Journal ArticleDOI
Distinct Sets of Genetic Alterations in Melanoma
John A. Curtin,Jane Fridlyand,Toshiro Kageshita,Hetal N. Patel,Klaus J. Busam,Heinz Kutzner,Kwang Hyun Cho,Setsuya Aiba,Eva B. Bröcker,Philip E. LeBoit,Daniel Pinkel,Boris C. Bastian +11 more
TLDR
The genetic alterations identified in melanoma at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.Abstract:
Background Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light. Methods We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas. Results We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of...read more
Citations
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Treating cancer with selective CDK4/6 inhibitors
TL;DR: Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile.
Journal ArticleDOI
KIT as a therapeutic target in metastatic melanoma
Richard D. Carvajal,Cristina R. Antonescu,Jedd D. Wolchok,Paul B. Chapman,Ruth-Ann Roman,Jerrold B. Teitcher,Katherine S. Panageas,Klaus J. Busam,Bartosz Chmielowski,Jose Lutzky,Anna C. Pavlick,Anne Fusco,Lauren M. Cane,Naoko Takebe,Swapna S. Vemula,Nancy Bouvier,Boris C. Bastian,Gary K. Schwartz +17 more
TL;DR: Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients, indicating positive selection for the mutated allele.
Journal ArticleDOI
Melanoma genome sequencing reveals frequent PREX2 mutations
Michael F. Berger,Michael F. Berger,Eran Hodis,Timothy P. Heffernan,Timothy P. Heffernan,Yonathan Lissanu Deribe,Michael S. Lawrence,Alexei Protopopov,Alexei Protopopov,Elena S Ivanova,Ian R. Watson,Ian R. Watson,Elizabeth Nickerson,Papia Ghosh,Hailei Zhang,Rhamy Zeid,Xiaojia Ren,Kristian Cibulskis,Andrey Sivachenko,Nikhil Wagle,Antje Sucker,Carrie Sougnez,Robert C. Onofrio,Lauren Ambrogio,Daniel Auclair,Timothy Fennell,Scott L. Carter,Yotam Drier,Petar Stojanov,Meredith A. Singer,Meredith A. Singer,Douglas Voet,Rui Jing,Gordon Saksena,Jordi Barretina,Alex H. Ramos,Alex H. Ramos,Trevor J. Pugh,Trevor J. Pugh,Nicolas Stransky,Melissa Parkin,Wendy Winckler,Scott Mahan,Kristin G. Ardlie,Jennifer Baldwin,Jennifer A. Wargo,Dirk Schadendorf,Matthew Meyerson,Matthew Meyerson,Stacey Gabriel,Todd R. Golub,Todd R. Golub,Todd R. Golub,Stephan N. Wagner,Eric S. Lander,Eric S. Lander,Gad Getz,Lynda Chin,Levi A. Garraway,Levi A. Garraway +59 more
TL;DR: A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome, intermediate in those originating from hair-bearing skin on the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb).
Journal ArticleDOI
Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Rizwan Haq,Jonathan Shoag,Pedro Andreu-Perez,Satoru Yokoyama,Satoru Yokoyama,Hannah E. Edelman,Glenn C. Rowe,Dennie T. Frederick,Aeron D. Hurley,Abhinav Nellore,Andrew L. Kung,Jennifer A. Wargo,Jun S. Song,David E. Fisher,Zolt Arany,Hans R. Widlund +15 more
TL;DR: It is shown that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1α, and a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of P GC1α.
Journal ArticleDOI
In vivo Switching of Human Melanoma Cells between Proliferative and Invasive States
Keith S. Hoek,Ossia M. Eichhoff,Natalie C. Schlegel,Udo Döbbeling,Nikita Kobert,Leo Schaerer,Silvio Hemmi,Reinhard Dummer +7 more
TL;DR: A new model for melanoma progression is presented that accounts for transcription signature plasticity and provides a more rational context for explaining observed melanoma biology, and challenge previous models of melan cancer progression that evoke one-way changes in gene expression.
References
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Mutations of the BRAF gene in human cancer
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A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4
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Comparison of discrimination methods for the classification of tumors using gene expression data
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High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays
Daniel Pinkel,Daniel Pinkel,Richard Segraves,Damir Sudar,Steven M. Clark,Ian Poole,David Kowbel,Colin Collins,Wen Lin Kuo,Chira Chen,Ye Zhai,Shanaz H. Dairkee,Britt-Marie Ljung,Joe W. Gray,Joe W. Gray,Donna G. Albertson,Donna G. Albertson,Donna G. Albertson +17 more
TL;DR: The implementation of array CGH is demonstrated to be able to measure copy number with high precision in the human genome, and to analyse clinical specimens by obtaining new information on chromosome 20 aberrations in breast cancer.
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