Genomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases

Jing Sun, Cheng Wang, Yi Zhang, Lingyan Xu, Weijia Fang, Yuping Zhu, Yi Zheng, Xiaofeng Chen, Xiju Xie, Xinhua Hu, Weidong Hu, Jingyu Zheng, Ping Li, Jian Yu, Zhu Mei, Xiaomin Cai, Biao Wang, Zhibin Hu, Yongqian Shu (), Hongbing Shen () and Yanhong Gu ()
Additional contact information
Jing Sun: The First Affiliated Hospital of Nanjing Medical University
Cheng Wang: Nanjing Medical University
Yi Zhang: The First Affiliated Hospital of Nanjing University of Chinese Medicine
Lingyan Xu: The First Affiliated Hospital of Nanjing Medical University
Weijia Fang: Zhejiang University
Yuping Zhu: The Zhejiang Cancer Hospital
Yi Zheng: Zhejiang University
Xiaofeng Chen: The First Affiliated Hospital of Nanjing Medical University
Xiju Xie: The First Affiliated Hospital of Nanjing Medical University
Xinhua Hu: The Affiliated Brain Hospital of Nanjing Medical University
Weidong Hu: The Second Affiliated Hospital of Soochow University
Jingyu Zheng: Nanjing University Medical School
Ping Li: The First Affiliated Hospital of Nanjing Medical University
Jian Yu: University of Pittsburgh School of Medicine
Zhu Mei: The First Affiliated Hospital of Nanjing Medical University
Xiaomin Cai: The First Affiliated Hospital of Nanjing Medical University
Biao Wang: The First Affiliated Hospital of Nanjing Medical University
Zhibin Hu: Nanjing Medical University
Yongqian Shu: The First Affiliated Hospital of Nanjing Medical University
Hongbing Shen: Nanjing Medical University
Yanhong Gu: The First Affiliated Hospital of Nanjing Medical University

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: Abstract Brain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue. Compared with primary CRC, BM exhibits elevated mutational signatures of homologous recombination deficiency (HRD) and mismatch repair deficiency (MMRD). Further analysis reveals two DNA damage response (DDR) signatures could emerge early and are enhanced in BM tissues but are eliminated eventually in matched primary CRC tissues. BM-specific mutations in DDR genes and elevated microsatellite instability (MSI) levels support the importance of DDR in the brain metastasis of CRC. We also identify BM-related genes (e.g., SCN7A, SCN5A, SCN2A, IKZF1, and PDZRN4) that carry frequent BM-specific mutations. These results provide a better understanding of the BM mutational landscape and insights into treatment.

Date: 2019
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DOI: 10.1038/s41467-019-10987-3

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