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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Deng, Q; Hu, H; Yu, X; Liu, S; Wang, L; Chen, W; Zhang, C; Zeng, Z; Cao, Y; Xu-Monette, ZY; Li, L; Zhang, M; Rosenfeld, S; Bao, S; Hsi, E; Young, KH; Lu, Z; Li, Y

Published Date

  • November 7, 2019

Published In

Volume / Issue

  • 10 / 1

Start / End Page

  • 5061 -

PubMed ID

  • 31699989

Pubmed Central ID

  • 31699989

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-019-13002-x

Language

  • eng

Conference Location

  • England