Dna Repair Capacity In Colon Cancer Patients - The Effect On The Response To Treatment And Long-Term Survival

Colorectal carcinoma (CRC) is the third most common cancer worldwide with the highest incidence in Central Europe. It is the fourth leading cause of cancer related deaths mainly due to the late diagnosis and low efficacy of treatment. CRC diagnosed in early stage has a five-year survival rate about 90% which drops to near 12% once distant metastases occur. It is a heterogenous disease with different molecular and clinicopathological features depending on the tumor location. Therefore, different treatment strategies are required. A standard treatment of locally advanced rectal cancer includes neoadjuvant chemoradiotherapy followed by surgery, whereas colon cancer treatment consists of surgical resection of the tumor and/or subsequent adjuvant chemotherapy based on disease characteristics. 5-fluorouracil (5-FU) alone or in combination with other compounds is the most used treatment in CRC. The mechanism of 5-FU on molecular level is either its incorporation into DNA or it imbalances the synthesis of thymidine from uracil resulting in false uracil DNA incorporation. These DNA lesions are repaired by base excision (BER) and mismatch repair (MMR) pathways. An effective DNA damage response (DDR) is essential for the maintenance of genome stability in healthy cells, whereas in malignant cells, the suppression of DNA repair capacity (DRC) would increase the effectiveness of chemotherapy through DNA damage accumulation and consequent apoptosis. In contrary the cells with high DRC may show better survival and therefore patients with these molecular characteristics may contend with poor response, resistance to treatment and decreased survival. The aim of our present study was to investigate DRC of BER and MMR in target tissue as a predictive marker for a treatment strategy and long-term survival. In order to minimize a bias by heterogenous therapy we focused only on patients with newly diagnosed colon cancer. Our set of patients was selected based on the criteria of follow-up at minimum 30 months, subsequent treatment with 5-FU and microsatellite stable tumor tissue characteristics. Tumor and adjacent non-affected tissue samples were obtained from one hundred patients at surgical resection. Protein extracts from tissues were isolated both for protein expression analysis and for measurement of DRC. DNA repair and DDR protein expression levels were tested by Western Blot. Functional assessments of DRC were performed by comet assay-based in vitro DNA repair assay. The analysis is running and the data will be statistically analyzed and compared with clinical data (TNM stage, type and course of treatment, presence of recurrence, patient´s performance, etc.). Understanding DRC effect on the treatment response might contribute to the concept assuming that targeted modulating of DNA repair processes can achieve clinical benefit in cancer treatment. Acknowledgements: GA UK 800216, COST LD14050, GACR P303/15/14789S and AZV 15-27580A. Citation Format: Sona Vodenkova, Michal Kroupa, Katerina Jiraskova, Alessio Naccarati, Alena Opattova, Pavel Vodicka. DNA repair capacity in colon cancer patients - The effect on the response to treatment and long-term survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1424. doi:10.1158/1538-7445.AM2017-1424