Rare germline variant (rs78378222) in the TP53 3' UTR: Evidence for a new mechanism of cancer predisposition in Li-Fraumeni syndrome

Cancer Genetics
Gabriel S MacedoPatricia Ashton-Prolla

Abstract

Germline mutations in TP53 are the underlying defects in Li-Fraumeni syndrome (LFS) and its variant, Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders that are characterized by predisposition to multiple early onset cancers. Here, we identified rs78378222 (A > C), a rare variant that is located in the 3' untranslated region (3' UTR) of TP53, in 7 probands (5.4%) of a cohort from LFS/LFL patients without TP53 germline mutations in the coding regions. To support its association with the LFS/LFL phenotype, we assessed p53 expression in tumor specimens and fibroblasts from rs78378222[C] carriers. Additionally, we investigated using in silico tools the evolutionary conservation and whether rs78378222[C] affects microRNA (miRNA) binding sites in the 3' UTR of TP53 mRNA. We found lower p53 protein levels in biological samples from rs78378222[C] carriers. Additionally, we showed that rs78378222[C] could interfere with a putative target site of miR-545-3p, a novel miRNA that is predicted to directly target the 3' UTR TP53. To our knowledge, this is the first description of rs78378222[C] in LFS/LFL patients. Moreover, these findings suggest that rs78378222[C] lead to haploinsufficiency of p53, a new mechanism of carcinogenesi...Continue Reading

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Citations

Oct 24, 2018·Human Mutation·Kelvin C de AndradeMaria I Achatz
Jun 4, 2019·Journal of Molecular Cell Biology·Thibaut BarnoudMaureen E Murphy
Oct 28, 2019·Pathology Oncology Research : POR·Pablo GargalloAdela Cañete
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Jun 15, 2020·Cellular and Molecular Neurobiology·José Alberto Carlos-EscalanteTalia Wegman-Ostrosky

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