A Hunter Shain1, Iwei Yeh, Ivanka Kovalyshyn, Aravindhan Sriharan, Eric Talevich, Alexander Gagnon, Reinhard Dummer, Jeffrey North, Laura Pincus, Beth Ruben, William Rickaby, Corrado D'Arrigo, Alistair Robson, Boris C Bastian. 1. From the Departments of Dermatology and Pathology (A.H.S., I.Y., E.T., A.G., J.N., L.P., B.R., B.C.B.) and the Helen Diller Family Comprehensive Cancer Center (A.H.S., I.Y., E.T., A.G., B.C.B.), University of California, San Francisco (UCSF), San Francisco; the Departments of Dermatology and Pathology, Cleveland Clinic, Cleveland (I.K.); the Department of Pathology, Orlando Health, Orlando, FL (A.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); and the Department of Dermatology, Dorset County Hospital, Dorchester (C.D.), and the Department of Dermatology, St. John's Institute of Dermatology, London (W.R., A.R.) - both in the United Kingdom.
Abstract
BACKGROUND: The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known. METHODS: We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas. RESULTS: Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed. CONCLUSIONS: Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.).
BACKGROUND: The pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known. METHODS: We sequenced 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. The histopathological spectrum of these areas included unequivocally benign lesions, intermediate lesions, and intraepidermal or invasive melanomas. RESULTS: Precursor lesions were initiated by mutations of genes that are known to activate the mitogen-activated protein kinase pathway. Unequivocally benign lesions harbored BRAFV600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations. A total of 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression. Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas. PTEN and TP53 mutations were found only in advanced primary melanomas. The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages. Copy-number alterations became prevalent only in invasive melanomas. Tumor heterogeneity became apparent in the form of genetically distinct subpopulations as melanomas progressed. CONCLUSIONS: Our study defined the succession of genetic alterations during melanoma progression, showing distinct evolutionary trajectories for different melanoma subtypes. It identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features. Finally, our study implicated ultraviolet radiation as a major factor in both the initiation and progression of melanoma. (Funded by the National Institutes of Health and others.).
Authors: Charlotte Philpott; Hannah Tovell; Ian M Frayling; David N Cooper; Meena Upadhyaya Journal: Hum Genomics Date: 2017-06-21 Impact factor: 4.639
Authors: Klaus G Griewank; Hansgeorg Müller; Louise A Jackett; Michael Emberger; Inga Möller; Johannes Ap van de Nes; Lisa Zimmer; Elisabeth Livingstone; Thomas Wiesner; Simone L Scholz; Ioana Cosgarea; Antje Sucker; Tobias Schimming; Uwe Hillen; Bastian Schilling; Annette Paschen; Henning Reis; Thomas Mentzel; Heinz Kutzner; Arno Rütten; Rajmohan Murali; Richard A Scolyer; Dirk Schadendorf Journal: Mod Pathol Date: 2017-04-14 Impact factor: 7.842