Mutation and deletion analysis of GFR alpha-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours.
Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRalpha-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRalpha-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRalpha-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRalpha-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRalpha-1 and/or nearby genes may contribute to the pathogenesis of these tumours.
Gimm
O
O
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Gössling
A
A
Marsh
D J
DJ
Dahia
P L
PL
Mulligan
L M
LM
von Deimling
A
A
Eng
C
C
D001932:Brain Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D029721:Drosophila Proteins; D005091:Exons; D017353:Gene Deletion; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006801:Humans; D007438:Introns; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
D004273:DNA, Neoplasm; D029721:Drosophila Proteins; C495039:GDNF protein, human; C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila