Abstract 4172: A role for RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus

Abstract

Abstract Although 80-90% of lung cancer patients smoke, only about 10% of heavy smokers develop lung cancer. This suggests that although tobacco smoke undoubtedly increases one's risk for lung cancer, genetic risk factors most likely predispose certain individuals. Recent genome-wide association studies identified variation in the recombination repair gene, RAD52, associated with increased lung cancer risk, and particularly with squamous cell lung carcinoma (SCC). SCC development is strongly associated with smoking and individuals who smoke have increased DNA repair, presumably to address ongoing DNA damage from exposure to tobacco smoke. Hence, it fits that the genomic region of 12p13.33 containing RAD52 shows both copy number amplification and an increase in gene expression in SCC tumors compared to normal. Functionally, we have previously demonstrated that overexpression of Rad52 in mouse bronchial epithelial and lung tumor cells leads to an increase in growth rate and that depletion leads to decreased cell growth, senescence, and an accumulation of cells in G2/M. Our current study focuses on genetic instability within lung tumor progression and how the DNA repair gene RAD52 allows primary tumor cells to become genetically stable enough to be able to invade and avoid apoptosis. C57BL6 wildtype or Rad52−/− mice at 8 weeks of age were randomized into two groups and treated topically with 0.04 M NTCU in 100-microliter drop, twice a week for 40 weeks. Unlike mouse lung adenocarcinomas, mouse SCC does not form visible solid nodules on the surface of the lung. Lungs were fixed and stained with H&E and examined histologically under a light microscope to establish tumor multiplicity and the types of lesions (invasive SCC, SCC in situ, or bronchial hyperplasia/metaplasia). Lung tissue was also stained for TUNEL analysis as well as markers of SCC and proliferation. Our novel findings demonstrate that depletion of Rad52 in vitro generates increased DNA damage and sensitivity to cell death, while knockout of the Rad52 gene in an in vivo mouse model of carcinogenesis decreases murine lung hyperplasia, in situ carcinoma and lung SCC. In addition, knockout appears to increase apoptosis. Thus, our functional studies continue to support genetic findings by revealing that loss of RAD52 can enhance cell death and DNA damage in lung tumor cells. This complementary evidence further strengthens the notion of RAD52 as a potential oncogene and implicates a major role for the process of recombinational repair in determining risk for SCC. Citation Format: Rachel Lieberman, Donghai Xiong, Ming You. A role for RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4172.