Tumor suppressor genes in the 9p21 gene cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumors

Functional inactivation of the Rb and p53 pathways appears to be a rite of passage for all cancerous cells. However, p53 and Rb alterations are rare e vents in neuroendocrine gastroenteropancreatic (GEP) tumors. CDKN2 locus on chromosome 9p21 sits at the nexus of both pathways harboring tumor suppres sor genes, which restrain cell growth by affecting the function of pRb and p53. Therefore, we analyzed the implication of their inactivation in 37 pri mary neuroendocrine GEP tumors and two cell culture models. RT-PCR analysis revealed loss of expression of at least one of the tumor suppressor genes CDKN2A/p16, CDKN2B/p15, and CDKN2D/p14 with distinct genetic profiles, most frequently in nonfunctional pancreatic tumors (57%) and small intestinal c arcinoids (44%), and less commonly in insulinomas (30%) and gastrinomas (22 %). DNA analysis and methylation-specific PCR attributed loss of expression to either homozygous deletion or 5 ' CpG island hypermethylation. 5-Aza-2- deoxycytidine treatment reversed CDKN2A/p16 and CDKN2B/p15 silencing with c oncurrent growth restraint. Thus, tumor suppressor genes localize in the 9p 21 gene cluster are specific targets of inactivation in neuroendocrine GEP tumors, and demethylating agents might hold promise for selective therapy.