Recurrent ZFX mutations in human sporadic parathyroid adenomas

Abstract

The molecular abnormalities leading to sporadic parathyroid adenomas, a common type of human endocrine neoplasm, are heterogeneous and incompletely understood. Using whole exome and direct sequencing of parathyroid adenoma DNA samples, we identified recurrent somatic mutations in the ZFX gene. ZFX is a member of Krueppel C2H2 type zinc finger protein family, was initially described as a homolog of ZFY, and has been implicated as a transcription factor regulating embryonic stem cell renewal. The ZFX mutations we identified were strikingly specific, focused in each tumor on one encoded residue in a hotspot of two consecutive highly conserved arginine residues (R786/787; arginine to glutamine, threonine or leucine) in a zinc finger domain near the C-terminus of the protein. The intragenic specificity of these recurrently selected mutations, their confirmed expression within the tumors, the absence of loss of heterozygosity, and the absence of these mutations among over 4000 ZFX alleles in the dbSNP137 database, strongly suggest a novel role for ZFX as a human proto-oncogene. Further, these observations highlight the mutated zinc-finger domain as a new focal point for understanding ZFX’s normal and tumorigenic functions, and for development of molecularly-targeted therapeutics.