Genes involved in the WNT and vesicular trafficking pathways are associated with melanoma predisposition |
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| Authors: | Maider Ibarrola‐Villava Rajiv Kumar Eduardo Nagore Meriem Benfodda Mickael Guedj Steven Gazal Hui‐Han Hu Jian Guan P Sivaramakishna Rachkonda Vincent Descamps Nicole Basset‐Seguin Armand Bensussan Martine Bagot Philippe Saiag Dirk Schadendorf Manuel Martin‐Gonzalez Matias Mayor Bernard Grandchamp Gloria Ribas Soufir Nadem |
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| Affiliation: | 1. Department of Haematology and Medical Oncology, Biomedical Research Institute INCLIVA, Valencia, Spain;2. Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany;3. Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain;4. Inserm U976, Centre de Recherche Sur la Peau, Hopital Saint Louis, Université Paris 7, Paris, France;5. Département de Génétique, H?pital Bichat, APHP, Paris, France;6. Laboratoire Statistiques et Genomes, Evry, France;7. UMR S738, Faculté de Médecine Xavier Bichat, Paris, France;8. Department of Dermatology, Hopital Bichat, APHP, Paris, France;9. Department of Dermatology, Hopital Saint Louis, APHP, Paris, France;10. Department of Dermatology, Hopital Ambroise Paré, APHP, Paris, France;11. Department of Dermatology, University Hospital Essen, Esse, Germany;12. Department of Dermatology, Hospital Ramon y Cajal, Madrid, Spain;13. Department of Dermatology, Hospital La Paz, Madrid, Spain |
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| Abstract: | Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high‐risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta‐analysis (3940 melanoma cases and 3620 controls) with two‐side p values of 0.002, (OR = 0.86) and 4.07 × 10?10 (OR = 0.80), respectively. Exome sequencing revealed a non‐synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR = 4.46, p = 0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma. |
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| Keywords: | exome sequencing case‐control study WNT3 VPS41 melanoma |
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