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 to 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 in MC1R, TYR, HERC/OCA2, IRF4, MTAP, PLA2G6 and MITF. Results Forty‐seven 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 (CI 95%) 2.7 (1.1–6.8) vs. 1.2 (0.8–1.9)] and PLA2G6 rs11570734*A/A [OR (CI 95%) 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 (CI 95%) 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.

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

“…Deleterious variants in TYR/ OCA1 were more common in AHM melanoma cases than in PM cases and the same was true for the OCA2 hypomorphic allele p.V443I. In our study, over half of the AHM patients had multiple primary melanoma (MPM) [18], and in all of these cases at least one was a PM. Furthermore, although 33 of the AHM patients had fair skin, 12 AHM patients had moderate skin complexion (5 single and 7 MPM).…”

“…There were 7 AHM recognized in the documentation describing this dataset, with the remaining 463 considered as PM (Table 5 and S4 Table). Previously we [18] and others [49,50] have reported a higher frequency of the highly penetrant MC1R R allele in AHM compared with PM patients. Although there were no R/R genotypes seen in the AHM samples they all carried either an r or R variant and no WT/WT, compared with a frequency of 19.7% of PM and 37.9% in other cancers.…”

“…A total of 20 coding region variants (S1 Table, gnomAD minor allele frequency (MAF)) were seen for the TYR gene with the two common alleles p.S192Y (36.4%) and p.R402Q (27.3%) having been previously reported in this dataset [18]. These findings were validated in this study with the common p.402Q allele occurring at a higher frequency in the AHM versus PM group (42.2% vs 32.6%; P = 0.07; P = 0.015 when compared to combined MGRB + BNMS controls).…”

“…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]. In the present study, we performed whole exome sequencing (WES) to detect rare, coding germline variants in a subgroup of 383 melanoma case patients (28 AHM, 303 PM, 52 unknown pigmentation status, S1 Fig).…”

“…AHM comprises 2% to 8% of all melanoma cases, and is more common in those who are over the age of 50 years, have red hair and/or fair skin type [17]. We have previously shown the common MC1R and TYR variants associated with fair skin occur at increased frequency in AHM [18]. Therefore, it is reasonable to hypothesize that rarer albinism-associated variants should also be more frequent in AHM cases as compared to pigmented melanoma (PM).…”