Table 4.

Tumor Suppressor Genes (TSGs) involved in ACC pathogenesis

Type	Protein	TSG Function	Role in ACC	Method of Inactivation
Cell cycle regulators	p53	Causes G1 arrest via p21 and triggers apoptosis 76,77,78	Involved in recurrence or metastasis86,87 Progression to more advanced disease85,89	Missense mutation79–81
	p16INK4A	G1 arrest of cell cycle via phosphorylation of Rb	Associated with more advanced disease and increased cell proliferation95	Homozygous deletion95,96 Methylation96
	FHIT and WWOX	DNA damage response and induction of proapoptotic signals97	Associated with progression of basaloid tumors98,99	Chromosomal loss97 Methylation100
	14-3-3 δ	Prevents cell cycle progression by binding cyclin/CDK complexes and inhibiting their interaction124 Activating ρS3 after DNA damage125	Expression decreased in ACC118 Irradiation did not promote heightened expression in ACC but did in normal samples118	Methylation118
	RASSF1A	Interacts with a number of signaling molecules involved in cell growth, survival, and apoptosis	Promoter methylation correlated with advanced tumor grade and stage117	Methylation96,117,1 19
Adhesion molecules	E-cadherin	Expressed on epithelial cells and mediates calcium- dependent cell-cell adhesion102,103 Sequesters 6-catenin at membrane104	Expression correlates inversely with tumorgrade and stage108 Promoter methylation associated with perineural invasion121	Mutations106–108 Methylation121,122 Change in 6 catenin structure97
	Beta-6 Integrin	Tissue repair110	Invasion111	Unknown
	NCAM Ineural cell adhesion molecule)	Immunoglobulin expressed by peripheral nerve sheath cells112–115	Overexpressed but no correlation was found with perineural invasion or recurrence112,115	Unknown