Molecular profiling of the "plexinome" in melanoma and pancreatic cancer

Asha Balakrishnan, Junia Y. Penachioni, Simona Lamba, Fonnet E. Bleeker, Carlo Zanon, Monica Rodolfo, Viviana Vallacchi, Aldo Scarpa, Lara Felicioni, Matthias Buck, Antonio Marchetti, Paolo M. Comoglio, Alberto Bardelli, Luca Tamagnone

Research output: Contribution to journalArticle

Abstract

Plexins are transmembrane high-affinity receptors for semaphorins, regulating cell guidance, motility, and invasion. Functional evidences implicate semaphorin signals in cancer progression and metastasis. Yet, it is largely unknown whether plexin genes are genetically altered in human tumors. We performed a comprehensive gene copy analysis and mutational profiling of all nine members of the plexin gene family (plexinome), in melanomas and pancreatic ductal adenocarcinomas (PDACs), which are characterized by high metastatic potential and poor prognosis. Gene copy analysis detected amplification of PLXNA4 in melanomas, whereas copy number losses of multiple plexin genes were seen in PDACs. Somatic mutations were detected in PLXNA4, PLXNB3, and PLXNC1; providing the first evidence that these plexins are mutated in human cancer. Functional assays in cellular models revealed that some of these missense mutations result in loss of plexin function. For instance, c.1613G>A, p.R538H mutation in the extracellular domain of PLXNB3 prevented binding of the ligand Sema5A. Moreover, although PLXNA4 signaling can inhibit tumor cell migration, the mutated c.5206C>T, p.H1736Y allele had lost this activity. Our study is the first systematic analysis of the "plexinome" in human tumors, and indicates that multiple mutated plexins may be involved in cancer progression.

Original languageEnglish
Pages (from-to)1167-1174
Number of pages8
JournalHuman Mutation
Volume30
Issue number8
DOIs
Publication statusPublished - Aug 2009

Keywords

  • Cancer
  • Melanoma
  • Pancreas
  • PLXNA4
  • Semaphorin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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  • Cite this

    Balakrishnan, A., Penachioni, J. Y., Lamba, S., Bleeker, F. E., Zanon, C., Rodolfo, M., Vallacchi, V., Scarpa, A., Felicioni, L., Buck, M., Marchetti, A., Comoglio, P. M., Bardelli, A., & Tamagnone, L. (2009). Molecular profiling of the "plexinome" in melanoma and pancreatic cancer. Human Mutation, 30(8), 1167-1174. https://doi.org/10.1002/humu.21017