Genes Determining Nevus Count and Dermoscopic Appearance in Australian Melanoma Cases and Controls

Duffy, David L.; Jagirdar, Kasturee; Lee, Katie J.; McWhirter, Seamus; McMeniman, Erin; De’Ambrosis, Brian; Pflugfelder, Annette; Rayner, Jenna E.; Whiteman, David C.; Brown, Matthew A.; Martin, Nicholas G.; Smithers, B. Mark; Schaider, Helmut; Soyer, H. Peter; Sturm, Richard A.

doi:10.1016/j.jid.2019.05.032

Cited by 14 publications

(24 citation statements)

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“…A total of 1244 individuals were enrolled in the Brisbane Naevus Morphology Study (BNMS), an epidemiological study of naevus and melanoma genes in participants recruited from South East Queensland between 2009 and 2016 . The 281 MPM and 304 SPM cases were mostly drawn from Brisbane public (Melanoma Unit and Dermatology Department of Princess Alexandra Hospital) and private dermatological oncology practices (Table S1; see Supporting Information).…”

Section: Methodsmentioning

confidence: 99%

“…Phenotypic characteristics were recorded, including total naevus number, sex, hair, eye and skin colour, and freckling scores, as detailed in Duffy et al . 2019 . Patients with MPM were classified as either ‘first diagnosis at age ≤ 40 years’ or ‘first diagnosis at age > 40 years’, based on literature suggesting that younger patients with melanoma are more likely to harbour genetic mutations …”

Section: Methodsmentioning

confidence: 99%

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The interplay of sun damage and genetic risk in Australian multiple and single primary melanoma cases and controls

et al. 2020

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Summary Background Skin phenotype, host genotype and ultraviolet (UV) damage play a role in the development of melanoma. Objectives To ascertain whether the level of UV damage at the site of melanomas was associated with genetic polymorphisms. Methods Deep phenotyping was performed on 1244 individuals; 281 with multiple primary melanomas (MPMs), 304 with single primary melanoma (SPM) and 659 convenience controls. Genotype data was generated using the Illumina CoreExome microarray platform, assaying over 500 000 single‐nucleotide polymorphisms. A subset of variants were combined to assess a polygenic risk score (PRS) for melanoma. Results Most MPM cases were diagnosed in patients aged > 40 years, in sites with visible chronic UV damage. Women and those diagnosed at age ≤ 40 years were less likely to have perilesional UV damage. Patients with MPM had higher frequencies of MITF E318K, MC1R R‐alleles and the ASIP risk haplotype. Individuals who had melanoma in a visibly UV‐damaged site were more likely to carry MC1R rs75570604 [odds ratio (OR) 2·5], 9q31.2 rs10816595 (OR 1·4) and MTAP rs869329 (OR 1·4). These same alleles were more common in patients with MPM who were diagnosed at age ≤ 40 years. The mean PRS was significantly higher in MPM than in SPM and controls. Naevus count was comparable in early‐onset MPM cases and those diagnosed at age > 40 years. Conclusions Our cohort demonstrated higher frequencies of previously reported alleles associated with melanoma. MPM melanomas more commonly occur in UV‐damaged areas, and these individuals are more likely to carry MC1R red hair colour alleles. Awareness of the interplay of genetic vulnerability with UV damage can stratify risk and guide recommendations for melanoma screening. What's already known about this topic? Skin phenotype, host genotype and ultraviolet (UV) damage all play a role in melanoma development. One of the main risk factors is a personal history of melanoma; second and subsequent primary melanomas account for over 20% of all melanomas registered in Queensland. Multiple loci are associated with melanoma risk, including many low‐penetrance loci, which may have a cumulatively significant risk. Population‐wide screening programmes for melanoma are not yet economically viable. What does this study add? Patients diagnosed with melanoma at age ≤ 40 years were more likely than older patients to have melanomas in non‐UV‐damaged sites. Patients with multiple melanomas had higher frequencies of MITF E318K, MC1R R‐alleles, and the ASIP extended risk haplotype than patients with single melanoma. CDKN2A, MC1R and MTAP variants were more frequent in patients who developed melanomas at a younger age, but also in those whose melanomas were all on visibly UV‐damaged sites. What is the translational message? Incorporating these genetic findings into the known risk factors of skin phenotype and visible UV damage may allow for a more customized and economically feasible approach to early detection of melanoma, particularly in younger patients. Plain la...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The interplay of sun damage and genetic risk in Australian multiple and single primary melanoma cases and controls

et al. 2020

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“…A total of 383 pathology report confirmed cutaneous melanoma individuals, identified as high risk with respect to age, melanoma and naevus counts, were selected from the 1266 BNMS participants [22]. Exome library preparation (SureSelect V5+UTR; Agilent, CA, USA) on 1ug saliva-derived DNA and whole exome sequencing was performed by a fee-for-service provider, the Australian Genome Research Facility using the Illumina platforms HiSeq 2500 (n = 1-24) and NovaSeq 6000 (n = 25-383) to > 60x targeted depth coverage.…”

Section: Whole Exome Sequencing and Data Analysismentioning

confidence: 99%

“…A total of 581 melanoma case and 652 control participants drawn from the Brisbane Naevus Morphology study (BNMS) were previously genotyped using a high density Illumina SNP array panel [22]. In earlier work we compared the phenotypic and candidate genotypic characteristics of 45 subjects with AHM, 25 of these with MPM, and 389 with pigmented melanoma cases, 203 with MPM [18].…”

Section: Analysis Of Albinism Gene Alleles In Pm and Ahm Casesmentioning

confidence: 99%

Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants

et al. 2020

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Amelanotic/hypomelanotic melanoma is a clinicopathologic subtype with absent or minimal melanin. This study assessed previously reported coding variants in albinism genes (TYR, OCA2, TYRP1, SLC45A2, SLC24A5, LRMDA) and common intronic, regulatory variants of OCA2 in individuals with amelanotic/hypomelanotic melanoma, pigmented melanoma cases and controls. Exome sequencing was available for 28 individuals with amelanotic/ hypomelanotic melanoma and 303 individuals with pigmented melanoma, which were compared to whole exome data from 1144 Australian controls. Microarray genotyping was available for a further 17 amelanotic/hypomelanotic melanoma, 86 pigmented melanoma, 147 melanoma cases (pigmentation unknown) and 652 unaffected controls. Rare deleterious variants in TYR/OCA1 were more common in amelanotic/hypomelanotic melanoma cases than pigmented melanoma cases (set mixed model association tests P = 0.0088). The OCA2 hypomorphic allele p.V443I was more common in melanoma cases (1.8%) than controls (1.0%, X 2 P = 0.02), and more so in amelanotic/hypomelanotic melanoma (4.4%, X 2 P = 0.007). No amelanotic/hypomelanotic melanoma cases carried an eye and skin darkening haplotype of OCA2 (including rs7174027), present in 7.1% of pigmented melanoma cases (P = 0.0005) and 9.4% controls. Variants in TYR and OCA2 may play a role in amelanotic/ hypomelanotic melanoma susceptibility. We suggest that somatic loss of function at these loci could contribute to the loss of tumor pigmentation, consistent with this we found a higher rate of somatic mutation in TYR/OCA2 in amelanotic/hypomelanotic melanoma vs pigmented melanoma samples (28.6% vs 3.0%; P = 0.021) from The Cancer Genome Atlas Skin Cutaneous Melanoma collection.

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“…Breslow tumour thickness, as is associated with nodular melanoma, is recognized as one of the most important prognostic factors. NM grows more rapidly than SSM (0.49 Distribution of melanoma risk factors in controls closely matches that in Australian population samples87 .Due to the small number of nodular cases, we would not expect any associations to reach genomewide significance (P=5x10 -8 ), therefore we chose to carry out a candidate gene based approach that tests only a small number of selected genes previously known to be involved in pigmentation or melanoma risk. This means the multiple testing adjustment we need to carry out is much less severe.…”

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Gene polymorphisms associated with amelanotic/hypopigmented and nodular melanoma

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Statement of parts of the thesis submitted to qualify for the award of another degree None Research involving human or animal subjects All human subjects who consented to participate in this research are part of the Brisbane Naevus Morphology Study (BNMS), unaffected control volunteers were drawn from the Brisbane Longitudinal Twin Study (BLTS) and QSkin study. This study was approved by the Human Research Ethics Committee of Princess Alexandra Hospital (approval HREC/09/QPAH, 7.2.2009) and The University of Queensland (approval #2009001590, 26.08.2009) and conducted in accordance with the Declaration of Helsinki. Participants provided written consent after receiving a Participant Information and Consent Form.

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Genes Determining Nevus Count and Dermoscopic Appearance in Australian Melanoma Cases and Controls

Abstract: TG, et al. Analysis of cultured human melanocytes based on polymorphisms within the SLC45A2/MATP, SLC24A5/NCKX5, and OCA2/P loci.

Cited by 14 publications

References 69 publications

The interplay of sun damage and genetic risk in Australian multiple and single primary melanoma cases and controls

The interplay of sun damage and genetic risk in Australian multiple and single primary melanoma cases and controls

Germline and somatic albinism variants in amelanotic/hypomelanotic melanoma: Increased carriage of TYR and OCA2 variants

Gene polymorphisms associated with amelanotic/hypopigmented and nodular melanoma

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