Elsevier

Oral Oncology

Volume 42, Issue 10, November 2006, Pages 994-1004
Oral Oncology

Genes associated with early development, apoptosis and cell cycle regulation define a gene expression profile of adenoid cystic carcinoma

https://doi.org/10.1016/j.oraloncology.2005.12.017Get rights and content

Summary

Adenoid cystic carcinoma (ACC) is an uncommon salivary gland malignancy characterized by indolent yet relentless growth that exhibits inherent resistance to systemic chemotherapy, surgical salvage and conventional radiotherapy. We used microarray analysis to characterize gene expression changes associated with ACC. Eight ACC patient specimens were compared with normal parotid gland tissue and the ACC3 cell line. Differentially expressed genes were identified (512 total) using supervised analysis methods and functional categories assigned using OntoExpress. Genes associated with morphogenesis, neurogenesis, proliferation and apoptosis characterized ACC tumors. Genes associated with saliva production and immune response characterized normal parotid tissues while the ACC3 cell line expressed genes primarily associated with proliferation, chromosome maintenance and the cell cycle. These results demonstrate that ACC tumors express genes associated with early developmental processes including morphogenesis and neurogenesis implicating oncogenic events that result in dedifferentiation of normal salivary glands.

Introduction

Adenoid cystic carcinoma (ACC) of the head and neck is a tumor derived from the major and minor salivary glands and represents approximately 7.5% of all salivary gland epithelial malignancies and 4% of all salivary gland neoplasms.1 For early stage disease, surgical resection continues to be the mainstay of therapy.2 In patients with adverse prognostic features including positive surgical margins and perineural invasion, neutron beam radiation therapy has been advocated for decreasing the risk of local recurrence.3 However, despite aggressive local treatment, approximately 40–60% of patients with ACC develop distant metastases to lungs, bone and soft tissues.1, 4 Thus, distant failure remains a significant obstacle in the long-term cure of patients with ACC emphasizing the need for a better understanding of the biological factors associated with this malignancy.

In order to explore ACC biology we used oligonucleotide microarray analysis to define a comprehensive molecular portrait of ACC. ACC tumor samples (N = 8) were compared to normal parotid gland samples (N = 4) and the ACC3 cell line (triplicate experiments) with the overall objective of identifying novel genes associated with ACC. We demonstrate that ACC tumors are characterized by the expression of genes associated with gene ontology defined early developmental processes including morphogenesis and neurogenesis. ACC tumors also express genes associated with well-defined carcinogenic processes such as apoptosis and cell cycle regulation. Our data also confirm the deregulation of several genes previously reported by other investigators5 and implicates several novel genes not previously described in ACC as potential factors in ACC tumor biology. Importantly, given the lack of efficacy of conventional treatment modalities, these results suggest that therapeutic strategies aimed at redifferentiation of ACC tumors may be beneficial.

Section snippets

Tissue samples and cell lines

Tissue sample procurement and processing, RNA extraction, probe preparation and microarray procedures were performed as previously described.6 Briefly, the University of Minnesota Cancer Center Tissue Procurement Facility obtained tumor samples from surgical resection specimens from patients undergoing surgery for ACC using standardized procedures. All samples were immediately placed on ice and within 30 min of devascularization frozen in liquid nitrogen after removal of portions needed for

Identification of genes overexpressed in ACC tumors

Tumor samples from eight patients (five females, three males) were available for this study (Table 1). Of the eight tumors examined two were from primary tumors and six were from resected metastatic lesions (4 lung, 1 lymph node, 1 pelvic soft tissue). Of the two primary tumors, one was from the parotid gland and one was of tracheal origin. Of the six metastatic lesions three were from parotid gland primaries and the rest from other sites (trachea, lacrimal gland, maxillary sinus). The

Discussion

Using supervised data analysis methods to define gene expression differences in eight ACC tumors, four normal parotid glands and the ACC3 cell line we identified a list of 512 genes that best represented the gene expression differences across all three sample classes. Our results concur with a recently published gene expression profiling study by Frierson et al., evaluating 15 ACC tumors, the ACC3 cell line and 5 normal major salivary gland tissues.5 From the list of 30 genes identified as most

Acknowledgements

We thank Matthew Ginos and Michaela Tsai for their expert technical assistance in preparing tissue specimens for microarray analysis. We also thank Sarah Bowell and Diane Rauch of the University of Minnesota Cancer Center Tissue Procurement Facility for assistance in procuring and preserving tissues, and Aaron Becker and Jill Plumb-Smith of the University of Minnesota Affymetrix Core Facility for performing the microarray procedures.

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