Inherited variations in human pigmentation-related genes modulate cutaneous melanoma risk and clinicopathological features in Brazilian population

Gustavo Jacob Lourenço,José Augusto Rinck-Junior,Aparecida Machado Moraes,Carmen Silvia Passos Lima,Sergio Vicente Serrano,Janet Keller Silva,Caroline Torricelli,Vinicius Lima Vazquez,Wesley Lima Oliveira,Gabriela Vilas Bôas Gomez,Benilton Sá Carvalho,Cristiane Oliveira

doi:10.1038/s41598-020-68945-9

Gustavo Jacob Lourenço, José Augusto Rinck-Junior + Show 10 more

Open Access

https://doi.org/10.1038/s41598-020-68945-9

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Abstract

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. The study was conducted in two stages. In stage 1, 103 CM patients and 103 controls were analyzed using Genome-Wide Human SNV Arrays in order to identify SNVs in pigmentation-related genes, and the most important SNVs were selected for data validation in stage 2 by real-time polymerase-chain reaction in 247 CM patients and 280 controls. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele “A” were under 1.79 and 1.47-fold increased risks of CM than others, respectively. Excesses of CREB1 AA and MITF AA genotype were seen in patients with tumors at Clark levels III to V (27.8% versus 13.7%) and at III or IV stages (46.1% versus 24.9%) compared to others, respectively. When compared to others, patients with ADCY3 TT had 1.89 more chances of presenting CM progression, and those with MITF GA or AA had 2.20 more chances of evolving to death by CM. Our data provide, for the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, not only can increase the risk to CM, but also influence CM patients’ clinicopathological features.

Highlights

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans
Controls were younger than patients, and CM patients presented more white skin color, referred more sun exposure and presented more nevi than controls, and all differences were corrected in comparisons involving patients and controls by appropriate statistical analysis
We found 12,495 new single-nucleotide variants (SNVs) associated with CM risk; 6,497 (52.0%) of them were in introns, 5,928 (47.4%) in gene regulatory regions, and 70 (0.6%) in coding regions

Summary

Introduction

Ultraviolet light exposure and cutaneous pigmentation are important host risk factors for cutaneous melanoma (CM), and it is well known that inherited ability to produce melanin varies in humans. The study aimed to identify single-nucleotide variants (SNVs) on pigmentation-related genes with importance in risk and clinicopathological aspects of CM. ADCY3 c.675+9196T>G, CREB1 c.303+373G>A, and MITF c.938-325G>A were selected for data validation among 74 SNVs. Individuals with CREB1 GA or AA genotype and allele “A” were under 1.79 and 1.47-fold increased risks of CM than others, respectively. For the first time, preliminary evidence that inherited abnormalities in ADCY3, CREB1, and MITF pigmentation-related genes, can increase the risk to CM, and influence CM patients’ clinicopathological features. Ultraviolet (UV) light exposure and individual pigmentation features are well-established host risk factors for CM1, and tumor depth and stage are the most important hallmarks of CM prognosis[2]. Melanogenesis induction is related to significant up-regulation of hypoxia-inducible factors (HIF) and these factors are key master regulators of cellular metabolism and therapeutic resistance[11,13], contributing to the increased aggressiveness of melanoma and shorter survival time of patients with pigmented metastatic melanoma than the ones with amelanotic lesion[11]

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