RGD Reference Report - The rs17084733 variant in the KIT 3' UTR disrupts a miR-221/222 binding site in gastrointestinal stromal tumour: a sponge-like mechanism conferring disease susceptibility. - Rat Genome Database

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The rs17084733 variant in the KIT 3' UTR disrupts a miR-221/222 binding site in gastrointestinal stromal tumour: a sponge-like mechanism conferring disease susceptibility.

Authors: Ravegnini, Gloria  Serrano, César  Simeon, Vittorio  Sammarini, Giulia  Nannini, Margherita  Roversi, Erica  Urbini, Milena  Ferrè, Fabrizio  Ricci, Riccardo  Tarantino, Giuseppe  Pantaleo, Maria A  Hrelia, Patrizia  Angelini, Sabrina 
Citation: Ravegnini G, etal., Epigenetics. 2019 Jun;14(6):545-557. doi: 10.1080/15592294.2019.1595997. Epub 2019 Apr 13.
RGD ID: 151709007
Pubmed: PMID:30983504   (View Abstract at PubMed)
PMCID: PMC6557610   (View Article at PubMed Central)
DOI: DOI:10.1080/15592294.2019.1595997   (Journal Full-text)

Several miRNAs are dysregulated in gastrointestinal stromal tumours (GIST), and miR-221/222 appear to have a prominent role in GIST biology. Therefore, we investigated the role of DNA variants located in miR-221/222 precursor sequences and their target KIT 3'UTR. Ninety-five polymorphisms were analysed in 115 GIST cases and 88 healthy controls. KIT 3'UTR rs17084733 and pri-miR-222 rs75246947 were found significantly associated with GIST susceptibility. Specifically, KIT rs17084733 A allele was more common in GIST, particularly in KIT wild-type (WT) patients (Padj = 0.017). rs17084733 variant is located within one of the three miR-221/222 binding sites in the KIT 3'UTR, resulting in a mismatch in this seed region. Conversely, KIT mRNA levels were lower in patients carrying the variant allele, except for KIT mutant GIST. Luciferase assay data in GIST cells, generated using a construct containing all the three miR-221/222 binding sites, are consistent with KIT mRNA levels in GIST patients. Reporter assay data, generated using a construct containing only the site encompassing rs17084733, confirmed that this is a functional variant disrupting the miR-221/222 binding site. In conclusion, this is the first study investigating the role of SNPs on miR-221/222 precursor sequences and their binding region on KIT 3'UTR in GIST. We identified the KIT variant rs17084733 as a possible novel genetic biomarker for risk of developing KIT-WT GIST. Moreover, our findings suggest the role of one of the three miR-221/222 binding sites on KIT 3'UTR as endogenous sponge, soaking up and subtracting miR-221/222 to the other two sites characterized by a higher affinity.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
gastrointestinal stromal tumor disease_progressionIAGP 151709007DNA:SNP: :rs17084733 (human)RGD 
gastrointestinal stromal tumor disease_progressionISOKIT (Homo sapiens)151709007; 151709007DNA:SNP: :rs17084733 (human)RGD 
gastrointestinal stromal tumor disease_progressionIAGP 151709007DNA:SNP: :rs75246947 (human)RGD 
gastrointestinal stromal tumor disease_progressionISOMIR222 (Homo sapiens)151709007; 151709007DNA:SNP: :rs75246947 (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Kit  (KIT proto-oncogene receptor tyrosine kinase)
Mir222  (microRNA 222)

Genes (Mus musculus)
Kit  (KIT proto-oncogene receptor tyrosine kinase)
Mir222  (microRNA 222)

Genes (Homo sapiens)
KIT  (KIT proto-oncogene, receptor tyrosine kinase)
MIR222  (microRNA 222)


Additional Information