Revealing the biphasic copy number evolution model of hepatocellular carcinoma through single-cell genome sequencing

September 1, 2021, the field of gastroenterology academic journal Gastroenterology in a long article published online in the form of a tumor transforming research results Research Center of Peking University First Hospital Zhang Ning Task Force
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In the research paper entitled "Single cell DNA sequencing reveals punctuated and gradual clonal evolution in hepatocellular carcinoma", the researchers comprehensively used single cell sequencing, model construction, large-scale data and experimental verification to systematically explore the genome at the single cell level of liver cancer It is the first to propose the discontinuous and progressive biphasic evolution mode (DPCNE) of liver cancer, reveals the relationship between the biphasic evolution mode in liver cancer, intratumoral heterogeneity and prognosis, and confirms the origin of polyploid liver cancer at the single-cell level for the first time In diploid cells, a new prognostic marker CAD was discovered

Figure 1 Screenshot of the research webpage

Hepatocellular carcinoma (referred to as liver cancer) accounts for about 80% of primary liver cancer, and its fatality rate ranks third among all cancers
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The response rate and therapeutic effect of existing targeted therapy and immunotherapy in liver cancer are very limited, and tumor heterogeneity is one of the important reasons for its drug resistance, recurrence and poor prognosis

In a recent study, the research team collected fresh or frozen liver cancer tissues and corresponding adjacent tissues.
Through single-cell DNA sequencing, low-depth whole-genome sequencing of 1275 cells in 10 liver cancer patients was completed.
356 cells underwent low-depth whole-genome sequencing based on ploidy analysis, and single-cell RNA sequencing was performed on 27344 cells in the other three patients
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The researchers then verified the transcriptome sequencing of 17 cases of liver cancer and adjacent tissues, 202 cases of tissue immunohistochemical staining, 21 cases of published single-cell DNA data, and 1196 cases of published RNA data (Figure 2)

Figure 2 Schematic diagram of the research route

The researchers systematically analyzed the copy number variation profiles of individual cells in 10 liver cancer patients and found three different cell subgroups: euploid, pseudo-euploid and aneuploidy
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Secondly, the researchers found that CNA accumulation has both discontinuous evolution and gradual evolution through model construction

Figure 3 Three models of copy number evolution

The research group also studied the ploidy heterogeneity
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Ploidy heterogeneity is an important aspect of liver cancer heterogeneity.

Dr.
Guo Lin and Dr.
Yi Xianfu from Tianjin Medical University, Dr.
Chen Lu and Professor Zhang Yu from Hepatobiliary Surgery Department of Tianjin Cancer Hospital are the co-first authors of this paper
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Professor Zhang Ning from the Cancer Transformation Center of Peking University First Hospital, the Tumor Cell Biology Laboratory of Tianjin Cancer Hospital, and Associate Researcher Xue Ruidong from the Cancer Transformation Center of Peking University First Hospital are the co-corresponding authors