title: Rare germline variant (rs78378222) in the TP53 3' UTR: Evidence for a new mechanism of cancer predisposition in Li-Fraumeni syndrome.
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 carcinogenesis in LFS/LFL.
authors.affiliation: Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, 15053, Rio Grande do Sul, Brazil; Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, 1247, Rio Grande do Sul, Brazil. Electronic address: gmacedoufrgs@gmail.com.
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Macedo
authors.affiliation: Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, 15053, Rio Grande do Sul, Brazil; Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, 1247, Rio Grande do Sul, Brazil.
authors.forename: Igor
authors.initials: I
authors.lastname: Araujo Vieira
authors.affiliation: Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, 1247, Rio Grande do Sul, Brazil.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Brandalize
authors.affiliation: Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, 1247, Rio Grande do Sul, Brazil; Hospital Tacchini, Bento Gonçalves, Rio Grande do Sul, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Giacomazzi
authors.affiliation: Molecular Oncology Research Center, Hospital do Câncer de Barretos, Barretos, 65009, São Paulo, Brazil.
authors.forename: Edenir
authors.initials: E
authors.lastname: Inez Palmero
authors.affiliation: Molecular Oncology Research Center, Hospital do Câncer de Barretos, Barretos, 65009, São Paulo, Brazil.
authors.forename: Sahlua
authors.initials: S
authors.lastname: Volc
authors.affiliation: Biology Department, Universidade Federal da Bahia, Salvador, 2600, Bahia, Brazil.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rodrigues Paixão-Côrtes
authors.affiliation: Hospital Moinhos de Vento, Porto Alegre, 21254, Rio Grande do Sul, Brazil.
authors.forename: Maira
authors.initials: M
authors.lastname: Caleffi
authors.affiliation: Service of Medical Physics and Radioprotection, HCPA, Porto Alegre, 1247, Rio Grande do Sul, Brazil.
authors.forename: Michele
authors.initials: M
authors.lastname: Silva Alves
authors.affiliation: Oncogenetics Department, International Research Center, AC Camargo Cancer Center, National Institute of Oncogenomics, São Paulo, 01508-010, São Paulo, Brazil.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Achatz
authors.affiliation: Institut Albert Bonniot- INSERM 823, University Grenoble-Alpes, Grenoble, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.affiliation: Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, 15053, Rio Grande do Sul, Brazil; Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, 1247, Rio Grande do Sul, Brazil; Department of Genetics, UFRGS, Porto Alegre, 15053, Rio Grande do Sul, Brazil; Medical Genetics Service, HCPA, Porto Alegre, 1247, Rio Grande do Sul, Brazil.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ashton-Prolla
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D019143:Evolution, Molecular; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged
chemical_list: D020413:3' Untranslated Regions
keywords: 3' UTR; Li-Fraumeni syndrome; haploinsufficiency; rs78378222