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

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• 作者：Gabriel S. Macedo^a ; ^b ; ¹ ; ^{gmacedoufrgs@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Igor Araujo Vieira^a ; ^b ; ¹ ; Ana Paula Brandalize^b ; Juliana Giacomazzi^b ; ^d ; Edenir Inez Palmero^e ; Sahlua Volc^e ; Vanessa Rodrigues Paixã ; o-Cô ; rtes^f ; Maira Caleffi^g ; Michele Silva Alves^h ; Maria Isabel Achatzⁱ ; Pierre Hainaut^j ; Patricia Ashton-Prolla^a ; ^b ; ^c ; ^k
• 关键词：3' UTR ; Li-Fraumeni syndrome ; haploinsufficiency ; rs78378222
• 刊名：Cancer Genetics
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：209
• 期：3
• 页码：97-106
• 全文大小：2721 K

文摘

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.