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Cancer is a word used for diseases where abnormal cells divide without control and invade other tissues. 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 spread to other body parts through the lymph and the systems.. Oncogenes are the genes that render immortal nature of the cell; these cells grow unchecked leading to the formation of visible Tumours. (Mark Stokes, The Rosen Publishing Group, 2005)
Colon Cancer is a type of malignant tumour that occurs in the large intestine, which is a common type of cancer affecting both men and women. 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 cause cancers. Sporadic and hereditary cancers differ in different ways. In case of hereditary cancer few mutations are inherited, while in sporadic cancer mutations oc-curred spontaneously..
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 (>)
MUTATIONS INVOLVED IN COLON CANCER:
Mutation of genes such as APC, p53, K-ras occur in majority of colorectal cancer.(>)
APC gene: :) () .
Adenomatous Polyposis Coli is a tumour suppressor gene which controls the expression of the gene which controls cell division. APC genes are known as gatekeeper in colorectal cancer. It encodes a 2843-amino acid protein Germline mutations occurring in the APC gene which is located on the chromosome 5q21 leads to the increased cell proliferation and results in the formation of polyps. Familial Adenomatous Polyposis is caused due to the mutated APC gene. Polyps are benign tumours made of up clones of cells carrying a APC mutant gene.
Somatic mutations in the APC gene were clustered within a small region of exon 15, designated as MCR (mutation cluster region)
In the APC gene somatic mutations were clustered in a region of 15 exon, this region is known as Mutation Cluster Region (MCR)
The majority of APC mutations were found to be frame shifts mutations, which introduce a premature stop codon
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 Human Hereditary Principles and Issues, seventh Edition, Thomson) (chart 1)
Inactivation of the APC tumour-suppressor gene is said to be the first event in colorectal (colon) carcinogenesis process causing the formation of Polyps ,which is followed by mutations in K-Ras oncogene on the chromosome 12p, allelic loss tumour suppressor gene in deleted colon cancer ( DCC) on chromosome 18q on chromosome and loss of short arm on 17p which are associated with mutations in p53 tumour suppressor gene causing a loss of function and allowing development of benign tumour to malignant tumour . In this process mutation of APC with the -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 (Bertagnolli et al.,1997).
Types of hereditary colon cancer.
Hereditary colorectal cancer has two forms
1.Familial adenomatous polyposis (FAP, AFAP) which is caused because of the germline mutations that occur in Adenomatous Polyposis Coli (APC gene) ?)
2.Hereditary nonpolyposis colorectal cancer (HNPCC), caused because of the germline mutations in mismatch repair genes.
FAP accounts to about 1% of colon cancer cases where as HNPCC accounts to about 15% of cases have been described in the text (Michael R. Cummings, Human Heredity Principles and Issues)
13 16Many families show colorectal cancer aggregation or adenomas, or both, showing no association with any hereditary syndrome; this is collectively known as familial colorectal cancer.2
Familial Adenomatous Polyposis :
FAP is an autosomal dominant disease, which accounts for nearly 1% of colorectal cancers. In this case patients develop hundreds to thousands of adenomas in the colorectum. (Herrera L. Familial adenomatous polyposis. New York: Alan R. Liss, 1990.)
The cause of FAP is mutation of the APC gene(adenomatous polyposis coli), which is located on 5q21 chromosome.5 . Mutated APC leads to the formation of polyps. 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 cause classical familial adenomatous polyposis (FPC). (o)
Mutations in the 3 half results in attenuated familial adenomatous polyposis( AFAP)
Autosomal recessive familial adenomatous polyposis is caused by Mutations in the 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 and colon cancer.
Hereditary Nonpolyposis Colorectal Cancer (Lynch) syndrome:
HNPCC is caused due to germline mutations in at least 7 genes that code for MMR system are mutated, these genes include hMSH2, hMSH3, hMSH6, hMLH1 , hPMS1, hPMS2, EXO1 but germline in hMSH2 which is located on chromosome 2p and hMLH1 which is on chromosome 3p account to majority of HNPCC cases. These mutations cause errors in DNA mismatch repair gene( MMR).( Mary S. Melton, Wafik S. El-Deiry,Humana Press, 2003 ) In this tumour the wild type MMR allele is lost causing alteration in gene resulting in DNA replication errors and making tumours likely.(Aaltonen et al.1993;Fishel et al.1993), and in DNA instability (Microsatellite Instability) () Microsatellite Instability (MSI) :
Mutations in short motifs of randomly repeated nucleotides sequences caused due to replica-tion errors or mutated mismatch repair (MMR) causing the alteration in the size of the mi-crosatellite is known as microsatellite instability Due to promoter methylation inactivation of mismatch repair gene MLH1 is caused, leading to High level of Microsatellite Instabil-ity(MSI-H). Promoter hyper methylation commonly occurs in tumours, leading to silencing of tumour-related genes (tumour suppressor genes)1*. Microsatellite instability allows to classify the tumours into Replication Error Positive (RER+) or Replication Error Negative ( RER-)( 2009 Jensen et al; licensee Biomed Central Ltd.)
Replication Errors (RER): Replication errors, are specific feature of hereditary colorectal cancers. These replication errors are detected by microsatellite-marker. (*)
The positive replication error (RER+) phenotype describes a subgroup of tumours belonging to HNPCC. (>)RER (Replication Errors) are linked to DNA mismatch repair genes defects in other types of cancers and are observed in both the forms of colorectal cancer.