Polymorphisms in the initiators of RET (rearranged during transfection) signaling pathway and susceptibility to sporadic medullary thyroid carcinoma.
BACKGROUND
Medullary thyroid carcinoma (MTC) is a characteristic tumor occurring in individuals with multiple endocrine neoplasia type 2 who carry germ-line mutations in RET (rearranged during transfection). However, most MTC occur in individuals without a family history.


OBJECTIVE
The objective of this study was to explore the possibility that susceptibility in these cases results from low penetrance alleles of RET, its coreceptors, and ligands.


METHODS
We carried out an association study in 135 sporadic MTC (sMTC) patients and 533 controls from the United Kingdom population.


CONCLUSIONS
We analyzed 33 polymorphisms in all nine genes involved in the glial cell line-derived neurotropic factor receptor-alpha (GFRalpha)-RET complex. This is the first association study in which all genes involved in this complex have been investigated for susceptibility to sMTC. We did not find any association between single nucleotide polymorphisms in the exonic regions of the GFRalpha2, GFRalpha3, GFRalpha4, glial cell line-derived neurotropic factor, neurturin, or persephin genes and risk of developing sMTC. We found a strong association between the disease and specific haplotypes of RET. We not only confirmed the previously described association with G691S and S904S (for heterozygotes: odds ratio, 1.85; range, 1.22-2.82; P = 0.004), but we found a novel protective effect associated with a specific haplotype (odds ratio, 0.39; range, 0.21-0.72; P = 0.005) revealing the existence of different genetic variants in the RET oncogene that either increase or decrease risk of sMTC.
Cebrian
Arancha
A
Cancer Research UK Human Cancer Genetics Research Group, Department of Oncology, University of Cambridge CB1 8RN, United Kingdom. arancha@srl.cam.ac.uk
Lesueur
Fabienne
F
Martin
Sam
S
Leyland
Jean
J
Ahmed
Shahana
S
Luccarini
Craig
C
Smith
Paula L
PL
Luben
Robert
R
Whittaker
Joanne
J
Pharoah
Paul D
PD
Dunning
Alison M
AM
Ponder
Bruce A J
BA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics*
C490886:ARTN protein, human; C494987:GFRA1 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009419:Nerve Tissue Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human