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Cancer is used to describe a diseases where cells divide abnormally without control and invade other tissues occurs. Cancer starts in cells, which are produced by dividing themselves and this process is governed by specific genes. Many numbers of events take place in this process, and if disturbed the cells get damaged and become immortal causing cancer. These Cancer cells also reach to other body parts through the lymph and the systems. Oncogenes are the genes that cause immortal nature of the cell; these cells grow unchecked leading to the formation of visible Tumours. A global report says that in an year cancer disease kills more than 7 million people in the world. (Global Cancer Facts and Figures 2007).
Figure : shows normal cell division and cancer cell division (2008 Nucleus Medical Art, Inc)
Colon Cancer is a type of malignant tumour that occurs in the large intestine, is a cancer which is observed commonly, affecting both the sex. Most of the colon cancers are not inherited and cannot be passed to the next generation, that is they are sporadic, this may be due to exposure to the environmental. However as per the National Genome Institute, 5% of the cancer individuals have hereditary forms.
DIFFERNCE BETWEEN SPORADIC AND HEREDITARY CANCER
Mutation in genes causes cancers. Sporadic and hereditary cancers differ in different ways. In case of hereditary cancer few inherited mutations are observed, while in case of sporadic cancer spontaneously occurred mutations are seen.
Hereditary cancers are caused when a gene changes are passed on from parents to the child. Example, in case of Hereditary colorectal cancer, and Breast cancer
In sporadic cancer patients, certain cells develop mutations which lead to cancer. These mutations can be caused by environmental exposure like to the sun, exposure to chemicals or radiations. Example, skin cancer.
The genes causing sporadic cancer are often the genes which cause hereditary cancer. Example Li-Fraumeni, retinoblastoma.
Figure : Mutations in the RB gene causing hereditary and sporadic retinoblastoma (Cooper 1992)
MUTATIONS INVOLVED IN COLON CANCER:
Mutation of genes such as APC, p53, K-ras occur in majority of colorectal cancer.
Adenomatous Polyposis Coli is a tumour suppressor gene which controls the expression of the gene that controls cell division. APC genes function as gatekeeper in colorectal cancer. It encodes a 2843-amino acid protein. Germline mutations occurring in this gene which is present on the chromosome 5q21 increases cell proliferation and leads to the formation of polyps. Polyps are benign tumours made of up clones of cells carrying a APC mutant gene. Familial Adenomatous Polyposis is resulted due to the mutated APC gene.
In these gene somatic mutations were clustered in a region of 15 exon, this region is known as Mutation Cluster Region (MCR).
The majority of these mutations were found to be frame shifts mutations, which introduce a stop codon causing deletion of carboxyl-terminal function.
p53 is made up on 11exons is located on the short arm of chromosome 17. (N R Rodrigues 1990)
It has a short half line and is almost present in most cells. When damage is detected in the cell, the activity of the p53 protein provides information if the cell should be repaired or be killed (apoptosis).
p53 also functions as a transcription factor, by binding to specific sequences in different genes and controls the cell cycle.
p53 has the properties of both tumour suppressor and oncogene and found mutated in many tumours, playing an important role in causing cancer.
In 70% of all colon cancers, the mutation of p53 gene is the most common phenomenon. These mutations may be a sporadic mutation that is they rise during the growth of the person, or they may be of inherited forms.
Kirsten-ras (K-ras gene):
This gene is located on chromosome 12 short arm, encodes a protein (p21ras) which is involved in signal transduction. Mutations in K-ras results in unregulated and increases cell proliferation causing tumour formation leading to cancers.
Mutation of K-ras gene at codons 12 and 13 is reported to be a common event in colorectal carcinogenesis, and is related to age. (Yuan Y 2010 Aug)
DNA mismatch repair (MMR) genes:
DNA mismatch repair (MMR) is a pathway that maintains genomic stability by rectifying mismatches caused during DNA replication and recombination. Defects or mutations in MMR are related to wide range of gene instability like Microsatellite Instability.
HNCC is one major type of cancer which is caused due to Mutations in MMR gene .
MULTISTEP PROCESS OF COLON CANCER:
Cancer formation is a multistep process involving initiation, promotion, conversion and progression. However more steps may be involved.
Colon carcinogenesis involves oncogenes and mutant tumour suppressor genes. (Cummings 2006) (figure 3)
Inactivation of the APC gene is reported as the first incident in colorectal (colon) carcinogenesis process which results in Polyps , the next step involves mutations in K-Ras oncogene , which is followed by allelic loss of tumour suppressor gene in deleted colon cancer DCC on chromosome 18q . The final step is loss of short arm on 17p which are associated with in p53 gene mutations. This results in the loss of function of the cell , leading to the development of benign tumour to malignant tumour . In this process mutation of APC with the β-catenin activate Wnt-signal transduction pathway which is observed in majority of colon cancer (Pennisi, 1998)
This process is facilitated by environmental factors and food habits along with mutation or deletion in tumour suppressor gene and of DNA repair enzyme
Figure : Image showing mutations occurring in colon cancer (Feronn et al)
Types of hereditary colon cancer.
Hereditary colorectal cancer has two forms-
1.Familial adenomatous polyposis (FAP, AFAP)
2.Hereditary nonpolyposis colorectal cancer (HNPCC
FAP accounts to about 1% of colon cancer cases where as HNPCC is reported in about 15% of cases have been described in the text . (Cummings 2006)
In another condition known as familial colorectal cancer many families show no hereditary syndrome but have colorectal adenomas or aggregation and sometimes both.
Familial Adenomatous Polyposis (FAP) :
Familial Adenomatous Polyposis is an autosomal dominant disease, which accounts for nearly one percent of colorectal cancers. Patients with this conditon develop numerous adenomas in the colorectum. (Bülow)
Mutation or defects in the Adenomatous Polyposis Coli (APC) causes FAP. Heterozygotes carry a copy of mutated APC gene in familial cases leading to the formation of 100-1000 polyps in the colon and rectum.
The location where the gene gets mutated results in two types of FAPs.
Mutations in the 5' half of the APC gene causes classical familial adenomatous polyposis (FPC). (Miyoshi Y 1992 May 15).Mutations in the 3' half results in attenuated familial adenomatous polyposis ( AFAP)
Autosomal recessive familial adenomatous polyposis (AFAP) is a result of mutations in MUTYH gene (MYH-associated polyposis).
These mutations stop cells from correcting mistakes which are caused when DNA is copied (DNA replication). These mistakes lead to increase in cell growth, leading to colon polyps causing cancer.
Hereditary Nonpolyposis Colorectal Cancer (Lynch) syndrome HNPCC:
Hereditary Nonpolyposis Colorectal Cancer doesn't show any polyposis formation, which is seen in FAP.
Germline mutations in more than 4 genes that code for MMR ( mismatch repair gene) system are mutated resulting in Hereditary Nonpolyposis Colon Cancer , these genes may include hMSH2, hMLH1 ,hMSH3, hMSH6, hPMS1 , hPMS2, EXO1.
Most of the HNPCC cases show germline mutations of hMSH2 and hMLH1. hMSH2 is present on chromosome 2p and chromosome 3p is the position where hMLH1 is present. (Bronner CE 1994 Mar 17)
In few cases hPMS1 and hPMS2 mutations are also seen in few families causing HNPCC. (Papadopoulos N 1997)
These mutations cause errors in DNA mismatch repair gene( MMR).(Wafik S. El-Deiry,Humana Press, 2003 ) In this tumour the MMR gene is mutated, resulting in DNA instability (Microsatellite Instability) and DNA replication errors(RER+), finally causing tumours formation (Müller A 2002)
Microsatellite Instability (MSI):
Mutations involved on short motifs of randomly repeated nucleotides sequences caused due to replication errors or mutated mismatch repair (MMR) gene resulting in the alteration of the size of the microsatellite and change in position of the nucleotide sequences, this phenomenon is known as microsatellite instability. In HNPCC Microsatellite Instability is seen in high frequency MSI-H. (Poulogiannis G 2010 Jan).Due to promoter methylation inactivation of mismatch repair gene MLH1 is caused, leading to High level of Microsatellite Instability (MSI-H). Promoter hyper methylation commonly occurs in tumours, leading to silencing of tumour-related genes or tumour suppressor genes (Bettstetter M 2007 Jun 1)
Microsatellite instability allows to classify the tumours into Replication Error Positive (RER+) or Replication Error Negative (RER-) (Koike J 1997 oct)
Replication Errors (RER):
Replication errors are specific feature of both sporadic and hereditary colorectal cancers. RER is always connected with defects and mutations in DNA mismatch repair genes. Positive replication error (RER+) describes a subgroup of tumours belonging to HNPCC.
RER (Replication Errors) are linked to different cancers forms, which are linked to mutated MMR gene and are observed in both the forms of colorectal cancer. (Ying Wu April 1997)