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A Variant in a MicroRNA complementary site in the 3′ UTR of the KIT oncogene increases risk of acral melanoma

Oncogene volume 30, pages 1542–1550 (2011)Cite this article

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Abstract

MicroRNAs (miRNAs) are small ∼22nt single stranded RNAs that negatively regulate protein expression by binding to partially complementary sequences in the 3′ untranslated region (3′ UTRs) of target gene messenger RNAs (mRNA). Recently, mutations have been identified in both miRNAs and target genes that disrupt regulatory relationships, contribute to oncogenesis and serve as biomarkers for cancer risk. KIT, an established oncogene with a multifaceted role in melanogenesis and melanoma pathogenesis, has recently been shown to be upregulated in some melanomas, and is also a target of the miRNA miR-221. Here, we describe a genetic variant in the 3′ UTR of the KIT oncogene that correlates with a greater than fourfold increased risk of acral melanoma. This KIT variant results in a mismatch in the seed region of a miR-221 complementary site and reporter data suggests that this mismatch can result in increased expression of the KIT oncogene. Consistent with the hypothesis that this is a functional variant, KIT mRNA and protein levels are both increased in the majority of samples harboring the KIT variant. This work identifies a novel genetic marker for increased heritable risk of melanoma.

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Acknowledgements

This work was supported by Yale SPORE in Skin Cancer funded by the National Cancer Institute grant number 1 P50 CA121974 (R Halaban, PI) and by a generous gift from Milstein–Meyer Center for Melanoma Research. JW is supported by K08 CA124484. AMM is supported by the CTSA Grant number UL1 RR024139 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research. The testing of the samples from the several world populations was supported by 1 P01 GM057672 (KK Kidd, PI).

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Authors and Affiliations

  1. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA

    S E Godshalk & F J Slack

  2. Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA

    T Paranjape, S Nallur, E Chan & J B Weidhaas

  3. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA

    W Speed & K K Kidd

  4. Division of Biostatistics, Yale University School of Public Health, New Haven, CT, USA

    A M Molinaro

  5. Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA

    A Bacchiocchi, K Hoyt, R Lazova & R Halaban

  6. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    K Tworkoski & D F Stern

  7. Section of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA

    M Sznol

  8. Department of Surgery, Yale University School of Medicine, New Haven, CT, USA

    S Ariyan

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  1. S E Godshalk
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  14. R Halaban
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Correspondence to J B Weidhaas or F J Slack.

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Godshalk, S., Paranjape, T., Nallur, S. et al. A Variant in a MicroRNA complementary site in the 3′ UTR of the KIT oncogene increases risk of acral melanoma. Oncogene 30, 1542–1550 (2011). https://doi.org/10.1038/onc.2010.536

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