Characterization of BRCA1-deficient premalignant tissues and cancers identifies Plekha5 as a tumor metastasis suppressor

Jianlin Liu,Xiaoling Xu,Ragini Adhav,Xueying Lyu,Un In Chan,Koon Ho Wong,Xu Zhang,Chuxia Deng,Sek Man Su,Xiaodong Shu,Jun Xu,Heng Sun,Kaeling Tan,Kai Miao,Lakhansing Pardeshi,Jianjie Li,Lihua Mo,Xin Zhang,Jianming Zeng

doi:10.1038/s41467-020-18637-9

Jianlin Liu, Xiaoling Xu + Show 17 more

Open Access

https://doi.org/10.1038/s41467-020-18637-9

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Journal: Nature Communications	Publication Date: Sep 25, 2020
Citations: 25	License type: open-access

Affiliation: University of Macau

Abstract

Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intratumor heterogeneity and identifying cancer drivers. So far, however, simultaneous analysis of single nucleotide variants (SNVs) and copy number variations (CNVs) of a single cell has been challenging. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Upon this, we finally identify a tumor metastasis suppressor Plekha5, whose deficiency promotes cancer metastasis to the liver and/or lung.

Highlights

Single-cell whole-exome sequencing is a powerful approach for deciphering intratumor heterogeneity and identifying cancer drivers
We demonstrate that tumors initiate from cells with random single nucleotide variants (SNVs) affecting driver genes in the premalignant stage and malignantly progress later via copy number variations (CNVs) acquired in chromosome regions with many cancer driver genes, including Plekha[5], which acts as a tumor metastasis suppressor
Analyses of CNV patterns in both mice and human patients were carried out, and each individual exhibited different amplification or deletion patterns, some common amplification regions existed (Fig. 1e; Supplementary Fig. 1f; Supplementary Data 3). This variability of CNV patterns among tumors was consistent with that observed in the Brca1-deficient mouse tumors from a previous study[27]

Summary

Introduction

Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intratumor heterogeneity and identifying cancer drivers. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Using a genetic approach in which mutant mice carrying targeted disruptions of p53, Atm, Chk[2], or 53BP1 are bred with Brca1-deficient mice, we found that these genes play critical roles in various aspects of tumorigenesis[15,16,17,18,19], yet many other putative tumor suppressors and oncogenes have not been identified

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