GENETIC PREDISPOSITION TO PHEOCHROMOCYTOMA - ANALYSIS OF CANDIDATE GENES GDNF, RET AND VHL

Inherited predisposition to phaeochromocytoma (MIM No 171300) occurs i n multiple endocrine neoplasia type 2 (MEN 2) (MIM No 171400), von Hip pel-Lindau (VHL) disease (MIM No 199300), and neurofibromatosis type 1 (NF1) (MIM No 162200), In addition, familial phaeochromocytoma alone has also been reported and we and others have identified germline VHL mutations in five of six kindreds analysed previously, Germline mutati ons in the RET proto-oncogene, which encodes a receptor tyrosine kinas e, and in the VHL tumour suppressor gene cause MEN 2 and VHL disease, respectively, To further investigate the genetics of phaeochromocytoma predisposition, we analysed three groups of patients with no evidence of VHL disease, MEN 2 or NF1: Group A, eight kindreds with familial p haeochromocytoma; Group B, two patients with isolated bilateral phaeoc hromocytoma; and Group C, six cases of multiple extra-adrenal phaeochr omocytoma or adrenal phaeochromocytoma with a family history of neuroe ctodermal tumours, Germline missense VHL mutations were identified in three of eight kindreds with familial phaeochromocytoma, A germline VH L mutation was also characterised in one of the two patients with bila teral phaeochromocytoma, No VHL or RET mutations were detected in the final group of patients with multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours, The absence of germline VHL and RET gene mutations in many of these families suggested that other phaeochromocytoma susceptibility loci may exist, Glial cell line-derived neurotrophic factor (GDNF) has been recently identified as a natural ligand for RET Thus, it seems p lausible that GDNF is a good candidate gene to play a role in phaeochr omocytoma susceptibility, We searched for germline mutations in GDNF i n 16 cases of familial phaeochromocytoma (groups A, B and C) and looke d for evidence of somatic change in GDNF in 28 sporadic phaeochromocyt omas, 12 MEN 2 phaeochromocytomas and five VHL phaeochromocytomas, No GDNF mutations were identified in patients with familial phaeochromocy toma disease, but a c277C-->T (R93W) sequence variant was identified i n one of 28 sporadic tumours, This candidate mutation was identified i n the germline and tumour tissue but was not present in 104 control GD NF alleles, GDNF sequence variants including R93W have been suggested previously to represent low penetrance susceptibility mutations for Hi rschsprung disease and the R93W was not identified in 376 control alle les studied by others, These findings suggest that although GDNF mutat ions do not appear to have a major role in the pathogenesis of familia l or sporadic phaeochromocytomas, allelic variation at the GDNF locus may modify phaeochromocytoma susceptibility.