Activating PIK3CA mutations coexist with BRAF or NRAS mutations in a limited fraction of melanomas

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• 作者：Antonella Manca (1)
  Amelia Lissia (2)
  Mariaelena Capone (3)
  Paolo A Ascierto (3)
  Gerardo Botti (3)
  Corrado Carac貌 (3)
  Ignazio Stanganelli (4)
  Maria Colombino (1)
  MariaCristina Sini (1)
  Antonio Cossu (2)
  Giuseppe Palmieri (1)
  
  1. Institute of Biomolecular Chemistry ; National Research Council (CNR) ; Traversa La Crucca 3 - Baldinca Li Punti ; 07100 ; Sassari ; Italy
  2. Department of Pathology ; Hospital-University Health Unit (AOU) ; Sassari ; Italy
  3. Istituto Nazionale Tumori ; Fondazione Pascale ; Naples ; Italy
  4. Skin Cancer Unit ; Istituto Scientifico Romagnolo Tumori (IRST) ; Meldola ; Italy
  
• 关键词：Melanoma ; Mutation analysis ; PIK3CA gene ; Resistance to BRAF/MEK inhibitors
• 刊名：Journal of Translational Medicine
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：13
• 期：1
• 全文大小：456 KB
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• 刊物主题：Biomedicine general; Medicine/Public Health, general;
• 出版者：BioMed Central
• ISSN：1479-5876

文摘

Background Activated PI3K-AKT pathway may contribute to decrease sensitivity to inhibitors of key pathogenetic effectors (mutated BRAF, active NRAS or MEK) in melanoma. Functional alterations are deeply involved in PI3K-AKT activation, with a minimal role reported for mutations in PIK3CA, the catalytic subunit of the PI3K gene. We here assessed the prevalence of the coexistence of BRAF/NRAS and PIK3CA mutations in a series of melanoma samples. Methods A total of 245 tumor specimens (212 primary melanomas and 33 melanoma cell lines) was screened for mutations in BRAF, NRAS, and PIK3CA genes by automated direct sequencing. Results Overall, 110 (44.9%) samples carried mutations in BRAF, 26 (10.6%) in NRAS, and 24 (9.8%) in PIK3CA. All identified PIK3CA mutations have been reported to induce PI3K activation; those detected in cultured melanomas were investigated for their interference with the antiproliferative activity of the BRAF-mutant inhibitor vemurafenib. A reduced suppression in cell growth was observed in treated cells carrying both BRAF and PIK3CA mutations as compared with those presenting a mutated BRAF only. Among the analysed melanomas, 12/245 (4.9%) samples presented the coexistence of PIK3CA and BRAF/NRAS mutations. Conclusions Our study further suggests that PIK3CA mutations account for a small fraction of PI3K pathway activation and have a limited impact in interfering with the BRAF/NRAS-driven growth in melanoma.