1.1. (Japan, Kuwait) and Eastern Europe. [1] Figure

1.1.         
Incidence, morbidity, and mortality of colorectal
cancer.

 

 
 
 
 
 
 
 
 

 
 
 
 
 
Figure1.1:
Cancer incidence worldwide,
GLOBOCAN, 2012.
 

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Cancers of the colon and rectum have been
considered as the same disease, namely colorectal cancer (CRC), which is one of
the most occurring type of cancer worldwide. Based on GLOBOCAN statistics, CRC
is the third most common cancer with nearly 1.4 million new cases are diagnosed
in 2012 worldwide, and about 693,900 deaths from colorectal cancer were
estimated, accounting for 8% of all cancer deaths. The high­est incidence rates were in Northern America, Australia,
New Zealand, Europe, and South Korea, while in Africa and South-Central Asia rates
were considerably low. However, the incidence of colorectal cancer is
increasing in certain countries where risk was historically low, the greatest
increases are in Asia (Japan, Kuwait) and Eastern Europe. 1

Figure 1.1.
Cancer incidence worldwide,
GLOBOCAN, 2012 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

 

 

In Saudi
Arabia, CRC is the most common cancer in men and second in women, for men and
women combined, it is the second commonest cancer. There were nearly 2047 cases
of colorectal cancer accounting for more than 11% of all newly diagnosed cancer
cases in 2012, with approximately 1089 deaths were reported in the same year
According to World Health Organization estimation for 2012 2,
making it the first leading cause of cancer-related mortality in Saudi Arabia. According
to Saudi Cancer Registry, over the period of 1994-2010 the percentage of
colorectal cancer cases of all diagnosed cancers increased two-fold from 4.8%
to 10.1% which indicates that CRC become a major health risk in the

 
 
 
 
 
 
 

Kingdom of Saudi Arabia 3.

 

    
    Figure 1.2 Incidence of cancer in Saudi Arabia, World Health
Organization 2012 2

 

1.1.2. Colorectal Cancer
types and risk factors.

 

CRC comprise of heterogeneous
diseases with different molecular pathways and biological Characteristics, both
genetic and environmental factors are implicated in CRC and are the driving
forces of tumorigenesis 4. Genetic changes involved mutations in
multiple oncogenes, tumor suppresser genes, and genes that regulate cell growth
and differentiation 5. A genome sequencing analyses have estimated
as many as 80 mutated genes in CRC 6. For instance, APC (adenomatous polyposis
coli) gene is found to be mutated in nearly 85% of colorectal cancer cells
which is considered as an early and key step in colorectal tumorigenesis development
7. In addition of genetic factors there are
various environmental factors contribute to CRC risk. Among of which diets rich
in unsaturated fats and red meat, excessive alcohol consumption, and reduced
physical activity 8, 9.

CRC presents in three major
forms: sporadic, familial, and inherited. The majority of CRCs (70-85%) are
sporadic which caused by somatic mutations with no family history nor inherited
mutations. Familial CRC associated with family history without germline
mutations. Inherited CRC derive from inheritance of germline mutations.

1.1.3. Colorectal cancer progression and
stages.

 

 
 

\
 
 

 
 
 
 

CRC begins as a growth of tissue called a
polyp in the inner lining of the colon and/or rectum slowly growing through the
so-called adenoma-carcinoma sequence, resulting first in hyperplasia moving
toward adenoma to carcinoma and then metastasis 10. Therefore, four-step progression
of colonic epithelium was proposed, which starts from transformation of normal
epithelium to an adenoma, proceeding to in situ carcinoma, and ultimately to
invasive and metastatic tumor 11 (Figure 1.3).

Figure
1.3. adenoma-carcinoma-metastasis process 12.

 

Cancer cells can spread into
nearby lymph nodes, blood, and tissues. The extent to which cancer has spread
is described as its stage. Four stages of CRC have been determined; stage1 ‘In
situ’; cancers that have not yet begun to invade colon wall, stage2 ‘Local’;
cancers that have grown into the wall of the colon or rectum but have not
extend to invade nearby tissues, stage3 ‘Regional’; cancers that have invaded
nearby tissue or nearby lymph nodes, and stage4 ‘distant’; cancers that have
spread to other parts of the body. Hence American Joint Committee on Cancer
(AJCC) set a tumor-node-metastasis (TNM) system which is used for colorectal
cancer staging. TNM classification is based on the depth of tumor invasion into
the wall of the intestine, lymph node metastasis and presence or absence of
distant metastasis to other organs 13.

1.1.2.    
Mechanisms of carcinogenesis in colorectal
cancer

 
 
 
 
 
 
 
  
 
 

Loss of genomic stability is a critical
feature in cancer formation and development. Three distinct pathways of genomic
instability have been recognized in CRC pathogenesis: Chromosomal Instability
(CIN), Microsatellite Instability (MSI), and CpG Island Methylator Phenotype
(CIMP) pathways 14. Majority of CRC cases results from CIN
pathway which suggests a stepwise pattern of mutational activation and
inactivation of oncogenes and tumor suppressor genes result in CRC respectively
as shown in Figure. 1.4 15, 16.

            Figure 1.4. Genetic instability
pathways that drive colon neoplasia 17.

 

CIN can
result from disruption in chromosomal segregation, telomere stability, and DNA
damage repair 16, 18. Previous study has revealed that excess
telomere breakage was found to be responsible for the transition from adenoma
to carcinoma in CRC, as well as telomere shortening was found to cause
instability 19. Thus, telomeres are important in managing
genomic stability.

 

1.2.1. Telomeres structure and function.

 

 
 
 
 
 
 
 

Telomeres are the end structure of the
chromosomes composed of a repetitive sequence of (TTAGGG) nucleotides and associated
proteins 20. Human
telomeres have an average length of 10 to 15 kilobases (kb), consisting of
duplex telomeric DNA and terminates in a G-rich single
stranded 3’overhang of 50-500 nucleotides long 21 which folds back on itself and anneal with
the double-stranded region to form the telomeric loop known as the T-loop 22, 23 (Figure
1.6). T-loops are a conserved aspect of telomere structure and have been proposed
to represent a primary mechanism for chromosome end protection 24.

 

Figure
1.5. structure of human telomere 25.

 

By forming loop structures, the end of telomere
is distinguished from a DNA break, thus protecting chromosomes from end-to-end
fusions and degradation 26. Therefore,
telomeres are essential for stabilizing chromosomes by protecting them from being
recognized as damaged DNA, restrict the access of telomerase to telomeres and
prevent 

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