Abstract 4578: Excision DNA repair: a biomarker of colorectal cancer onset and its chemotherapy
Authors: Vodicka Pavel E. , Vodickova Ludmila , Svoboda Miroslav , Slyskova Jana , Pardini Barbara , Naccarati Alessio , Hemminki Kari 
Published: August 2015

Introduction: DNA repair maintains universal genomic stability and preserves cellular functions. Defective DNA repair predisposes individuals to cancer by accumulating DNA damage and mutations. Measurement of DNA repair capacity (DRC) through functional assays integrates effects of epigenetic factors, genetic polymorphisms, gene expression, stability of gene product, effect of inhibitors/stimulators, environmental and lifestyle factors.

Methods: We recently developed functional assays to measure nucleotide (NER) and base excision (BER) repair capacities in human tissues (1). MiRNA, lncRNA and DNA repair transcript levels were analysed by RT PCR, protein expressions by western blotting and immunohistochemistry, activities of SMUG1 and UNG1,2 by fluorimetric assay. SNPs were determined by KASP genotyping, their functional relevance by a luciferase reporter assay.

Results: Healthy subjects exposed to chemical carcinogens exhibited decreased DNA damage and increased BER capacity. On the contrary, DRC were significantly lower and DNA damage higher in incident colorectal cancer (CRC) patients than in matched control subjects. In CRC patients the DRC, significantly lower at the time of diagnosis, increased to the levels observed in healthy controls following the completion of chemotherapy(2). We measured DRC in blood cells, healthy mucosa and tumor tissues from 70 patients with sporadic CRC. Lymphocytes in contrast to tumor tissues exhibited lowest DRC(1). SNPs in miRNA binding sites of SMUG1 affected significantly survival in 5-fluorouracil(5FU)-treated CRC patients(3). Further mechanistic investigation comprises transcript levels, protein expressions as well as uracil glycosylase activities in cell lysate.

Discussion/Evaluation: Our data indicate clearly alterations in excision DNA repair kinetics in CRC patients. However, the DRC should be determined in particular histo-pathological subtypes separately as well as in precancerous adenomas. Mechanistic investigations are undertaken on BER, SMUG1 and UNG1,2 gylcosylases in particular, in relation to 5FU-treated CRC. The data are being evaluated regarding post-transcriptional regulation of DNA repair by miRNA and lncRNA, as suggested by our recent report(3).

Conclusion: Our data on DRC in modulating the chemotherapy outcome are quite promissing. However, the analysis of sequential steps from subjects in risk to cancer patients may further elucidate the prognostic value of DNA excision repair.

References:

1. Slyskova et al. Clin.CancerRes.2012;18:5878-5887

2.Slyskova et al. Molec.Carcinogenesis2014,Epub ahead of print

3.Pardini et al. Clin.CancerRes.2013;19:6044-6056

4.Yang et al. MolCellProbes.2011;25:219-221

Support: CZ:GACR:P310/12/1585, CZ:IGA MZCR NT 13424 and 14329

Citation Format: Pavel E. Vodicka, Ludmila Vodickova, Miroslav Svoboda, Jana Slyskova, Barbara Pardini, Alessio Naccarati, Kari Hemminki. Excision DNA repair: a biomarker of colorectal cancer onset and its chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4578. doi:10.1158/1538-7445.AM2015-4578