Dataset Information

Recurrent inactivating RASA2 mutations in melanoma.

ABSTRACT: Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ?30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer.

SUBMITTER: Arafeh R

PROVIDER: S-EPMC4954601 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Recurrent inactivating RASA2 mutations in melanoma.

Arafeh Rand R Qutob Nouar N Emmanuel Rafi R Keren-Paz Alona A Madore Jason J Elkahloun Abdel A Wilmott James S JS Gartner Jared J JJ Di Pizio Antonella A Winograd-Katz Sabina S Sindiri Sivasish S Rotkopf Ron R Dutton-Regester Ken K Johansson Peter P Pritchard Antonia L AL Waddell Nicola N Hill Victoria K VK Lin Jimmy C JC Hevroni Yael Y Rosenberg Steven A SA Khan Javed J Ben-Dor Shifra S Niv Masha Y MY Ulitsky Igor I Mann Graham J GJ Scolyer Richard A RA Hayward Nicholas K NK Samuels Yardena Y

Nature genetics 20151026 12

Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer. ...[more]

PMID: 26502337

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Project description:BackgroundMalignant melanoma of the female genital tract is relatively uncommon and accounts for 3-7% of all melanoma localizations. This study aimed to identify driver genes in melanoma of the female genital tract with the purpose of enhancing understanding of disease pathogenesis and identifying potential new therapeutic targets to develop effective therapies.MethodsKIT (CD117) and BRAF expression were detected immunohistochemically. Polymerase Chain Reaction (PCR) and Sanger sequencing techniques were performed to identify the mutational status of BRAF, NRAS, KRAS, NF1, KIT, PDGFRA and SF3B1 on 19 melanomas of the female genital tract, paired with 25 cutaneous melanomas, 18 acral melanomas and 11 melanomas of nasal cavity.ResultsSomatic variant analysis identified KRAS (6/19; 32%) as the most commonly mutated gene, followed by KIT (4/19; 21%), SF3B1 (3/19; 16%) and NRAS (1/19; 5%). None of the cases were found to harbor BRAF, NF1 and PDGFRA mutations in melanomas of the female genital tract. However, none of the cases were found to harbor SF3B1 and KIT mutations in cutaneous melanomas, acral melanomas and melanomas of nasal cavity. Recurrent KIT mutations, as well as mutations in the less frequently mutated genes NRAS and SF3B1, were exclusively detected in vulvovaginal melanomas, but not in tumors arising in the cervix. However, recurrent KRAS mutations were detected in similar frequencies in tumors of the vulva, vagina, and cervix. Additionally, recurrent KRAS and KIT mutations occurred predominantly in polygonal and epithelioid cell types of melanoma in the female genital tract. Immunohistochemistry revealed moderate or strong cytoplasmic CD117 expression in 6 of the 19 cases (31.6%).ConclusionsWe observed that gynecologic melanoma harbored distinct mutation rates in the KIT, BRAF, SF3B1, KRAS, and NRAS genes. Our findings support the notion that gynecologic melanoma is a distinct entity from non-gynecologic melanoma, and these findings offer insights into future therapeutic options for these patients.

Dataset Information

Recurrent inactivating RASA2 mutations in melanoma.

Publications

Recurrent inactivating RASA2 mutations in melanoma.

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