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
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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 × 10–4, whereas exonuclease-deficient
Pol ε has an error rate 46 × 10–4 [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 × 10–6, where the exonuclease-deficient Pol δ
has an error rate of 44 × 10–6 [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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