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, Yong Li

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number5061
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Deng, Q., Hu, H., Yu, X., Liu, S., Wang, L., Chen, W., Zhang, C., Zeng, Z., Cao, Y., Xu-Monette, Z. Y., Li, L., Zhang, M., Rosenfeld, S., Bao, S., Hsi, E., Young, K. H., Lu, Z., & Li, Y. (2019). Tissue-specific microRNA expression alters cancer susceptibility conferred by a TP53 noncoding variant. Nature communications, 10(1), [5061]. https://doi.org/10.1038/s41467-019-13002-x