Tissue-specific MicroRNA Expression Alters Cancer Susceptibility Conferred by a TP53 Noncoding Variant

Abstract

Patients carrying TP53 germline mutations develop Li-Fraumeni syndrome (LFS), a rare genetic disorder with high risk of several cancers, most notably breast cancer, sarcoma, and brain tumors. A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was associated with moderate risk of brain, colon, and prostate tumors, and other neoplasms. We found a positive association between this variant and soft tissue sarcoma (odds ratio [OR] = 4.55, P = 3.3 x 10-5). In sharp contrast, this variant was protective against breast cancer (OR = 0.573, P = 0.0078). We generated a mouse line carrying this variant and found that this variant accelerated spontaneous tumorigenesis and tumor development at the brain, prostate, colon, and skeletal muscle, but strikingly, it significantly delayed mammary tumorigenesis. The variant created a miR-382 targeting site and compromised a miR-325 targeting site. Their differential expression resulted in p53 downregulation in the brain and several other tissues, but p53 upregulation in the mammary gland of the mutant mice compared to that of wild-type littermates. Thus, this TP53 variant is at odds with LFS mutants in breast cancer predisposition yet consistent with LFS mutants in susceptibility to soft tissue sarcoma and glioma. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.