title: Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation.
abstract: Inactivation of Ras GTPase activating proteins (RasGAPs) can activate Ras, increasing the risk for tumor development. Utilizing a melanoma whole genome sequencing (WGS) data from 13 patients, we identified two novel, clustered somatic missense mutations (Y472H and L481F) in RASA1 (RAS p21 protein activator 1, also called p120RasGAP). We have shown that wild type RASA1, but not identified mutants, suppresses soft agar colony formation and tumor growth of BRAF mutated melanoma cell lines via its RasGAP activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. Moreover, R-Ras increased and RASA1 suppressed Ral-A activation among Ras downstream effectors. In addition to mutations, loss of RASA1 expression was frequently observed in metastatic melanoma samples on melanoma tissue microarray (TMA) and a low level of RASA1 mRNA expression was associated with decreased overall survival in melanoma patients with BRAF mutations. Thus, these data support that RASA1 is inactivated by mutation or by suppressed expression in melanoma and that RASA1 plays a tumor suppressive role by inhibiting R-Ras, a previously less appreciated member of the Ras small GTPases.
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.|Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Hyeran
authors.initials: H
authors.lastname: Sung
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Krishna L
authors.initials: KL
authors.lastname: Kanchi
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.|Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.|Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Hill
authors.affiliation: Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.|Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.|Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Messina
authors.affiliation: Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Kim
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Dees
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO, USA.|Department of Medicine, Washington University, St. Louis, MO, USA.|Department of Genetics, Washington University, St. Louis, MO, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.affiliation: Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.|Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Shengyu
authors.initials: S
authors.lastname: Yang
authors.affiliation: Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.|Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Amod A
authors.initials: AA
authors.lastname: Sarnaik
authors.affiliation: Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.|Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Vernon K
authors.initials: VK
authors.lastname: Sondak
authors.affiliation: Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.|Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Mulé
authors.affiliation: The Genome Institute, Washington University, St. Louis, MO, USA.|Department of Genetics, Washington University, St. Louis, MO, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Department of Medicine, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
authors.affiliation: Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA.|Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA.|Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA.
authors.forename: Minjung
authors.initials: M
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005500:Follow-Up Studies; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D011379:Prognosis; D012189:Retrospective Studies; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D020729:p120 GTPase Activating Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C557248:RASA1 protein, human; D020729:p120 GTPase Activating Protein; C085929:RRAS protein, human; D018631:ras Proteins
keywords: R-Ras; RASA1; RasGAP; melanoma; whole genome sequencing