Genetic alterations in RAS-regulated pathway in acral lentiginous melanoma

Centro Investigación Biomédica en Enfermedades Raras (CIBERER), ISCIII, Barcelona, Spain
Experimental Dermatology (Impact Factor: 3.76). 02/2013; 22(2):148-50. DOI: 10.1111/exd.12080
Source: PubMed


Studies integrating clinicopathological and genetic features have revealed distinct patterns of genomic aberrations in Melanoma. Distributions of BRAF or NRAS mutations and gains of several oncogenes differ among melanoma subgroups, while 9p21 deletions are found in all melanoma subtypes. In the study, status of genes involved in cell cycle progression and apoptosis was evaluated in a panel of 17 frozen primary acral melanomas. NRAS mutations were found in 17% of the tumors. In contrast, BRAF mutations were not found. Gains of AURKA gene (20q13.3) were detected in 37.5% of samples, gains of CCND1 gene (11q13) or TERT gene (5p15.33) in 31.2% and gains of NRAS gene (1p13.2) in 25%. Alterations in 9p21 were identified in 69% of tumors. Gains of 11q13 and 20q13 were mutually exclusive, and 1p13.2 gain was associated with 5p15.33. Our findings showed that alterations in RAS-related pathways are present in 87.5% of acral lentiginous melanomas.

Download full-text


Available from: Joan anton Puig-Butillé, Oct 01, 2014
    • "The reported frequency of KIT mutations in ALM is ranging between 10 and 15% [21,23–27]. ALMs are also characterized by a high frequency of amplification of certain genes such as CCND1, CDK4 and GAB2 [5] [20] [28] [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acral lentiginous melanoma (ALM) accounts for <10% of all melanomas in Caucasians. Although the involvement of KIT, NRAS and BRAF mutations is well known in ALM, the impact of these mutations on clinicopathological features has not been established. To define the KIT, NRAS, BRAF and PTEN mutation frequencies in Swedish patients with ALM and to evaluate the impact of mutation status on patient and tumor characteristics. Tumor cells were microdissected from 88 primary ALMs and 16 paired metastases and analyzed for KIT, NRAS and BRAF mutations. A subset of 25 ALMs was also evaluated for PTEN mutations. BRAF mutations were identified in 17% of the primary ALMs. Both NRAS and KIT mutations were found at a similar frequency of 15%. Only one of the ALMs that were screened for PTEN harbored a mutation (4%). The KIT, NRAS and BRAF mutation status in paired primary and metastatic ALMs was identical. Patients with BRAF mutated tumors were significantly younger (57 years) than those with BRAF wild-type tumors (73 years, p=0.028). BRAF mutations were significantly more common in females (p=0.011) and more often found in tumors located on the feet (p=0.039). Anatomical site was an independent prognostic factor for overall survival; patients with ALMs on the hands or under fingernails had a better prognosis than those with tumors on the feet or under toenails (p=0.025). Our results confirm the presence of KIT, NRAS and BRAF mutations in ALM and provide evidence that mutations in these genes occur at similar frequencies. Our results also show that PTEN is mutated in a small subset of ALM tumors.
    No preview · Article · Aug 2013 · Journal of dermatological science
  • [Show abstract] [Hide abstract]
    ABSTRACT: Malignant melanoma is refractory to various chemotherapeutics including antitubulin agents such as paclitaxel. Previous studies have suggested a link between βIII-tubulin overexpression and paclitaxel resistance through alterations in the properties of the mitotic spindle. We found that paclitaxel treatment induced temporary mitotic arrest in 7 melanoma cell lines irrespective of the βIII-tubulin level, suggesting that βIII-tubulin had no significant influence on spindle properties. On the other hand, the amount of BCL2, an anti-apoptotic protein, was well correlated with paclitaxel resistance. Treatment of the paclitaxel-resistant cell lines with ABT-737, an inhibitor of BCL2 and BCLxL, or simultaneous knock-down of BCL2 and BCLxL dramatically increased the cells' sensitivity, while knock-down of MCL1, another member of the BCL2 family, had only a minimal effect. Our results suggest that the paclitaxel sensitivity of melanoma cells is attributable to apoptosis susceptibility rather than a change in spindle properties and that BCL2 and BCLxL play a pivotal role in the former.
    No preview · Article · May 2013 · Experimental Dermatology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients treated with BRAF inhibitors (e.g. vemurafenib), a novel targeted therapy for advanced melanoma harboring certain BRAF mutations, develop numerous adverse cutaneous side effects, including skin tumors such as squamous cell carcinoma or non-malignant verruciform keratinocyte proliferations, termed BRAF inhibitor associated verrucous keratosis lesions (BAVK). These keratinocyte proliferations are believed to be caused by paradoxical hyperactivation of the MAPK pathway in cells with wild-type BRAF but mutated RAS. However, due to the clinical and histological verruca-like appearance of these lesions additional etiologic cofactors, such as infectious agents (i.e. oncogenic viruses) might be suspected. Therefore we performed 454 high-throughput sequencing of BAVK lesions from vemurafenib treated patients on the transcript level to identify actively transcribed viral sequences of known (e.g. human papilloma viruses (HPV)) or even yet unknown viruses. Next generation sequencing did not identify transcripts of any human viruses out of 1,595,161 reads obtained from BAVK lesions of four patients. Nevertheless, all controls were recognized correctly and the detection of sequences derived from the cutaneous microbiome (e.g. skin commensals and bacterial phages) confirmed the validity and sensitivity of the sequencing data. Our results are consistent with preliminary histological and immunohistochemical findings recently reported by others, who also failed to detect the expression of HPV proteins in BAVK. Although the patient number is limited and we cannot exclude the possibility of having missed a viral transcript of very low abundance, our study argues against a viral etiology of BRAF inhibitor associated verruciform keratoses occurring under vermurafenib. This article is protected by copyright. All rights reserved.
    No preview · Article · Sep 2013 · Experimental Dermatology
Show more