WIF1, an inhibitor of the Wnt pathway, is rearranged in salivary gland tumors

Abstract

Chromosome rearrangements involving 12q13-15 are frequent among several tumors, including pleomorphic adenomas. The common molecular target for these aberrations is the HMGA2 gene, but various fusion partners of HMGA2 have been reported in tumors. Here we report the identification of the WNT inhibitory factor 1 (WIF1) gene as a novel HMGA2 fusion partner in a salivary gland pleomorphic adenoma. In normal salivary gland tissue WIF1 is expressed at a high level and HMGA2 is not expressed. However, in the pleomorphic adenoma expressing the HMGA2/WIF1 fusion transcript, we observed re-expression of HMGA2 wild-type transcripts and very low levels of WIF1 expression. These data suggest a possible synergistic effect between upregulation of HMGA2 and downregulation of WIF1. We screened 13 additional benign and malignant salivary gland tumors and detected WIF1 rearrangement in one out of two carcinomas ex-pleomorphic adenoma analyzed. In this malignant tumor, the rearrangement of one WIF1 allele coexists with loss of the other allele, a classic signature of a tumor suppressor gene. WIF1 is an antagonist of the Wnt signaling pathway, which plays a critical role in human cancer. In transgenic mouse models, Wnt activation leads to a high frequency of benign and malignant salivary gland tumors. To our knowledge, this is the first report suggesting that WIF1 is a recurrent target in human salivary gland oncogenesis and that downregulation of WIF1 plays a role in the development and/or progression of pleomorphic adenomas.

Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice

“…Wif1 -/-mice were predisposed to the development of radiocarcinogen-induced osteosarcoma. The median latency of tumor onset (measured as a visible growth, palpable tumor, limping, or paralysis and verified by 18 F-PET scan) in 45 Ca-treated Wif1 -/-mice was shortened by 14 wk compared with littermate controls (P = 0.0032, Mantel-Cox; Figure 6D). Mean time to onset was 58.32 ± 2.9 wk in WT mice (n = 23) and 47.12 ± 2.5 wk in Wif1 -/-mice (n = 22; Figure 6E).…”

“…To quantitate the tumor suppressor role of Wif1 in the development of osteosarcoma, we used a radiocarcinogen model (35), since irradiation is a known risk factor for osteosarcoma. 45 Ca is a long-lived, low-energy β-emitter that is incorporated into the skeleton and induces osteosarcomas in mice with 100% penetrance. Cohorts of Wif1 -/-mice and littermate controls were injected with 45 Ca from 4 to 8 wk of age ( Figure 6B).…”

“…45 Ca is a long-lived, low-energy β-emitter that is incorporated into the skeleton and induces osteosarcomas in mice with 100% penetrance. Cohorts of Wif1 -/-mice and littermate controls were injected with 45 Ca from 4 to 8 wk of age ( Figure 6B). Tumor emergence was monitored clinically and by the use of 18 F-PET, which provided a sensitive marker for sites of osteoblast activity (our unpublished observations).…”

“…Tumor emergence was monitored clinically and by the use of 18 F-PET, which provided a sensitive marker for sites of osteoblast activity (our unpublished observations). The first osteosarcomas were seen approximately 26 wk after 45 Ca exposure and developed in the spine, hind and fore limbs, pelvis, and cranium ( Figure 6C). Histologically, the tumors resembled human osteosarcoma, with malignant osteoid production ( Figure 6A, left).…”

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers

“…Interestingly, WIF1 is located closely upstream of HMGA2 and transcribed from the opposite strand. WIF1 also is a recurrent translocation partner of HMGA2 in pleomorphic adenomas of the salivary gland (36).…”