M Pracht1,2, A Mogha3,4, A Lespagnol4,5, A Fautrel4,6, N Mouchet3,4, F Le Gall2,4,7, V Paumier2,8, C Lefeuvre-Plesse1,2, N Rioux-Leclerc4,7, J Mosser4,5, E Oger4,9, H Adamski2,4,10, M-D Galibert2,3,4, T Lesimple1,2. 1. Service d'Oncologie Médicale, Centre Eugene Marquis, Rennes, France. 2. Brittany Melanoma Network, GRoupe Ouest Mélanome (GROUM), Rennes, France. 3. Gene Expression and Oncogenesis Team, Institut de Génétique et Developement de Rennes, CNRS UMR6290, Rennes, France. 4. CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France. 5. CHU Pontchaillou, Service de Génétique Moléculaire et Génomique des Cancers, Rennes, France. 6. SFR Biosit UMS CNRS 3480/US INSERM 018, Rennes, France. 7. Service d'Anatomopathologie, CHU Pontchaillou, Rennes, France. 8. Laboratoire d'Anatomopathologie Atalante, Rennes, France. 9. Centre d'Investigations Cliniques et Unité de Pharmacologie et de Pharmaco-épidémiologie, Rennes, France. 10. CHU Pontchaillou, Service de Dermatologie, Rennes, France.
Abstract
BACKGROUND: Mutations of BRAF, NRAS and c-KIT oncogenes are preferentially described in certain histological subtypes of melanoma and linked to specific histopathological features. BRAF-, MEK- and KIT-inhibitors led to improvement in overall survival of patients harbouring mutated metastatic melanoma. OBJECTIVES: To assess the prevalence and types of BRAF, NRAS, c-KIT and MITF mutations in cutaneous and mucous melanoma and to correlate mutation status with clinicopathological features and outcome. METHODS: Clinicopathological features and mutation status of 108 samples and of 98 consecutive patients were, respectively, assessed in one retrospective and one prospective study. Clinicopathological features were correlated with mutation status and the predictive value of these mutations was studied. RESULTS: This work identified significant correlations between BRAF mutations and melanoma occurring on non-chronic sun-damaged skin and superficial spreading melanoma (P < 0.05) on one hand, and between NRAS mutations and nodular melanoma (P < 0.05) on the other hand. Younger age (P < 0.05), microscopic (P < 0.05) and macroscopic (P < 0.05) lymphatic involvement at diagnosis of primary melanoma were significantly linked to BRAF mutations. A mutated status was a positive predictive factor of a response to BRAF inhibitors (OR = 3.44). Mutated melanoma showed a significantly (P = 0.038) higher objective response rate to cytotoxic chemotherapy (26.3%) than wild-type tumours (6.7%). CONCLUSION: Clinical and pathological characteristics of the primary melanoma differed between wild-type and BRAF- or NRAS-mutated tumours. Patients with BRAF-mutated tumours were younger at diagnosis of primary melanoma. Patients carrying mutations showed better responses better to specific kinase inhibitors and interestingly also to systemic cytotoxic chemotherapy.
BACKGROUND: Mutations of BRAF, NRAS and c-KIT oncogenes are preferentially described in certain histological subtypes of melanoma and linked to specific histopathological features. BRAF-, MEK- and KIT-inhibitors led to improvement in overall survival of patients harbouring mutated metastatic melanoma. OBJECTIVES: To assess the prevalence and types of BRAF, NRAS, c-KIT and MITF mutations in cutaneous and mucous melanoma and to correlate mutation status with clinicopathological features and outcome. METHODS: Clinicopathological features and mutation status of 108 samples and of 98 consecutive patients were, respectively, assessed in one retrospective and one prospective study. Clinicopathological features were correlated with mutation status and the predictive value of these mutations was studied. RESULTS: This work identified significant correlations between BRAF mutations and melanoma occurring on non-chronic sun-damaged skin and superficial spreading melanoma (P < 0.05) on one hand, and between NRAS mutations and nodular melanoma (P < 0.05) on the other hand. Younger age (P < 0.05), microscopic (P < 0.05) and macroscopic (P < 0.05) lymphatic involvement at diagnosis of primary melanoma were significantly linked to BRAF mutations. A mutated status was a positive predictive factor of a response to BRAF inhibitors (OR = 3.44). Mutated melanoma showed a significantly (P = 0.038) higher objective response rate to cytotoxic chemotherapy (26.3%) than wild-type tumours (6.7%). CONCLUSION: Clinical and pathological characteristics of the primary melanoma differed between wild-type and BRAF- or NRAS-mutated tumours. Patients with BRAF-mutated tumours were younger at diagnosis of primary melanoma. Patients carrying mutations showed better responses better to specific kinase inhibitors and interestingly also to systemic cytotoxic chemotherapy.
Authors: Michael Lattanzi; Yesung Lee; Danny Simpson; Una Moran; Farbod Darvishian; Randie H Kim; Eva Hernando; David Polsky; Doug Hanniford; Richard Shapiro; Russell Berman; Anna C Pavlick; Melissa A Wilson; Tomas Kirchhoff; Jeffrey S Weber; Judy Zhong; Iman Osman Journal: J Natl Cancer Inst Date: 2019-02-01 Impact factor: 13.506
Authors: Ashley M Poenitzsch Strong; Scott M Berry; David J Beebe; Jian-Liang Li; Vladimir S Spiegelman Journal: Mol Carcinog Date: 2018-02-12 Impact factor: 4.784
Authors: Markus V Heppt; Timo Siepmann; Jutta Engel; Gabriele Schubert-Fritschle; Renate Eckel; Laura Mirlach; Thomas Kirchner; Andreas Jung; Anja Gesierich; Thomas Ruzicka; Michael J Flaig; Carola Berking Journal: BMC Cancer Date: 2017-08-10 Impact factor: 4.430