Abstract
To investigate the expression pattern and significance of DNA repair genes JWA and X-ray repair cross complement group 1 (XRCC1) in gastric cancer. Expressions of JWA and XRCC1 were assessed by immunohistochemistry in a training cohort and they went into a second testing cohort and finally to a validating cohort. Prognostic and predictive role of JWA and XRCC1 expression status in cases treated with surgery alone or combined with adjuvant chemotherapy was evaluated, respectively. JWA and XRCC1 protein levels were significantly downregulated in gastric cancer lesions compared with adjacent noncancerous tissues. Low tumoral JWA or XRCC1 expression significantly correlated with shorter overall survival (OS), as well as with clinicopathologic characteristics in patients without adjuvant treatment. Multivariate regression analysis showed that low JWA and XRCC1 expressions, separately and together, were independent negative markers of OS. Adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) significantly improved OS compared with surgery alone (log-rank test, P = 0.01). However, this effect was evident only in the JWA or XRCC1 low expression group (HR = 0.44; 95% CI: 0.26-0.73; P = 0.002, and HR = 0.44, 95% CI: 0.26-0.75; P = 0.002, respectively); Adjuvant fluorouracil-leucovorin-platinol (FLP) did not improve OS, except in the patients with low JWA and XRCC1 expressions (P = 0.010 for JWA and 0.024 for XRCC1, respectively). JWA and XRCC1 protein expressions in tumor are novel candidate prognostic markers and predictive factors for benefit from adjuvant platinum-based chemotherapy (FLO or FLP) in resectable human gastric carcinoma.
Highlights
Our findings indicate that JWA and X-ray repair cross complement group 1 (XRCC1) may be candidate prognostic and predictive biomarkers and potentially interesting for the personalized chemotherapy of gastric cancer patients
We recently showed that JWA, called ADP ribosylation–like factor 6 interacting protein 5 (ARL6ip5), may serve as a novel regulator of XRCC1 in the Base excision repair (BER) protein complex to facilitate repair of DNA damage [18]
We aimed to address this paucity of translational information and identify the expression patterns of JWA and XRCC1 in 3 large independent cohorts of gastric cancer patients and to examine the possible prognostic and predictive role of these markers
Summary
Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death worldwide [1].Authors' Affiliations: 1Department of Molecular Cell Biology and Toxicology, Jiangsu Key Lab of Cancer Biomarkers, Prevention & Treatment, Cancer Center; School of Public Health, Nanjing Medical University, Nanjing; 2Department of Pathology, Nantong Cancer Hospital, Nantong; 3Department of Oncology, Yixing Hospital, Yixing, Jiangsu Province; 4Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu Province, People's Republic of China; 5Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; 6Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim; and 7Cancer Clinic, Levanger Hospital, Nord-Trøndelag Health Trust, Levanger, NorwayNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).Ó2012 American Association for Cancer Research.Despite the improved prognosis of patients with gastric cancer resulting from earlier diagnosis, radical surgery, and the development of adjuvant therapy, the 5-year survival rate across all stages is only about 20%. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Despite the improved prognosis of patients with gastric cancer resulting from earlier diagnosis, radical surgery, and the development of adjuvant therapy, the 5-year survival rate across all stages is only about 20%. Chemotherapy both in resectable and advanced disease has only limited efficacy [2, 3]. New molecular markers pivotal to tumor biology, to improve prognosis and prediction of the adjuvant treatment regimens are urgently needed
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