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Somatic mutations in VHL germline deletion kindred correlate with mild phenotype
Author(s) -
Wait Scott D.,
Vortmeyer Alexander O.,
Lonser Russell R.,
Chang David T.,
Finn Michael A.,
Bhowmick Deb A.,
Pack Svetlana D.,
Oldfield Edward H.,
Zhuang Zhengping
Publication year - 2004
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10807
Subject(s) - germline , loss of heterozygosity , germline mutation , carcinogenesis , genetics , point mutation , biology , allele , mutation , phenotype , tumor suppressor gene , cancer research , gene
Generally, von Hippel–Lindau (VHL) disease is caused by a germline mutation of the VHL gene (chromosome 3p), and tumorigenesis is initiated from a “second‐hit” deletion. A subset of VHL patients have a germline deletion of the VHL gene, and the molecular events leading to tumorigenesis are not fully understood. To determine the molecular pathogenesis of tumor formation in this setting, we analyzed five central nervous system hemangioblastomas from three patients of a single VHL germline deletion kindred, all displaying mild clinical phenotype. Rather than loss of heterozygosity (the “second hit” in VHL germline mutation patients), all tumors from this kindred showed “second‐hit” point mutations on the wild‐type allele. Moreover, in two patients who each had two hemangioblastomas resected each tumor contained a unique mutation. The specific germline deletion and the overall genetic makeup of the patient did not predict these random “second‐hit” point mutations. These results suggest that in patients with germline deletion of a tumor suppressor gene there is a unique genetic mechanism underlying tumorigenesis. This unique genetic mechanism correlates with and may help to understand the mild clinical phenotype seen in these patients.