RESUMEN
Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.
Asunto(s)
Melanoma/genética , Mutación , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-met/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Sustitución de Aminoácidos , Bélgica , Fosfatidilinositol 3-Quinasa Clase Ia , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Irlanda , Masculino , Melanoma/metabolismo , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfatidilinositol 3-Quinasas/metabolismo , Mutación Puntual , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Neoplasias Cutáneas/metabolismo , Melanoma Cutáneo MalignoRESUMEN
AIMS: Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer (BC) deaths, owing to its intrinsic aggressiveness and a lack of treatment options, especially targeted therapies. Thus, there is an urgent need for the development of better targeted treatments for TNBC. Molecular alteration of AKT-3 was previously reported in oestrogen receptor (ER)-positive BC. AKT-3 has also been suggested to play a role in hormone-unresponsive BC. The aim of this study was to investigate molecular alterations of AKT-3 in TNBC, to perform associated survival analysis, and to compare these findings with the incidence of AKT-3 molecular alterations in ER-positive BC. RESULTS: Our study revealed AKT-3 amplification and deletions in 11% (9/82) and 13% (11/82) of TNBCs, respectively. In contrast, 1% (2/209) of ER-positive BCs were found to have AKT-3 amplifications and deletions. A higher prevalence of AKT-3 copy number gains was observed in TNBC [26% (21/82)] than in ER-positive BC [9% (19/209)]. AKT-3 amplification together with Akt-3 protein expression was negatively associated with recurrence-free survival in TNBC. Furthermore, a negative association between high AKT-3 copy number and recurrence-free survival was observed. CONCLUSION: AKT-3 amplification could represent a potentially relevant oncogenic event in a subset of TNBCs that may, in turn, select cells sensitive to Akt-3 inhibitors.
