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Cell Res. 2014 Jun;24(6):701-12. doi: 10.1038/cr.2014.43. Epub 2014 Apr 4.

Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing.

Author information

1
BGI-Shenzhen, Shenzhen, Guangdong 518083, China.
2
Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
3
Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital/Institute, Beijing 100142, China.
4
1] BGI-Shenzhen, Shenzhen, Guangdong 518083, China [2] Institute of Digestive Disease and the Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
5
1] BGI-Shenzhen, Shenzhen, Guangdong 518083, China [2] School of Biological Science and Medical Engineering, Southeast University, Nanjing, China [3] State Key Laboratory of Bioelectronics, Southeast University, Nanjing, Jiangsu 210096, China.
6
1] BGI-Shenzhen, Shenzhen, Guangdong 518083, China [2] Department of Peadiatrics & Adolescent medicine, The University of Hong Kong, Hong Kong, China.
7
1] BGI-Shenzhen, Shenzhen, Guangdong 518083, China [2] Department of Computational Medicine and Bioinformatics, Medical School, University of Michigan, Ann Arbor, USA.
8
Department of Surgery, Peking University School of Oncology, Beijing Cancer Hospital/Institute, Beijing 100142, China.
9
1] BGI-Shenzhen, Shenzhen, Guangdong 518083, China [2] Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark [3] Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia [4] Macau University of Science and Technology, Avenida Wai long, Taipa, Macau 999078, China.

Abstract

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.

PMID:
24699064
PMCID:
PMC4042168
DOI:
10.1038/cr.2014.43
[Indexed for MEDLINE]
Free PMC Article

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