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A.-C.D. was supported by the Horizon 2020 program and innovation program under the Marie Sklodowska-Curie grant agreement No. 666003 and the Ligue Nationale Contre le Cancer. A.H. was supported by the Site de Recherche Integree sur le Cancer (SiRIC) of Institut Curie. L.M. was supported by the Horizon 2020 program UM Cure (No. 667787). D.L. was supported by "Region Ilede-France'' and Fondation pour la Recherche Medicale. M.R. was supported by the "Interface Inserm" grant. This study was funded by the Institut National de la Santeet de la Recherche Medicale (Inserm), the Institut Curie, and the Ligue Nationale Contre le Cancer (Labellisation).

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Functional characterization of 5p15.33 risk locus in uveal melanoma reveals rs452384 as a functional variant and NKX2.4 as an allele-specific interactor

Publicated to:American Journal Of Human Genetics. 109 (12): 2196-2209 - 2022-12-01 109(12), DOI: 10.1016/j.ajhg.2022.11.004

Authors: Derrien, Anne-Celine; Houy, Alexandre; Ganier, Olivier; Dingli, Florent; Ningarhari, Massih; Mobuchon, Lenha; Diaz, Maria Isabel Espejo; Loew, Damarys; Cassoux, Nathalie; Cussenot, Olivier; Cancel-Tassin, Geraldine; Margueron, Raphael; Noirel, Josselin; Zucman-Rossi, Jessica; Rodrigues, Manuel; Stern, Marc-Henri

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Abstract

The TERT/CLPTM1L risk locus on chromosome 5p15.33 is a pleiotropic cancer risk locus in which multiple independent risk alleles have been identified, across well over ten cancer types. We previously conducted a genome-wide association study in uveal melanoma (UM), which uncovered a role for the TERT/CLPTM1L risk locus in this intraocular tumor and identified multiple highly correlated risk alleles. Aiming to unravel the biological mechanisms in UM of this locus, which contains a domain enriched in active chromatin marks and enhancer elements, we demonstrated the allele-specific enhancer activity of this risk region using reporter assays. In UM, we identified the functional variant rs452384, of which the C risk allele is associated with higher gene expression, increased CLPTM1L expression in UM tumors, and a longer telomere length in peripheral blood mononuclear cells. Electrophoretic mobility shift assays and quantitative mass spectrometry identified NKX2.4 as an rs452384-T-specific binding protein, whereas GATA4 preferentially interacted with rs452384-C. Knockdown of NKX2.4 but not GATA4 resulted in increased TERT and CLPTM1L expression. In summary, the UM risk conferred by the 5p locus is at least partly due to rs452384, for which NKX2.4 presents strong differential binding activity and regulates CLPTM1L and TERT expression. Altogether, our work unraveled some of the complex regulatory mechanisms at the 5p15.33 suscepti-bility region in UM, and this might also shed light on shared mechanisms with other tumor types affected by this susceptibility region.

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