Michael Krauthammer 1 , Yong Kong 2 , 3 , Byung Hak Ha 4 , Perry Evans 1 , Antonella Bacchiocchi 5 , James P McCusker 1 , Elaine Cheng 5 , Matthew J Davis 4 , Gerald Goh 6 , 7 , Murim Choi 6 , 7 , Stephan Ariyan 8 , Deepak Narayan 8 , Ken Dutton-Regester 9 , 10 , Ana Capatana 1 , Edna C Holman 5 , Marcus Bosenberg 5 , Mario Sznol 11 , Harriet M Kluger 11 , Douglas E Brash 5 , 6 , 12 , David F Stern 1 , Miguel A Materin 13 , Roger S Lo 14 , Shrikant Mane 6 , 15 , 16 , Shuangge Ma 17 , Kenneth K Kidd 6 , Nicholas K Hayward 10 , Richard P Lifton 6 , 7 , Joseph Schlessinger 4 , Titus J Boggon 4 , Ruth Halaban 5
29 July 2012
We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1 P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1 P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.