Research

PKU and Tianjin Medical University discover the Convergent Evolution of CNAs in Tumour Cells

JUN . 12 2017
Peking University May 31,2017: on May 9th, a research paper titled Single-Cell Sequencing Deciphers a Convergent Evolution of Copy Number Alterations was published by the Journal Genome Research. The research team, led by Professors Bai Fan and Xiaoliang Sunney Xie, Peking University and Professor Zhang Ning TianJin Medical University Cancer Institute and Hospital, studied the genomic alterations in single primary tumor cells and circulating tumor cells (CTCs) from the same patient and discovered the evolutionary process of CNAs in the routes to cancer metastases.
 
Cancer metastases, the dissemination and colonization of tumor cells at distant sites, led to the majority of cancer-related deaths. CTCs are cancer cells that successfully escape from the primary tumor site, enter the peripheral blood and survive the circulation. Genomic analyses of CTCs are crucial for understanding the underlying mechanism of cancer metastasis and could lead to the development of new methods for non-invasive cancer diagnosis and prognosis in the clinic.
                                                   
Evolution of SNVs and Large-scale CNAs in Primary Tumor cells and CTCs.
 
The team first analyzed the distribution of SNVs among 28 primary tumor cells and 5 CTCs from a colon, then they focused on CNA patterns, which is a general approach to analyze single-cell CNAs affecting larger than megabases of genome with low sequencing depth. Through observation, the team suggested that CNAs were exacerbated and accumulated consecutively in certain regions with high probability, leading to a converging pattern in CTCs and metastases.
 
 
CTCs exhibited substantial decreases (left ) and increases (right ) in copy numbers in regions containing the tumor suppressor gene PTEN and oncogene MYC
 
The team also proposed a two-step model to explain the multi-region copy number gains in Chromosome 8. This model explains the relatively uniform focal gains across multiple regions in Chromosome 8 of the selected patient.
A two-step model to elucidate the CNAs involving four regions
on Chromosome 8 containing the MYC gene
 
The team analyzed CNAs at the single-gene level across CTCs from all 23 patients,
searching for recurrent gains or losses (more than ten copies or homozygous losses) that appeared in at least two patients, which results in the identification of a set of 11 genes (Fig. below), illustrating the capability of CTC sequencing as a method to detect important, clinically relevant chromosome alterations at the single-gene level.
 
Integrative Analyses of the CNA Patterns of CTCs from Patients with Different Types of Cancer
 
All in all, the correlation analyzes at the single-cell level provide a new avenue for identifying related oncogenic events and could guide the clinical practice of combinatorial treatments that target multiple genomic alterations.
 
Professors Bai Fan, Xiaoliang Sunney Xie and Zhang Ning are the corresponding authors of the paper, and Gao Yan, Su Zhe, Ni Xiaohui, Guo Hua, Ba Yi are the co-first authors. The research project is funded by the National High Technology Research and Development Program of China, the National Basic Research Program of China the National Science Fund for Distinguished Young Scholars, the National Key Research and Development Program, the Beijing Municipal Science and Technology Commission and the Recruitment Program of Global Youth Experts.

Background Information

Genome Research: Launched in 1995, it is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine.

Written by: Li Xiaotong
Edited by: Wang YuqingGan Zhonghao
Source: PKU News (Chinese)
Link: http://pkunews.pku.edu.cn/xwzh/2017-05/19/content_297906.htm