Genetic alterations in primary melanoma in Taiwan

Abstract

Summary Background Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral cutaneous melanoma (NAM) in Asians are not well understood. Objectives To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma. Methods We performed comprehensive genomic profiling of 409 cancer‐associated genes, using next‐generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs. Results Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild‐type (triple‐WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell‐cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell‐cycle aberrations were independent prognostic factors of melanoma‐specific survival. Conclusions This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians. What's already known about this topic? Mutation frequencies of driver genes vary between melanoma subtypes. Acral melanoma is the most common subtype of melanoma in Asians. KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype What does this study add? NRAS/KRAS mutations, cell‐cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment. Melanomas with cell‐cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration. What is the translational message? Cell‐cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma‐specific survival. These observations should be explored further for future drug development.

Characterizations of Gene Alterations in Melanoma Patients from Chinese Population

“…No other mutation was detected in the reported putative driver genes (KDR, GNAQ, and GNA11) in Western countries [18]. e NF1 subgroup has the lowest rate (10.3%) in our series, which were in accordance with those (9.1-14%) in the reported studies [33,35].…”

“…As a previous study reported [33], the Triple-WT subgroup has the highest mutation rate in comparison to the BRAF mut , RAS mut , and NF1 mut subtypes. Within the Triple-WT group, KIT took the most frequent mutations and assumed to be an important oncogene like other studies [33,34]. No other mutation was detected in the reported putative driver genes (KDR, GNAQ, and GNA11) in Western countries [18].…”

“…We divided our cohort into 4 subgroups based on the TCGA classification of melanoma [16]. As a previous study reported [33], the Triple-WT subgroup has the highest mutation rate in comparison to the BRAF mut , RAS mut , and NF1 mut subtypes. Within the Triple-WT group, KIT took the most frequent mutations and assumed to be an important oncogene like other studies [33,34].…”

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

“…Acral melanoma is rare in Caucasian populations, while it is the most common subtype of melanoma in Asian, African, and Latin American populations [2]. Although several genomic profiling studies of melanoma have been conducted, the numbers of acral melanoma cases in these were limited [11][12][13][14][15]. Furthermore, the genetic heterogeneity of acral melanoma has not been fully investigated.…”

Topical MTII Therapy Suppresses Melanoma Through PTEN Upregulation and Cyclooxygenase II Inhibition

“…Melanoma development is frequently accompanied with several genetic alternations, including N-RAS and BRAF mutation, PTEN, CDKN2A, and E-cadherin loss [3]. However, different from in Europe and the United States, acral melanoma is often diagnosed in Asia with distinct genetic alterations, probably due to the difference in genetic background and lifestyle [4][5][6]. Therefore, apart from the current focus on receptor tyrosine kinases (RTKs) and mutant BRAF V600E , other therapeutic strategies are needed for melanoma control.…”