• Distribution and clinical role of KIT gene mutations in melanoma according to subtype: a study of 492 Spanish patients

      Millán-Esteban, D.; García-Casado, Z.; Manrique-Silva, E.; Virós, Amaya; Kumar, R.; Furney, S.; López-Guerrero, J. A.; Requena, C.; Bañuls, J.; Traves, V.; et al. (2021)
      Background: KIT mutations are primarily associated with acral and mucosal melanoma, and have been reported to show higher prevalence in chronic sun-damaged (CSD) than non-CSD melanomas. Objectives: To investigate the prevalence of KIT mutations in melanoma according to subtype, and determine the clinical role of such mutations. Material & methods: We present results from a study of a Spanish population of 492 melanomas, classified according to the latest World Health Organization (WHO) guidelines. We analysed the mutational status of KIT and correlated with different clinical variables related to sun exposure and family history. Results: KIT mutations were significantly more frequent in acral (3/36; 8.3%) and mucosal (4/8; 50%) melanomas than non-acral cutaneous melanomas. No significant difference was observed in KIT mutational status between CSD and non-CSD melanomas. Conclusion: Our results suggest that KIT mutations in melanoma tumours are unrelated to the development of nevi or chronic sun damage, but their presence is associated with aggressive melanomas which show ulceration, vascular invasiveness, and increased Breslow thickness. These findings are consistent with those reported by The Cancer Genome Atlas network.
    • Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility

      Landi, MT; Bishop, D T; MacGregor, S; Machiela, MJ; Stratigos, AJ; Ghiorzo, P; Brossard, M; Calista, D; Choi, J.; Fargnoli, MC; et al. (2020)
      Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 x 10(-8)) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
    • Molecular characterization of fast-growing melanomas

      Gaudy-Marqueste, C.; Macagno, N.; Loundou, A.; Pellegrino, E.; Ouafik, L.; Budden, Timothy; Mundra, Piyashkumar A; Gremel, Gabriela; Akhras, V.; Lin, L.; et al. (2021)
      Background: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM), and its potential to stratify patients at high risk of death, has not been comprehensively studied. Objective: To investigate the epidemiological, clinical and mutational profile of primary cutaneous melanomas with a thickness ≥ 1mm, stratified by rate of growth (ROG). Methods: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin embedded primary melanoma samples. Comparison of FGMM (ROG >0.5mm/month) and non-FGMM (ROG≤0.5 mm/month). Results: Two hundred patients were enrolled among which 70 were FGMM. The relapse free survival was lower in the FGMM group (p=0.014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than non-FGMM (p=0.033). Ulceration (p=0.032), thickness (p=0.006), lower sun exposure (p=0.049), and FGFR2 mutations (p=0.037) were significantly associated with fast growth. Limitations: Single-center study, cohort size, potential memory bias, number of investigated genes. Conclusion: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness and FGFR2 mutations associate with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM which are probably good candidates for adjuvant therapies.
    • Mutational characterization of cutaneous melanoma supports divergent pathways model for melanoma development

      Millán-Esteban, D.; Peña-Chilet, M.; García-Casado, Z.; Manrique-Silva, E.; Requena, C.; Bañuls, J.; López-Guerrero, J. A.; Rodríguez-Hernández, A.; Traves, V.; Dopazo, J.; et al. (2021)
      According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being BRAF. The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included NF1, ROS1, GNA11, and RAC1. We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.
    • Positive attributes of anti-TERT CD4 T-Helper Type 1 immune responses in melanoma

      Nagore, E.; Virós, Amaya; Kumar, R.; Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain (2021)
      Nardin et al's (2021) study on melanoma reports anti-TERT CD4 T helper type (Th) 1 responses in more than half of patients. Besides indicating a trend for improved survival, increased anti-TERT CD4 Th1 responses predicted better outcomes for patients treated with immune checkpoint inhibitors. Thus, harnessing systemic anti-TERT CD4 Th1 responses together with tumor-specific elevation of telomerase can potentially open new avenues for biomarkers and treatment in melanoma.