Phenotypic and Genotypic Analysis of Amelanotic and Hypomelanotic Melanoma Patients

Abstract

Background

Amelanotic/hypomelanotic melanoma is associated with poorer outcomes due to a more advanced disease stage at diagnosis.

Objective

To determine phenotypic risks and genotypic associations with amelanotic/hypomelanotic melanoma to develop a clinical and genetic profile that could assist in identifying high‐risk individuals.

Methods

The Brisbane Naevus Morphology Study conducted from 2009‐2016 has recruited a core of 1254 participants. Participants were drawn from a combination of volunteers from dermatology outpatient clinics, private dermatology clinics, the Brisbane Longitudinal Twin Study and QSkin study. Case participants had a personal history of melanoma and control participants no personal history of melanoma. We specifically examined seven known candidate pigmentation and melanoma genes and pigmentary phenotypic characteristics in participants with amelanotic/hypomelanotic melanoma compared to pigmented melanomas. This assayed single nucleotide polymorphisms (SNPs) in MC1R, TYR, HERC/OCA2, IRF4, MTAP, PLA2G6 and MITF.

Results

47 participants had at least one amelanotic/hypomelanotic melanoma and 389 had pigmented melanomas, with amelanotic/hypomelanotic melanoma patients significantly older than pigmented melanoma participants (63.3 ± 13.0 vs 54.6 ± 15.3 years; P<0.001). Amelanotic/hypomelanotic melanoma patients were more likely than pigmented melanoma patients to have red hair (34% vs 15%; P=0.01), severe hand freckling (13% vs 5%; P=0.01) and propensity to sunburn (63% vs 44%; P=0.01). MC1R R/R genotype was much more frequent in our amelanotic/hypomelanotic melanoma population (31.1% vs 11%; P<0.001; OR 26.4 vs 5.9; control 1.0). Amelanotic/hypomelanotic melanoma was associated with TYR rs1126809*A/A (OR[CI95%] 2.7 [1.1‐6.8] vs 1.2 [0.8‐1.9]) and PLA2G6 rs11570734*A/A (OR[CI95%] 3.7 [1.0‐13.6] vs 1.3[0.9‐2.0]). The MTAP melanoma risk SNP genotype, associated with darker pigmentation, (rs4636294*A/A) was less common in amelanotic/hypomelanotic melanoma patients (OR[CI95%] 0.8 [0.3‐2.1] vs 2.0 [1.3‐3.1]).

Conclusions

Knowledge of phenotypic and genotypic associations of amelanotic/hypomelanotic melanoma can help predict risks and associations of this difficult to diagnose melanoma, which may ultimately assist clinical management and patient skin self‐examination.

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