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Altered GOLM1 expression is associated with tumorigenesis, but only one GOLM1 variant (p.S307L), has ever been reported in association with disease (familial melanoma).1 Exome data was filtered for coding variants GOLM1 in a high-risk primary melanoma cohort (n=384 unrelated probands). Five rare (frequency<0.005) missense GOLM1 variants were detected in 11/384 (2.9%). One of these, p.S307L was identified in seven individuals. This variant was significantly more frequent in this melanoma cohort (1.8%) compared with the general population (0.2%)(p=0.03). To our knowledge, this is the second report supporting the role of GOLM1, specifically the rare variant p.S307L, in melanoma susceptibility.
Australia has the highest rate of cutaneous melanoma globally, estimated to affect 1 in 17 Australians by 85 years of age (https://www.canceraustralia.gov.au/cancer-types/melanoma/statistics). While ultraviolet radiation is a known risk factor, twin studies have shown that 58% of melanoma risk is heritable.2 Specifically, 10% of melanoma cases have a positive family history and 1% are diagnosed with familial melanoma (≥3 melanoma-affected individuals who are first and/or second relatives).3 4 Between 20% and 40% of familial melanoma cases carry a pathogenic/likely pathogenic germline variant in a high-penetrance melanoma gene (CDKN2A, CDK4, BAP1, TERT, TERF2IP, POT1, ACD, POLE).4 5 CDKN2A is the primary high-risk gene for familial melanoma, accounting for ~90% of mutation-positive cases.4 Genome-wide association studies and candidate gene studies have also revealed moderate melanoma susceptibility loci and variants (MC1R, MITF, EBF3, NEK11, GOLM1).3 4
Golgi-phosphoprotein-2/Golgi-membrane-protein-GP73 (GOLM1) encodes a Golgi transmembrane protein localised in epithelial lineage cells. GOLM1 is comprised of 401 amino acids with five characterised domains: cytoplasmic tail (N-terminal), transmembrane domain, coiled-coil region, irregular loose structure domain (ILSD) and the C-terminal domain.6 The coiled-coil domain is the most characterised to date with the functional significance of the remaining domains yet to be …
Contributors EM wrote the paper (80%), edited the manuscript (30%), assembled figures (50%) and analysed the WES data (90%). CW wrote the paper (5%) and edited the manuscript (5%). ED assembled figures (50%). DJS did bioinformatic processing of samples (100%) and edited the manuscript (5%). BBS edited the manuscript (5%). LGA edited the manuscript (5%). MSS edited the manuscript (5%), conceptualised the study (10%) and obtained ethics. RS edited the manuscript (5%), conceptualised the study (10%) and obtained ethics. HPS edited the manuscript (5%). AML wrote the paper (15%), edited the manuscript (35%), conceptualised the study (80%), obtained ethics and analysed the WES data (10%).
Funding HPS holds an NHMRC MRFF Next Generation Clinical Researchers Program Practitioner Fellowship (APP1137127). AML currently holds an Australian Skin and Skin Cancer Early Career Research Grant, and held an NHMRC Early Career Fellowship (APP1158111) during this project and is currently supported by a University of Queensland Faculty of Medicine Fellowship. EM and CW are funded by a Research Training Stipend from the Australian Department of Education. Exome sequencing was funded by an Australian Skin and Skin Cancer Research Centre ECF grant (AML and BBS). The participants were originally recruited to the Brisbane Naevus Morphology Study (BNMS), funded by the NHMRC (APP1062935) and Centre of Research Excellence for the Study of Naevi (APP1099021). This work was also made possible by a Metro South Health Research Support Scheme Program Grant (RSS_2021_028). This research was carried out at the Translational Research Institute (TRI), Woolloongabba, Queensland, Australia.
Competing interests PS is a shareholder of MoleMap Limited and e-derm consult and undertakes regular teledermatological reporting for both companies. PS is a medical consultant for Canfield Scientific, Blaze Bioscience and MoleMap Australia Limited, and a medical advisor for First Derm.
Provenance and peer review Not commissioned; externally peer reviewed.