Molecular profiling of the "plexinome" in melanoma and pancreatic cancer.
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.
Balakrishnan
Asha
A
Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.
Penachioni
Junia Y
JY
Lamba
Simona
S
Bleeker
Fonnet E
FE
Zanon
Carlo
C
Rodolfo
Monica
M
Vallacchi
Viviana
V
Scarpa
Aldo
A
Felicioni
Lara
L
Buck
Matthias
M
Marchetti
Antonio
A
Comoglio
Paolo M
PM
Bardelli
Alberto
A
Tamagnone
Luca
L
D000230:Adenocarcinoma / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics*; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics*
D011956:Receptors, Cell Surface