الفهرس 
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of
cancer in the world, accounting for 85–90 % of the total primary liver
cancer burden worldwide. It is also the third most frequent cause of
cancer-related mortality. In Egypt, HCC is the second and sixth most
common malignancy in men and women; respectively. The rising
incidence of HCC may be due to high prevalence of HCV and its
complications. HCV infection causes inflammation of the liver and a
variable grade of damage to the organ that over decades can lead to
cirrhosis.
Previous reports identified two specific genetic factors to HCVrelated
HCC, the Dishevelled, Egl-10 and Pleckstrin Domain-Containing
5 (DEPDC5) locus and the MHC class I polypeptide-related sequence A
(MICA) locus in Japanese patients.
DEPDC5 gene is located on the long arm of chromosome 22,
22q12.3 and it encodes a cytoplasmic protein which has been lately
shown to have an important function in focal epilepsy, a neurological
disorder. DEPDC5 protein has been established to block the effect of
mammalian target of rapamycin (mTOR), a multi-functional protein
participated in many cellular process including inflammation, growth of
the cell and tumor formation including hepatocarcinogenesis.
MICA is localized on chromosome 6p21. MICA is a membrane
protein that is up-regulated in various cancer cells and also stimulated in
response to various cellular stresses such as infection, hypoxia, and heat
shock. It is an essential part of the innate immune response, where MICA
can be linked to the natural killer group 2 member D receptor and then
activate NK cells and CD8+ cells.
The catechol-O-methyltransferase (COMT) gene is localized on
chromosome 22q11.2. It is a vital enzyme participated in the inactivation
of endogenous catecholamine and catechol estrogens. Catechol estrogens
have the capability to destroy DNA and carcinogenetic agents. So, the
damage, the loss of or changes in COMT is hypothetically contributed to
genomic instability and tumor formation.
The aim of the current study was to investigate the association of
the DEPDC5 (rs1012068), MICA (rs2596542) and COMT (rs4680) with
HCC risk related HCV cases in Egypt.
One hundred HCC cases were recruited from National Cancer
Institute, Cairo University and one hundred healthy controls were
recruited from National Liver Institute, Manoufia University.
Ten ml of blood was withdrawn from all cases and controls under a
complete aseptic condition in two vacutainer tubes containing EDTA.
One tube of each sample was centrifuged at 2000 rpm for 10 min, plasma
and buffy coat were separated, aliquoted and stored at −80°C. Plasma
samples were used for the determination of HCV Ab, HBsAg, and AFP.
AST, ALT, TBIL, ALB. Also, plasma was used to perform in-house RT
HCV PCR for the detection of HCV. Buffy coat was used for detection of
polymorphism of DEPDC5, MICA and COMT genes by real time PCR
technique, the other whole blood tube was used for determination of HB
and platelets.
No significant variation was found between the two studied groups
in age and gender (P = 0.365 and 0.626 respectively), this is due to
selection criteria. In addition, HCV infection (100%) is detected in HCC
group. The laboratory parameters such as AFP, liver enzymes (ALT,
AST), TBIL, ALB, HB and platelet count were detected in the two
studied group. The levels of AFP, AST, ALT and TBIL were
significantly increased in HCC group compared to the controls. On the other hand, the platelet count and HB concentration were significantly
decreased.
Out of the three gene polymorphisms analyzed, the DEPDC5 and
MICA variants were significantly related with the development of HCC
(P < 0.0001) among HCV-infected patients, while COMT is not
associated with HCC risk (P = 0.607). Only the DEPDC5 variants
showed a high (P < 0.0001) significant difference in patients with
cirrhosis. No significant percentage was demonstrated on the levels of the
three gene polymorphisms in gender and age except the COMT was
observed in aged patients (P = 0.018). Moreover, Studying DEPDC5,
MICA and COMT variants with some biochemical and hematological
parameters showed no significant association between the SNPs and
some of the studied parameters as AFP, ALT, AST, TBIL, ALB, HB and
platelets, but only the DEPDC5 variants were significantly correlated
with low platelets count (P < 0.045).
In conclusion, the current findings suggested that the genetic
polymorphisms in DEPDC5 (rs1012068) and MICA (rs2596542), but not
COMT (rs4680) are significantly associated with HCC development in
Egyptian patients with HCV infection.