XPC, a novel lung tumor suppressor gene

5254 Lung cancer is the leading cause of cancer deaths among American men and women. One of the most frequent cytogenetic alterations in lung cancer, which occurs early in lung tumorigenesis, is allelic loss on chromosome 3p. Although several potential tumor suppressor genes have been identified in this region, critical genes with etiological roles in lung tumorigenesis remain elusive. We have identified the DNA repair gene XPC at 3p25 as a candidate tumor suppressor in lung tumorigenesis. Deletion of XPC leads to spontaneous, late-onset lung tumors in 100% of mice, while a single allele is haploinsufficient to prevent lung tumors. Mice lacking both or a single XPC allele accumulate more lung mutations than wt mice implicating diminished DNA repair capacity as an etiological factor in lung tumorigenesis in these mice. Allelic loss of XPC occurs in up to 100% of small cell lung cancer and at a high frequency in non-small cell lung cancer. We propose that allelic loss of XPC in the lung leads to a mutator phenotype that, coupled with carcinogens such as those found in cigarette smoke, results in lung tumorigenesis.