DNA damage response pathways are important for maintaining genomic stability. The oncogenic phosphatase Wip1 plays a crucial role in DNA damage response by inhibiting several cell cycle proteins, including p53. Although Wip1 gene amplification has been reported in various primary tumors, including lung cancer, its biological significance for survival of primary lung tumor patients remains unclear. We investigated the expression of Wip1 in cancer epithelial cells immunohistochemically in 84 consecutive resected cases of lung adenocarcinoma. Increased Wip1 expression was observed in 54 (64.3%) of the 84 cases. Wip1 expression was found to be correlated significantly with two clinicopathological factors: c-H2AX expression, and invasion to the pulmonary vein. A univariate analysis and log-rank test indicated a significant association between Wip1 expression and lower overall survival rate (P = 0.019 and P = 0.0099, respectively). A multivariate analysis also indicated a statistically significant association between increased Wip1 expression and lower overall survival rate (hazard ratio, 4.3; P = 0.026). The Ki67 index level was higher in the Wip1-positive group than in the negative group (P < 0.04, Mann-Whitney U-test). Moreover, in a subgroup analysis of only stage I patients, increased Wip1 expression was also significantly associated with a lower overall survival rate (P = 0.023, log-rank test). These results indicate that the increased expression of Wip1 in cancer epithelial cells has significant value for tumor progression and the clinical prognosis of patients with primary lung adenocarcinoma. (Cancer Sci 2011; 102: 1101-1106 C ellular DNA is constantly exposed to various environmental and endogenous mutagenic insults. To maintain genomic integrity and prevent cancers caused by these potentially mutagenic events, a sophisticated array of damage sensors, signaling molecules, and repair functions have evolved. Among the key sensors of DNA damage are the phosphoinositide-3-kinaserelated kinase family, which includes ATM (ataxia-telangiectasia mutated), ATR (ataxia-telangiectasia and Rad3-related), and DNA-PK cs (DNA-dependent protein kinase catalytic subunit).(1,2) A direct role for the ATM ⁄ ATR-initiated damage response pathways in cancer prevention has been recently determined.(3,4) Human pre-neoplastic lesions from a variety of different human cancers were shown to express various markers reflecting responses to DNA damage response, including activated and phosphorylated ATM, Chk2, p53, and H2AX. (3,4) In particular, phosphorylated H2AX (called c-H2AX) plays a crucial role in recruiting DNA damage response factors to damage sites for accurate DNA repair and is considered a specific and sensitive molecular marker of DNA damage and repair. Interestingly, late-stage tumors often show loss of these DNA damage response markers, suggesting that a decrease in the activity of DNA damage response pathways may contribute to cancer progression. (3,4) Wild-type p53-induced phosphatase 1 (Wip1), also called PPM1D, is a me...