Tissue-specific microRNA expression alters cancer susceptibility conferred by a TP53 noncoding variant

Qipan Deng, Hui Hu, Xinfang Yu, Shuanglin Liu, Lei Wang, Weiqun Chen, Chi Zhang, Zhaoyang Zeng, Ya Cao, Zijun Y. Xu-Monette, Ling Li, Mingzhi Zhang, Steven Rosenfeld, Shideng Bao, Eric Hsi, Ken H. Young, Zhongxin Lu () and Yong Li ()
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Qipan Deng: Section of Epidemiology and Population Sciences, Baylor College of Medicine
Hui Hu: Lerner Research Institute, Cleveland Clinic
Xinfang Yu: Section of Epidemiology and Population Sciences, Baylor College of Medicine
Shuanglin Liu: Section of Epidemiology and Population Sciences, Baylor College of Medicine
Lei Wang: Lerner Research Institute, Cleveland Clinic
Weiqun Chen: Central Hospital of Wuhan
Chi Zhang: Central Hospital of Wuhan
Zhaoyang Zeng: Lerner Research Institute, Cleveland Clinic
Ya Cao: Central South University; Key Laboratory of Carcinogenesis, Chinese Ministry of Health
Zijun Y. Xu-Monette: Division of Hematopathology, Duke University Medical Center
Ling Li: the First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province
Mingzhi Zhang: the First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province
Steven Rosenfeld: Lerner Research Institute, Cleveland Clinic
Shideng Bao: Lerner Research Institute, Cleveland Clinic
Eric Hsi: Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic
Ken H. Young: Division of Hematopathology, Duke University Medical Center
Zhongxin Lu: Central Hospital of Wuhan
Yong Li: Section of Epidemiology and Population Sciences, Baylor College of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.

Date: 2019
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DOI: 10.1038/s41467-019-13002-x

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