be of a biclonal origin, and suggests that low-prevalence mutations in a cohort may also play important protumorigenic roles at the individual level.
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