Loss of Inositol Polyphosphate 5-Phosphatase Is an Early Event in Development of Cutaneous Squamous Cell Carcinoma

Abstract

Cutaneous squamous cell carcinoma (SCC) occurs commonly and can metastasize. Identification of specific molecular aberrations and mechanisms underlying the development and progression of cutaneous SCC may lead to better prognostic and therapeutic approaches and more effective chemoprevention strategies. To identify genetic changes associated with early stages of cutaneous SCC development, we analyzed a series of 40 archived skin tissues ranging from normal skin to invasive SCC. Using highresolution array-based comparative genomic hybridization, we identified deletions of a region on chromosome 10q harboring the INPP5A gene in 24% of examined SCC tumors. Subsequent validation by immunohistochemistry on an independent sample set of 71 SCC tissues showed reduced INPP5A protein levels in 72% of primary SCC tumors. Decrease in INPP5A protein levels seems to be an early event in SCC development, as it also is observed in 9 of 26 (35%) examined actinic keratoses, the earliest stage in SCC development. Importantly, further reduction of INPP5A levels is seen in a subset of SCC patients as the tumor progresses from primary to metastatic stage. The observed frequency and pattern of loss indicate that INPP5A, a negative regulator of inositol signaling, may play a role in development and progression of cutaneous SCC tumors. Cancer Prev Res; 3(10); 1277-83. ©2010 AACR.

From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma

“…Additional molecular events associated with AK formation include increased activation or levels of SFKs, EGFR, Myc, and ATF-3 (30)(31)(32)(33). In addition, decreased levels of inositol polyphosphate 5′-phosphatase have also been reported in AKs, which could result in increased PI3K/Akt signaling (34).…”

Cross-species identification of genomic drivers of squamous cell carcinoma development across preneoplastic intermediates

“…Amplifications of epidermal growth factor receptor ( EGFR ) and c-MYC have been identified in AK and cuSCC1011. Loss of INPP5A and CKS1B amplification have been demonstrated in human cuSCC and smaller proportions of AKs1213. Gene signatures that distinguish SCC from AK or irradiated skin have been identified, but they have not been refined to identify a mechanistic basis for progression141516.…”

Identification of Novel Genetic Alterations in Samples of Malignant Glioma Patients

“…It was shown that loss of INPP5A was an early event in development of cutaneous squamous cell carcinoma [37]. Speed et al [38] showed that absence or loss of this enzyme activity was also associated with transformation of NRK cells, while Mengubas et al [39] connected decrease of inositol polyphosphate 5-phosphatase activity with several human leukaemias.…”