Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers.
Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis.
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Ji-Hyun
JH
Lee
Department of Computer Science and Technology, Tongji University , Shanghai, China.
Xing-Ming
XM
Zhao
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
Ina
I
Yoon
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
Jin Young
JY
Lee
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
Nam Hoon
NH
Kwon
Department of Computer Science and Technology, Tongji University , Shanghai, China.
Yin-Ying
YY
Wang
Department of Surgery, Seoul National University College of Medicine , Seoul, Republic of Korea.
Kyung-Min
KM
Lee
Department of Surgery, Seoul National University College of Medicine , Seoul, Republic of Korea.
Min-Joo
MJ
Lee
Department of Surgery, Seoul National University College of Medicine , Seoul, Republic of Korea.
Jisun
J
Kim
Department of Surgery, Seoul National University College of Medicine , Seoul, Republic of Korea.
Hyeong-Gon
HG
Moon
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
Yongho
Y
In
LERIA, University of Angers , Angers, France.
Jin-Kao
JK
Hao
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea.
Kyung-Mii
KM
Park
Department of Surgery, Seoul National University College of Medicine , Seoul, Republic of Korea.
Dong-Young
DY
Noh
Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
Wonshik
W
Han
Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
Sunghoon
S
Kim
RNA sequencing; driver mutations; exome sequencing; integrative analysis; metastatic breast cancer