CHCHD7-PLAG1 and TCEA1-PLAG1 gene fusions resulting from cryptic, intrachromosomal 8q rearrangements in pleomorphic salivary gland adenomas

Pleomorphic salivary gland adenomas are characterized by recurrent chromosome rearrangements of 8q 12, leading to activation of the PLAGI oncogene. Here we demonstrate that CHCHD7-PLAGI is a novel and recurrent gene fusion generated by a cytogenetically cryptic rearrangement in pleomorphic adenomas. CHCHD7 is a newly identified member of a multifamily of proteins containing a conserved (coiled coil I)-(helix I)-(coiled coil 2)-(helix 2) domain. Northern blot analysis revealed that the gene is ubiquitously expressed. Its biological function is unknown and the gene has hitherto not been associated with neo-plasia. CHCHD7 and PLAGI are located head-to-head about 500 bp apart in 8q12. Molecular analyses of 27 tumors revealed CHCHD7-PLAGI fusions in three tumors, two of which had t(6;8) and t(8;15) translocations as the sole anomalies and one a normal karyotype. FISH analyses of interphase nuclei and nuclear chromatin fibers of a fourth adenoma with a normal karyotype revealed that a second fusion partner gene, TCEAI, located about 2 Mb centromeric to PLAGI, also is fused to PLAGI as a result of a cryptic 8q rearrangement. The breakpoints in both fusions occur in the 5'-noncoding regions of the genes, leading to activation of PLAGI by promoter swapping/substitution. Western blot and immunohistochemical analyses demonstrated that the PLAGI protein was overexpressed in epithelial, myoepithelial, and mesenchymal-like tumor cells in tumors with both fusions. Our findings further emphasize the significance of PLAGI activation in pleomorphic adenomas and demonstrate that the gene is more frequently activated than previously anticipated. (c) 2006 Wiley-Liss, Inc.