The Genetic Evolution of Melanoma from Precursor Lesions
A. Hunter Shain,Iwei Yeh,Ivanka Kovalyshyn,Aravindhan Sriharan,Eric Talevich,Alexander Gagnon,Reinhard Dummer,Jeffrey P. North,Laura B. Pincus,Beth S. Ruben,William Rickaby,Corrado D’Arrigo,Alistair Robson,Boris C. Bastian +13 more
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TLDR
The succession of genetic alterations during melanoma progression was defined, showing distinct evolutionary trajectories for different melanoma subtypes, and an intermediate category of melanocytic neoplasia was identified, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features.Abstract:
BackgroundThe pathogenic mutations in melanoma have been largely catalogued; however, the order of their occurrence is not known. MethodsWe 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. ResultsPrecursor 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...read more
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Activation of the DNA damage checkpointandgenomicinstabilityin human precancerous lesions
Vassilis G. Gorgoulis,Leandros-Vassilios F. Vassiliou,Panagiotis Karakaidos,Panayotis Zacharatos,Athanassios Kotsinas,Triantafillos Liloglou,Monica Venere,Richard A. DiTullio,Meenhard Herlyn,Christos Kittas,Thanos D. Halazonetis,Roy Castle +11 more
TL;DR: It is proposed that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.
Journal ArticleDOI
High frequency of BRAF mutations in nevi.
Pamela M. Pollock,Ursula Harper,Katherine S. Hansen,Laura M. Yudt,Mitchell S. Stark,Christiane M. Robbins,Tracy Moses,Galen Hostetter,Urs Wagner,John W. Kakareka,Ghadi Salem,Tom Pohida,Peter J. Heenan,Paul H. Duray,Olli Kallioniemi,Nicholas K. Hayward,Jeffrey M. Trent,Paul S. Meltzer +17 more
TL;DR: In this article, the authors evaluated the timing of mutations in BRAF during melanocytic neoplasia and found that mutations resulted in the V599E amino acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi.
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