Abstract
The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors.
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Acknowledgements
Thanks to our patients and their families who are the main reason for our studies, and to nurses from the Melanoma Unit of Hospital Clínic of Barcelona, D. Gabriel, P. Iglesias, and M.E. Moliner for helping to collect patient data.
Funding
The research at the Melanoma Unit in Barcelona is partially funded by Spanish Fondo de Investigaciones Sanitarias grants 09/1393, 12/00840, and 15/00716; CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund “A way to achieve Europe” ERDF; AGAUR 2014_SGR_603 and 2017_SGR_1134 of the Catalan Government, Spain; European Commission under the 6th Framework Programme, contract no. LSHC-CT-2006-018702 (GenoMEL), by the European Commission under the 7th Framework Programme, Diagnoptics, and by the European Union’s Horizon 2020 research and innovation programme, IMMUSPHINX; The National Cancer Institute (NCI) of the US National Institute of Health (NIH) (CA83115), a grant from “Fundació La Marató de TV3, 201331-30”, Catalonia, Spain, CERCA Programme/Generalitat de Catalunya, and grant GCB15152978SOEN from “Fundación Científica de la Asociación Española Contra el Cáncer”, Spain. Part of the work was carried out at the Esther Koplowitz Center, Barcelona. SNP genotyping services were provided by the “Centro Nacional de Genotipado” (CEGEN-ISCIII, Santiago de Compostela, Spain) (www.cegen.org) and by the “Instituto de investigación sanitaria INCLIVA” (Valencia, Spain). M.P. is the recipient of a PhD Fellowship FI14/00231 (PFIS) from Instituto de Salud Carlos III, Spain. Data analysis was performed at the Division of Genetic Epidemiology facilities, University of Utah, Utah, US, while M.P. was doing a lab visit funded by the MV15/00016 mobility fellowship (M-AES) from Instituto de Salud Carlos III, Spain.
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Potrony, M., Puig-Butille, J.A., Farnham, J.M. et al. Genome-wide linkage analysis in Spanish melanoma-prone families identifies a new familial melanoma susceptibility locus at 11q. Eur J Hum Genet 26, 1188–1193 (2018). https://doi.org/10.1038/s41431-018-0149-8
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DOI: https://doi.org/10.1038/s41431-018-0149-8
