DETECTION OF ALLELIC VARIANTS OF THE POLE AND POLD1 GENES IN COLORECTAL CANCER PATIENTS
Pätzold LA, Bērziņa D, Daneberga Z, Gardovskis J, Miklaševičs E*
*Corresponding Author: Professor Dr. Edvīns Miklaševičs, Institute of Oncology, Riga Stradiņš University, Dzirciema iela 16, Riga LV1007, Latvia. Tel: +371-6770-4028. Fax: +371-6706-9545. E-mail: edvins. miklasevics@rsu.lv
page: 83

INTRODUCTION

In 2012, the incidence of new colorectal cancer cases were 3421 per 100,000 and mortality 150 per 100,000 individuals of both sexes in Europe [1]. Colorectal cancer is caused by an accumulation of environmental factors and genetic alterations. Hereditary colorectal cancer can develop as a part of a hereditary syndrome. Familial adenomatous polyposis (FAP) develops by allelic variations in the APC gene causing polyposis and early development of colorectal cancer. The MLH1, MSH2 or MSH6 genes are responsible for the mismatch repair (MMR) system and alterations in these can lead to hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Allelic variants of these genes cover only part of hereditary colo-rectal cancer cases. There is a suspected correlation between colorectal cancer and allelic variants of the POLE and POLD1 genes [2,3]. Replication of the DNA is mostly carried out by three major polymerases, polymerase α (Pol α), polymerase δ (Pol δ) and polymerase ε (Pol ε) that are coded by POLA1, POLD1 and POLE genes, respectively. Fidelity of the polymerases, proofreading and the MMR system follow each other to ensure the most accurate replication. It is a highly accurate process and only an error rate of one genetic variant per DNA replication, is observed [4]. Errors during replication are usually corrected by excision of the mismatched nucleotide and reinsertion of the correct base. Ninety to 99.9% of base-base mismatches are corrected by exonuclease activity of the polymerase itself (Pol δ, Pol ε) or by other exonucleases [5]. Occasional errors of proofreading are at last corrected by the MMR system. Pol ε has a proofreading function due to the POLE domain enabling correction of mistakes caused by the replication process. Those mistakes are caused by either the polymerase itself or polymerase α that has no proofreading capacity [2]. Exonuclease-proficient Pol ε has an error rate of 6.5 × 104, whereas exonuclease-deficient Pol ε has an error rate 46 × 104 [4]. Polymerase δ and its catalytic and exonuclease subunit POLD1 have the function of bulk replication of DNA of the lagging strand. It is the equivalent to the Pol ε and it also has the ability of proofreading, base excision repair and Okazaki fragment maturation. The exonuclease-proficient Pol δ has an error rate of 4.5 × 106, where the exonuclease-deficient Pol δ has an error rate of 44 × 106 [6]. Palles et al. [2] confirmed an association between the formation of colorectal adenomas and carcinomas and heterozygous allelic variants of these genes. They found rare missense allelic variants, p.S478N (rs397514632) in the POLD1 gene and p.L424V (rs483352909) in the POLE gene, which caused malfunctions of the exonuclease subunit of Pol δ and Pol ε [2]. Jansen et al. [3] described two germline variants in POLE/ POLD1 and different somatic variants in POLE/POLD1 and MMR genes in HNPCC patients with no known disease causing germline variant in MMR genes. The patients were suspected of carrying HNPCC because of Amsterdam II and Bethesda criteria. They concluded that loss of proofreading might be the cause of faulty MMR and the cause of the tumor formation [3]. Albertson et al. [7] also showed high incidence of sporadic intestinal adenomas and carcinomas in mice with inbred homozygous genetic variants in the POLE gene. Mice with inbred POLD1 genetic variants showed tumor formations of the skin, lungs and thymus [7]. The aim of the present study was to look for associations between the allelic variants in POLE (rs483352909) and POLD1 (rs397514632) and colorectal cancer.



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