Abstract 2219: Identification of oncogenes in mutant Rpa1 associated tumorigenesis

Genetic instability is a hallmark of human cancers. However, the precise molecular mechanism and its role in cancer remain elusive. We have demonstrated that a missense mutation in Rpa1 causes defective DNA repair, genetic instability and predisposes mice to cancer, thereby providing one of the first evidence showing a replication associated protein is essential in maintaining genome stability and suppressing tumorigenesis. In humans, loss of the chromosomal locus containing RPA1 and genetic polymorphisms in RPA1 have been found in a wide range of cancers. Hence, a better understanding about the role of Rpa1 mutation in genetic instability and cancer should have critical clinical implications. The studies from our lab and others established the association between mutant Rpa1 and tumors. However, it remains unknown which target is most related to cancer development associated with mutant Rpa1. To search for the candidate target genes, we applied whole genome array comparative genomic hybridization (aCGH) in the tumors developed in Rpa1 mutant mice. This genome-wide chromosome copy number analysis uncovered multiple chromosomal aberrations involving multiple genetic loci along the chromosomes in Rpa1 mutant tumor cells. Moreover, chromosomal profiling analysis revealed unique pattern of chromosomal changes in Rpa1 mutant lymphomas, which is distinct from lymphomas developed in other knockout mouse models carrying mutations in different tumor suppressors. Furthermore, we analyzed all the currently known tumor related genes and found 10 oncogenes to be involved in the chromosomal gains in Rpa1 mutant tumors including c-Myc on chromosome 15 which appears to be the most recurrent. We confirmed overexpression of c-Myc in Rpa1 mutant tumors while the other candidate oncogenes showed variable expression among different tumors. These results strongly suggest an important role of c-Myc in mutant Rpa1 mediated tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2219.