Assessing the genetic risk of nodular melanoma using a candidate gene approach.

Autor:	Stark MS; Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Qld, Australia., Sturm RA; Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Qld, Australia., Pan Y; Victorian Melanoma Service, The Alfred Hospital, Melbourne, Vic, Australia.; Central Clinical School, Faculty of Medicine, Nursing and Health Sciences., Smit DJ; Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Qld, Australia., Kommajosyula V; Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Qld, Australia., Lee KJ; Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Qld, Australia., Jagirdar K; Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Qld, Australia., McLean C; Victorian Melanoma Service, The Alfred Hospital, Melbourne, Vic, Australia.; Central Clinical School, Faculty of Medicine, Nursing and Health Sciences., Duffy DL; Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Qld, Australia.; QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia., Soyer HP; Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Qld, Australia.; Dermatology Department, Princess Alexandra Hospital, Brisbane, Qld, Australia., Mar VJ; Victorian Melanoma Service, The Alfred Hospital, Melbourne, Vic, Australia.; School of Public Health and Preventive Medicine; Monash University, Melbourne, Vic, Australia.
Jazyk:	angličtina
Zdroj:	The British journal of dermatology [Br J Dermatol] 2024 Jan 23; Vol. 190 (2), pp. 199-206.
DOI:	10.1093/bjd/ljad365
Abstrakt:	Background: Nodular melanoma (NM) is a challenge to diagnose early due to its rapid growth and more atypical clinical presentation, making it the largest contributor to melanoma mortality. Objectives: Our study aim was to perform a rare-variant allele (RVA) analysis of whole-exome sequencing of patients with NM and non-NM (minor allele frequency ≤ 1% non-Finnish European) for a set of 500 candidate genes potentially implicated in melanoma. Methods: This study recruited 131 participants with NM and 194 with non-NM from South-east Queensland and patients with NM from Victoria to perform a comparative analysis of possible genetic differences or similarities between the two melanoma cohorts. Results: Phenotypic analysis revealed that a majority of patients diagnosed with NM were older males with a higher frequency of fair skin and red hair than is seen in the general population. The distribution of common melanoma polygenic risk scores was similar in patients with NM and non-NM, with over 28% in the highest quantile of scores. There was also a similar frequency of carriage of familial/high-penetrant melanoma gene and loss-of-function variants. We identified 39 genes by filtering 500 candidate genes based on the greatest frequency in NM compared with non-NM cases. The genes with RVAs of greatest frequency in NM included PTCH1, ARID2 and GHR. Rare variants in the SMO gene, which interacts with PTCH1 as ligand and receptor, were also identified, providing evidence that the Hedgehog pathway may contribute to NM risk. There was a cumulative effect in carrying multiple rare variants in the NM-associated genes. A 14.8-fold increased ratio for NM compared with non-NM was seen when two RVAs of the 39 genes were carried by a patient. Conclusions: This study highlights the importance of considering frequency of RVA to identify those at risk of NM in addition to known high penetrance genes. Competing Interests: Conflicts of interest H.P.S. is a shareholder of MoleMap NZ Limited and e-derm consult GmbH and undertakes regular teledermatological reporting for both companies. H.P.S. is a medical consultant for Canfield Scientific Inc. and MoleMap Australia Pty Ltd, and a medical advisor for First Derm. V.J.M. has received speaker fees from Bristol Myers Squibb, Janssen, Merck and Novartis, and has participated in advisory boards for L’Oreal and MSD. The other authors have no conflicts of interest to declare. (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)
Databáze:	MEDLINE
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