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Molecular Biomarkers of Colorectal Cancer: A Review of Published Articles From Iran


1 Department of Pathology, Transplant Research Center, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, IR Iran
*Corresponding author: Bita Geramizadeh, Department of Pathology, Transplant Research Center, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, IR Iran. Tel/Fax: +98-7136683664, E-mail: geramib@sums.ac.ir.
Annals of Colorectal Research. 3(3): e30100 , DOI: 10.17795/acr-30100
Article Type: Review Article; Received: May 19, 2015; Revised: Jul 1, 2015; Accepted: Jul 3, 2015; epub: Oct 9, 2015; collection: Oct 2015

Abstract


Context: Colorectal cancer is one of the most common cancers worldwide (the third most common cancer in the world) and is especially more common in Western countries; however, its incidence has been increased significantly during the last few years in Eastern countries such as Iran and considered as one of the five common cancers in this country. According to molecular pathways, numerous biomarkers have been identified for colorectal cancers which help patients’ management.

Evidence aquisition: In this study, we tried to review published articles about the molecular biomarkers of colorectal cancer from Iran. We searched medical databases such as google scholar, Scopus, PubMed, Magiran, SID and Iran Medex for keywords of “colon cancer, KRAS, BRAF, mismatch repair gene, Microsatellite instability, molecular genetics, molecular pathogenesis, biomarker and Iran” to find studies published about colorectal cancers from Iran regarding molecular biomarkers.

Conclusion: This study showed that molecular biomarkers in colorectal cancer of Iranian patients are not so different from Western population.

Keywords: Biological Markers; Colorectal Cancer; Cancer

1. Introduction


Colorectal cancer is one of the most common cancers worldwide (the third most common cancer in the world), and is especially more common in Western countries; however, its incidence has been increased significantly during the last few years in Eastern countries such as Iran and considered as one of the five common cancers in this country (1). According to the annual reports of the Cancer Institute, colorectal cancer is the third common cancer in Iranian women and the fifth common cancer in Iranian men. Incidence rate of the disease has been increased during the past 25 years in Iran (2).


The other important finding about this cancer is significant surge of incidence in younger age population compared to older population (3). The underlying cause of this epidemiological increase can be due to changing in lifestyle and environmental factors; however, familial clustering and genetic predisposition should be considered (4). Colorectal cancers can be sporadic, familial and hereditary. HNPCC (hereditary nonpolyposis colon cancer) or Lynch syndrome is the most common form of hereditary colorectal cancer accounting for 5 - 10% of entire colorectal cancer population. Based on previous studies in Iran, clinical diagnosis of HNPCC was observed in 4.7% of probands in Tehran (5).


Molecular pathogenesis of colorectal cancer has been extensively studied and its molecular carcinogenesis has been identified far more than any other cancer. Recent advances in molecular biomarkers to personalize therapy contributed to a major progress in the treatment and prognosis of the disease (6). Many of these molecular changes and biomarkers are now a part of routine laboratory tests and some would be in the near future.


There are several molecular pathways leading to colon cancer. The three most important recognized pathways are 1) Genomic instability which can be somatic and germ line; several forms of genomic instability are chromosomal instability in tumor suppressor genes such as SMAD-4, TP53 and APC (Adenomatous polyposis gene); DNA repair defects (in mismatch repair genes) and aberrant DNA methylation are two other patterns of chromosomal instability; 2) Mutational inactivation of tumor suppressor genes mostly in APC (adenomatous polyposis gene), TP53, TGF-β tumor suppressor pathway, and mismatch repair genes (MMR) and 3) Activation of oncogenic pathways of RAS, BRAF, Phosphatidyl inositol 3-kinase (PIK-3) (7).


According to these molecular pathways, numerous biomarkers have been identified for colorectal cancers to help patients’ management (8). In this study, we tried to review published articles about the molecular biomarkers of colorectal cancer from Iran. We searched medical databases such as google scholar, Scopus, PubMed, Magiran, SID and Iran medex for keywords “colon cancer, KRAS, BRAF, mismatch repair gene, Microsatellite instability, molecular genetics, molecular pathogenesis, biomarker and Iran” to find studies published about the colorectal cancers from Iran regarding molecular biomarkers.

3. KRAS Mutation


Management of metastatic colorectal carcinoma (mCRC) has been considerably improved after discovering a number of novel drugs, including targeted agents like bevacizumab, cetuximab, and panitumumab. The overall survival of advanced disease has been considerably improved by adding newer targeted biologic agents. In the recent years, more studies have been focused on selecting patients who would benefit from these targeted therapies. This focuses on the role of the KRAS mutation in the growth and histopathology of the tumor, clinical outcomes and management choice of cancer of the large bowel (19, 20). This proto-oncogene, KRAS, is regularly mutated (30 - 50% in different surveys) in CRC. Roughly, 90% of the activating mutations that are influential solitary amino acid replacement in the GTPase pocket and guide a block of the activity of KRAS-p21 protein, are recognized in codons 12 (GGT) and 13 (GGC) of exon 1 and almost 5% in codon 61 (CAA) situated in exon 2. The most regularly found kinds of mutations are G > A and G > T transitions (21). KRAS testing has a vital improvement in the treatment of CRCs, especially after metastasis (19, 20, 22). There are very few studies about the frequency of K-ras mutation from the Middle East and Iran; consequently, in the present study, we reviewed KRAS mutation rate and spectrum in previous studies from Iran.


As Table 2 shows, the prevalence of KRAS mutation in Iran is similar to studies from other countries; the overall reported prevalence from different countries have been as low as 20 to 50%, and in the few studies from Iran, this was 12.5% - 37.4% (29-32). The most common KRAS mutation in most previous studies has been 12G - A, and in one study from south of Iran was 12 G - C (29-32).


Table 2.
Reported KRAS Mutation in Previous Studies on Iranian Population

4. BRAF Mutation


BRAF is the last discovered member of RAF family proteins in MAPKinase signaling pathway, which acts with KRAS as a downstream serine threonine kinase effector downstream to epidermal growth factor receptor (EGFR), promoting cell proliferation (33). The most prevalent mutation in the BRAF gene in all cancers involves transversion of thymidine to adenosine at nucleotide position 1799 of exon 15, leading to conversion of GTG codon (Valine) to GAG (Glutamic acid), labeled as V600E, accounting for more than 90% of the observed mutations in this gene (33, 34). V600E BRAF gene mutation is associated with older age, female gender, proximal colon location, poor differentiation, mucinous histology, infiltrating lymphocytes and advanced stage (35, 36). BRAF mutations occur more frequently in MSI and CIMP-H (Cpg island methylator phenotype-high) CRCs and only rarely with MSS CRCs and mutually exclusive with KRAS mutations (35-37). BRAF seems to be an independent negative prognostic factor in CRCs (38, 39). In some studies, BRAF gene mutation analysis has been suggested for exclusion of HNPCC Syndrome (40, 41). Two monoclonal antibodies, Cetuximab and Panitumumab, target EGFR, and have been approved to treat metastatic CRC (42). Analysis of mutational status of the BRAF gene is recommended before initiating these new targeted therapies in metastatic CRC patients (42, 43). Most previous reports from different parts of the world showed that frequency of BRAF gene mutation is usually low. The frequency of BRAF mutation has been reported as low as zero in Thailand (44) and Mexico (45) to 12.2% in Australia (46). Studies from Western countries such as the USA (United States of America) reported the prevalence of about 9% - 10% (47). There are very few studies from Iran. Table 3 shows previous studies from Iran with BRAF mutation prevalence from 0 to 3.7% (18, 30, 48, 49).


Table 3.
Reported BRAF Mutation in the Previous Studies in Iranian Population

5. P53


TP53 is the pivotal mediator of growth arrest and apoptosis in response to DNA damage. It stops cell cycle in damaged cells until alteration is properly repaired, otherwise it starts apoptosis cascade in damaged cells. Human P53 gene is composed of 11 exons and codes a protein with 393 amino acids (50). About 13 types of polymorphisms have been described in this gene (51). These polymorphisms can affect colorectal cancer risk, prognosis and response to treatment (52, 53).


There are about 9 studies from Iran regarding different roles of P53 gene in colorectal cancer. One of the most frequent studied polymorphism has been in codon 72, exon 4. The studies regarding this polymorphism have shown that different people with different genotypes in this codon can have more risk of developing colorectal cancer in patients from Iran (54-56). There are also reports about the prognosis and response to specific treatment in patients with some mutations in exons 4, 5 and 6 (57, 58). This biomarker is still not a part of recommended biomarker panel for patients with colorectal cancers; however, some studies recommended evaluation of specific mutational analysis in P53 to predict response to treatment and prognosis (59).

6. Other Biomarkers in Colorectal Cancer


In addition to the above mentioned most common and important molecular biomarkers of colorectal cancer, there are other studies regarding less common and known biomarkers in colorectal cancer of Iranian patients in both genes of hereditary cancers such as APC (adenomatous polyposis coli) gene and sporadic CRCs such as Smad-7, EGF (epidermal growth factor) and MGMT (O 6- ethylguanine-DNA methyltransferase) (60-63). There are very few studies in Iranian population regarding these newly recommended biomarkers such as NRAS and PIK3CA to be the source of decision about prognosis or risk of CRC in Iranian patients with this cancer.

7. Conclusions


CRC is one of the most common cancers in Iranian population, which emphasizes the need to find better methods to screen, diagnose and treat patients with this cancer. Molecular biomarkers can help in prediction of the risk of CRC in people, early diagnosis of this cancer, treat patients more efficiently and safely and at last increase the survival of patients with this cancer.

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Table 1.

Reported MMR Gene Mutations from Different Studies on Iranian Population

Author Year Study Population Number of Cases Methology MSI a MSI-H a MSI-L a MSS a Most Common Instable Marker
Bishehsari et al. ( 16 ) 2006 HNPCC 12 PCR-Sequencing 100 100 None 0 -
Sporadic 170 19.40 19.40 80.60
Salehi et al. ( 17 ) 2008 HNPCC 32 PCR-SSCP-Sequencing 62.50 - - 37.50 -
Haghighi et al. ( 19 ) 2010 HNPCC 78 PCR-sequencing 41 26.90 14.10 59 NR- 21
Moghbeli et al. ( 20 ) 2011 Sporadic CRC 67 PCR-sequencing 43.30 26.90 16.40 56.70 BAT-25
Shemirani et al. ( 9 ) 2011 HNPCC 80 PCR -sequencing - - - - NR-21
Sporadic CRC 80 - - - -
Faghihi et al. ( 21 ) 2012 Sporadic 96 PCR-sequencing 22.90 - - 77.10 BAT-26
Brim et al. ( 22 ) 2014 Sporadic 27 PCR-Sequencing 66.60 14.80 18.50 44.40 -
Zeinalian et al. ( 24 , 25 ) 2015 HNPCC 31 IHC and PCR-sequencing 29 19.40 9.60 61 BAT-26
a Data are presented as %.

Table 2.

Reported KRAS Mutation in Previous Studies on Iranian Population

Study Year Number of Cases Methodology Prevalence of KRAS Mutation
Shemirani ( 29 ) a 2011 48 PCR-Sequencing 12.5%
Naghibalhossaini ( 30 ) 2011 86 PCR-RFLP 28%
Bishehsari ( 16 ) a 2006 182 PCR-Sequencing 37.4%
Sobhani ( 31 ) a 2010 59 PCR-Sequencing 20.3%
Omidifar ( 32 ) a 2015 100 PCR-Sequencing 32%
a Most common mutation 12 G - A.

Table 3.

Reported BRAF Mutation in the Previous Studies in Iranian Population

Study Year No of CASES Methodology Percentage
Brim ( 18 ) 2008 53 PCR-Sequencing 2%
Naghibalhossaini ( 30 ) 2011 110 PCR-RFLP 0
Ghaffarpour ( 48 ) 2011 27 PCR-Sequencing 3.7%
Javadi ( 49 ) 2014 100 PCR-Sequencing 0