Human leukocyte antigen Class II alleles associated with acral lentiginous melanoma in Mexican Mestizo patients: A case-control study

Plain Language summary

The incidence of skin cancers has been rising in recent decades and melanoma is the most aggressive among these. Melanomas include four genetic and clinical variants. One rare variant is acral lentiginous melanoma, a subtype arising from palms, soles, and nail units. The acral lentiginous melanoma incidence, prevalence and prognosis differ among populations. Melanoma progression has been linked to different expression of major histocompatibility complex class II proteins. However, the available literature reports variable findings regarding the melanoma association with specific HLA Class II loci. This study compares HLA Class II allele frequencies in acral lentiginous melanoma Mexican Mestizo patients with the frequencies presented in healthy individuals. Three alleles (HLA-DRB1*13:01, HLA-DQA1*01:03 and HL-DQB1*02:02) were found to confer susceptibility to develop acral lentiginous melanoma in Mexican Mestizo patients. HLA susceptibility alleles differ among melanoma subtypes, which suggests differences in the immunopathological mechanism. Potentially, HLA typing could be useful to discriminate between melanoma subtypes and could possibly help in guiding the treatment plan.

Introduction

Cutaneous melanoma is a relatively common skin cancer with different clinical subtypes that vary with respect to progression and clinical presentation.^1,2 The rarest type of melanoma is acral lentiginous melanoma; this melanoma variant occurs mainly on the palms, soles, and nail units.³ It begins as a flat patch of discoloured skin that may enlarge slowly over time; it can become invasive and spread as the condition advances. Usually, this entity is diagnosed at advanced stages. Thus, prognosis tends to be worse than with other subtypes of melanoma.^4-6

Melanoma is considered an immunogenic malignancy. In an idyllic state, antigen-presenting cells lead to the activation of effector memory T-cells in the lymph nodes that mediate anti-tumour effects at the cancer site, producing new antigens from destroyed malignant cells and creating a tumour-immunity cycle.⁷ One of the contributory factors to melanoma progression is the failure of melanoma cells expressing HLA Class II molecules to process oxidised or cysteinylated peptides.⁸ This phenomenon leads to a modified epitope presentation to CD4+ T-cells and a resultant absence of immune response against the tumour.⁹ HLA-DR mediated signalling is another factor that plays a role in melanoma progression, increasing the migration and invasion of melanoma cells.¹⁰

HLA-DR mediated signalling is strongly influenced by the high polymorphism of these molecules.¹⁰ Importantly, the variability and richness of HLA molecules in Mexican Mestizos are strongly influenced by admixture;¹¹ and in many cases, the introduced and fixed alleles have been responsible for susceptibility to different diseases. However, the specific alleles which generate susceptibility and change signalling in melanoma cells are not yet described for acral lentiginous melanoma. Consequently, this work aims to determine the frequencies of major histocompatibility complex Class II alleles, namely, HLA-DRB1, HLA-DQB1 and HLA-DQA1 in Mexican Mestizo patients with acral lentiginous melanoma and compare them with ethnically matched healthy controls.

Methods

Results

Clinical and socio-demographic characteristics of acral lentiginous melanoma patients

Eighteen patients with acral lentiginous melanoma were diagnosed by clinical [Figure 1] and histopathological criteria [Figure 2]. The mean age at diagnosis was 56 years; females outnumbered males with a ratio of 2.6:1. Lesions were most often located on the lower extremities, in 10/18 of cases (55.5%).

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Figure 1:

Acral lentiginous melanoma on the lateral aspect of the left foot showing irregularly bordered and variable pigmentation with a slightly centre ulcerated lesion

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Figure 2:

Acral lentiginous melanoma, showing epidermis with acanthosis, in papillary dermis atypical melanocytes with melanin granules and large nuclei. (H&E, ×100)

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Discussion

Melanoma in Mexico has a prevalence of 0.4 per 100 thousand inhabitants.¹⁹ However, acral lentiginous melanoma prevalence is not known and limited information has been published about acral lentiginous melanoma and HLA susceptibility alleles. Acral lentiginous melanoma is included as a rare disease in the National Institute of Health Database and Genetic and Rare Diseases Information Center.²⁰ Its severity is often the result of the delayed diagnosis or misdiagnosis and the fundamental cause of acral lentiginous melanoma is poorly understood. It is not related to sun exposure, unlike other forms of skin cancer.^21,22 Major histocompatibility complex expression is known to influence melanoma severity and its response to anti-cancer therapy. However, only few associations have been described between HLA-specific alleles and melanoma and even less is known in this regard for acral lentiginous melanoma.

In this study, we found, three HLA Class II susceptibility alleles, namely, HLA-DRB1*13:01, HLA-DRQB1*02:02 and HLA-DQA1*01:03, which confer high risks for the development of acral lentiginous melanoma in Mexican Mestizos. HLA-DQA1*01:03 was previously associated with melanoma in the Japanese population.²³ However, it is the first time that HLA-DQB1*02:02 and HLADRB1*13:01 have been associated with melanoma in any population. Remarkably, each one of these three alleles confers an independent risk for the development of acral lentiginous melanoma. More importantly, these alleles are not recognized as native of Mexican Amerindians; this fact adds an anthropological angle to the results, which in turn influences the biomedical traits. Therefore, the biomedical, clinical, and anthropological importance of the results is discussed.

The complex ethnic background of Mexicans contributes to the unusual situation where alleles such as HLA-DRB1*13:01 and HLA-DRB1*02:02, found in haplotypes mainly from African and Caucasian populations, respectively, increase the susceptibility of Mexican patients to develop acral lentiginos melanoma. Mexicans are among the population groups with the highest richness of admixture worldwide. This fact affects the biomedical traits and consequently, favours the development of diseases and altered immunological responses in Mexicans,²³ as has been seen in other diseases and autoimmune conditions.

The biomedical repercussions chiefly concern the aberrant participation of HLA-DR in melanoma cell signalling, allowing, and enhancing melanoma cell migration and invasion, which has been previously demonstrated.^8-10,24 But hitherto, not much was known regarding specific HLA Class II susceptibility alleles for acral lentiginous melanoma in Mexicans. Quite possibly the acral lentiginous variant shares the invasion mechanism modified by HLA-DR that has been described in common melanoma. Besides, recently it has been demonstrated that major histocompatibility complex proteins are determinants of both melanoma prognosis²⁵ as well as its sensitivity to different anti-CTLA-4, anti-PD-1 and MAPK inhibitors.^26,27

Some studies about HLA alleles and susceptibility to melanoma have been inconclusive.^28,29 But recently, a Genome-Wide Association Study has confirmed the role of HLA in melanoma.²⁸ In this study, HLA-DQA1*01:03 has been associated with susceptibility to develop acral lentiginous melanoma, which has also been confirmed in Japanese patients (P = 0.013, odds ratio = 2.4).²³ Moreover, the HLA-DQA1 locus has been associated with melanoma in Spaniards,^30,31 but the risk alleles found were different from those found in Mexicans. In our study, HLADQA1*01:03 presented a strong statistical association with acral lentiginous melanoma patients with carriers having a more than nine-fold risk of developing the disease.

The second allele which presented a significant statistical association with acral lentiginous melanoma in our study was HLA-DQB1*02:02, imparting an almost four-fold increased risk of developing this type of melanoma. HLA-DQB1 locus has been studied in Italian melanoma patients; some alleles were found more frequently in patients, but the results were not statistically significant.³¹ Interestingly, other studies have observed that patients with localised melanoma who carried HLA-DQB1*03:01 presented an increased risk of developing recurrent disease compared with stage-matched patients who lacked this allele.^33-35

The third allele which presented strong statistical association with acral lentiginous melanoma in our studied patients was HLA-DRB1*13:01, conferring a more than six-fold increased risk of developing the disease. Studies about the -DRB1 locus have been performed in different groups of melanoma patients. A study involving Italian melanoma patients found an increased frequency HLA-DRB1*11:01 but without reaching statistical significance.³² Nevertheless, another study noticed that HLA-DRB1*11:01 was the strongest predictor of melanoma recurrence. In addition, these patients showed increased levels of IFN-gamma compared with patients lacking this allele,³⁶ which could be contributory to recurrence.

Regarding anthropological aspects, the presence of three foreign HLA Class II alleles in Mexicans could be explained on the basis that these susceptibility alleles were introduced and fixed because of an advantage against infections. However, antigen presentation by these alleles is not favourable and probably permits acral lentiginous melanoma cells to escape immune responses.

Human migration dynamics could explain the increased frequency of the susceptibility alleles in Mexican Mestizo acral lentiginous melanoma patients. The HLA region is commonly used in anthropology studies because the allele and haplotype distributions at these loci vary widely among ethnic groups.^37,38 Thus, according to the data available in allele frequency net database,¹⁸ the allele HLA-DQA1*01:03 is most prevalent in the region along the ancient commercial route called the “Silk Road,”^37,39 which is depicted in Figure 3. In contrast, HLA-DQA1*01:03 is found in low frequencies in Amerindian natives [Table 4]. This allele was introduced by Europeans during migrations processes to the Americas.^40,41

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Figure 3:

World map showing the Silk Road and other ancient commercial routes from east to west and some slave routes from Africa to America used in the colonial period. Also marked are regions populated by the Jewish diaspora and regions with high prevalence (≥9%) of HLA-DQA1*01:03, HLA-DQB1*02:02 and HLA-DRB1*13:01 alleles

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As for HLA-DQB1*02:02, it is common in Europe. High allele frequencies are observed in Portugal and Spain, ranging from 0.175–0.178. In Mexican Mestizos, this allele has been previously identified in haplotypes of Caucasian origin.¹⁷ In this study, the frequency of this allele in Mexican Mestizo acral lentiginous melanoma patients is 0.194, which is like its frequency in the Caucasian population. However, the allele frequency is diminished in Mexican Mestizo healthy individuals being 0.060.^17,42

The third allele of interest, HLA-DRB1*13:01 has been reported at a lower frequency of 0.020 in the native Amerindian population. HLA-DRB1*13:01 appearance in Amerindians is considered to be a product of admixture with Spaniard conquerors.^39,43 However, the highest frequencies of this allele have been found in African haplotypes.¹⁷

Acral lentiginous melanoma is the rarest type of melanoma, but is most common in non-Caucasian ethnicities, with 15% presenting in Hispanics and only 2–8% in Caucasians. However, it is interesting that one of the main alleles imparting susceptibility to Mexicans is Caucasian, which suggests a genetic interaction with Mexican genes resulting in disease, which manifests much less often in Caucasians. Importantly, the Mexican Americans do not develop acral lentiginous melanoma.

More significantly, the medical implication of this study is that, although informally, medicine in Mexico is increasingly taking the ethnic aspect more seriously in suspecting a disease involving a genetic component. Gradually, ethnicity is taking its place as a novel criterion in the screening and decision algorithm of some diseases.⁴⁴

Conclusion

This study shows the role of HLA alleles in susceptibility to develop acral lentiginous melanoma in Mexican Mestizos. The presence of HLA-DQA1*01:03, HLA-DRB1*02:02 and HLADRB1*13:01 increased the risk of acral lentiginous melanoma in this study. These differ from the alleles found in other studies of HLA and common melanoma. The differences in susceptibility alleles could indicate important differences in the immunopathological mechanisms; or besides the differences could be attributable to the ethnic and admixture background.

Adding the determination of HLA Class II to the battery of genetic studies conducted on acral lentiginous melanoma in Mexican patients when there are doubts about the melanoma diagnosis could be beneficial.