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TERT gene amplification is associated with poor outcome in acral lentiginous melanoma

Alba Diaz, MD , Joan Anton Puig-Butillé, PhD , Concha Muñoz , Dolors Costa, PhD , Anna Díez, MSc , Adriana Garcia-Herrera, MD, PhD , Cristina Carrera, MD, PhD , Celia Badenas, PhD , Francesc Solé, PhD , Josep Malvehy, MD, PhD , Susana Puig, MD,PhD, et.al.

Journal of the American Academy of Dermatology
Volume 71, Issue 4, Pages 839–841, October 2014

To the Editor: The current World Health Organization classification of melanocytic tumors recognizes four major melanoma subtypes based on clinicopathologic features but with a very little prognostic relevance. Among them, acral lentiginous melanoma (ALM) has distinct epidemiologic and clinicopathologic features. Studies with comparative genomic hybridization have demonstrated that ALMs are characterized as having a high frequency of amplifications in small genomic regions.1 Some of these amplifications contain genes involved in oncogenesis and tumor progression, such as cyclin D1 (CCND1) at 11q13 and telomerase reverse transcriptase (TERT) at 5p15.33.2

In a series of 43 formalin-fixed and paraffin-embedded samples of infiltrating ALM, we have studied CCND1 and TERT gene status by fluorescence in situ hybridization (FISH). For CCND1, the commercially available probe LSI Cyclin D1/CEP 11 (Vysis; Abbott Molecular, Des Plaines, IL) was used. For TERT, noncommercial FISH probes using bacterial artificial chromosomes were developed and MCTP1 gene was used as chromosome control, as previously described.3 Gene amplifications were considered when the ratio between gene copy number and centromere or chromosome control copy number was greater than 2. FISH results were correlated with clinicopathologic parameters.

The main clinicopathologic features of the cohort collected at diagnosis and their relationship with overall survival (OS) are expressed in Table I. Overall, the median follow-up period was 30 months (mean: 33.98; range: 1-161). CCND1 gene amplifications were found in 10 cases (23.3%) with a median CCND1-to-CEP11 ratio of 4.16 and TERT gene amplifications were detected in 9 cases (20.9%), with a median TERT-to-MCTP1 ratio of 3.10. CCND1 and TERT amplifications were mutually exclusive. Fig 1 shows a FISH image of an ALM harboring TERT gene amplification. In univariate survival analysis, TERT amplifications significantly reduced OS (P = .025), while the patients with CCND1 amplifications had no significant differences in OS (P = .987) (see Table I). In multivariate survival analysis, Breslow index and TERT amplifications retained significance for OS (P = .006; hazard ratio [HR] 9.20; 95% confidence interval [CI] 1.90-44.59 and P = .019; HR 4.63; 95% CI 1.29-16.62, respectively).

In this preliminary study, we are reporting the prognostic value of TERT gene amplification evaluated by FISH in a series of ALMs. TERT is a gene encoding for the catalytic subunit of telomerase reverse transcriptase. Gene amplification is the most frequent mechanism for TERT activation, promoting cell survival and proliferation. However, the prognostic relevance of TERT amplification has only been proved in non-small cell lung carcinomas, to date.4 Recently, recurrent somatic mutations in the TERT promoter region have been described in some cancers, including melanomas. They could represent an additional potential mechanism of TERT activation, different from the well-recognized TERT copy number gains. In fact, a more recent study has demonstrated that TERT promoter mutations are uncommon in ALMs.5 These results are consistent with the supposed relation of these mutations with the UV light exposure and supports the evidence that melanomas may show different pathogenesis depending on body site and levels of sun exposure.1 Interestingly, we found TERT and CCND1 gene amplifications in different ALM subsets, and they were mutually exclusive in accordance with previous studies.2 This fact suggests that ALM may have different pathways of oncogenesis. Further studies including a larger number of cases are needed to confirm our results.