The INK4 family includes the structurally and functionally related p15, p16 and p18 genes. in vitro they arrest the cell in G1 phase, thus far in an apparently similar manner. It is not clear yet how their functions relate in vivo, whether these genes have distinct or redundant functions. The INK4 genes are thought to be candidates for tumor suppressor genes. The p16 gene has been found to be inactivated in many tumor types, usually by homozygous deletion. In most tumors it was noted that the deletions involve the neighboring p15 gene as well, thus it was not clear whether these inactivation events targeted p16, p15, or both genes. p16 was also found to be inactivated by intragenic mutations in 40% of pancreatic carcinomas; these cancers provide a unique opportunity to test whether p16 and p15 must both be inactivated during tumorigenesis. If p15 were a second target at chromosome 9p, it would be predicted to be inactivated in at least some of these tumors. In addition to studies of the p15 gene in these pancreatic cancers, we assayed for mutations in the p18 gene, which offered a third, independent site to infer possible redundant functions of the INK4 proteins. Sequence analysis indicated that p15 and p18 were not targets of inactivation in pancreatic carcinoma. p16, therefore, plays a different role in vivo, since inactivation of only this gene had proven to confer a selective growth advantage to evolving clones of pancreatic tumor cells. The preference for homozygous deletions as a means to inactivate p16 remains unexplained.

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