Integrative sequencing discovers an ATF1-motif enriched molecular signature that differentiates hyalinizing clear cell carcinoma from mucoepidemoid carcinoma. (June 2021)

• Record Type: Journal Article
• Authors: Heft Neal, M.E.; Gensterblum-Miller, E.; Bhangale, A.D.; Kulkarni, A.; Zhai, J.; Smith, J.; Brummel, C.; Foltin, S.K.; Thomas, D.; Jiang, H.; McHugh, J.B.; Brenner, J.C.
• Is Part Of: Oral oncology. Volume 117(2021)
• Publication Date: 2021-06
• Subjects: HCCC -- IGF2 -- EWSR1 -- ATF1 -- CXCR4; HCCC Hyalinizing clear cell carcinoma -- MEC Mucoepidermoid carcinoma; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2021.105270
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: This work provides the first full integrated sequencing of hyalinizing clear cell carcinoma. HCCC samples contained insulin-like growth factor alterations and aberrant IGF2 and/or IGF1R expression. We demonstrate a unique gene signature that separates HCCC from MEC. The HCCC signature is enriched for genes with an ATF1 binding motif supporting a functional role of EWSR1-ATF1 fusion. Abstract: Objectives: Salivary gland tumors are comprised of a diverse group of malignancies with widely varying prognoses. These cancers can be difficult to differentiate, especially in cases with limited potential for immunohistochemistry (IHC)-based characterization. Here, we sought to define the molecular profile of a rare salivary gland cancer called hyalinizing clear cell carcinoma (HCCC), and identify a molecular gene signature capable of distinguishing between HCCC and the histopathologically similar disease, mucoepidermoid carcinoma (MEC). Materials and methods: We performed the first integrated full characterization of five independent HCCC cases. Results: We discovered insulin-like growth factor alterations and aberrant IGF2 and/or IGF1R expression in HCCC tumors, suggesting a potential dependence on this pathway. Further, we identified a 354 gene signature that differentiated HCCC from MEC, and was significantly enriched for genes with an ATF1 binding motif in their promoters, supporting a transcriptional pathogenic mechanism of the characteristic EWSR1 - ATF1 fusion found in these tumors. Of the differentially expressed genes, IGF1R, SGK1 and SGK3 were found to be elevated in the HCCCs relative to MECs. Finally, analysis of immune checkpoints and subsequent IHC demonstrated that CXCR4 protein was elevated in several of the HCCC cases. Conclusion: Collectively, our data identify an ATF1-motif enriched gene signature that may have clinical utility for molecular differentiation of HCCCs from other salivary gland tumors and discover potential actionable alterations that may benefit the clinical care of recurrent HCCC patients.