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Cancer is described as a disease due to uncontrolled growth of cells or cells in a tissue. Depending on the location of the cell, there are different types of cancer over 100. This uncontrolled growth produces a mass of cells called tumor (Leonard Maurice Franks 1997) . Depending on the movement of the cell it is classified as benign tumor and malignant tumor. Benign tumor does not cause cancer, it only grow at one place and does not invade other tissue. Malignant tumors cause cancer due to metastasis property (Organisation 2002). The division of cancer cells is due to overreaction for growth signals. Tumor requires continuous blood supply to grow and spread (Gary S. Stein 2004). In some cancers two mutations are enough like in retinoblastoma. Other requires more mutations for producing oncogenes like colon cancer (Cummings 2006). Colon is the part of large intestine that forms about six inches. It plays main role in absorbing water, minerals and nutrients and to pass the waste material (Fayed 2008). If cancer forms in colon then it is called colon cancer. Usually colon cancer initially as begnin tumor (called as polyps) later develops into malignant. Hence polyps are called colon cancer precursor which are normally present. When mutations occur in polyps based on the APC and microsatellite instability it is classified as FAP and HNPCC. Genes involved in DNA repair and tumor suppressor showed vision for colon cancer (Cummings 2006).
Physical carcinogens like ionizing radiation and ultra violet (WHO 2009).
Chemical carcinogens like arsenic, aflatoxin, asbestos, tobacco smoke (WHO 2009).
Biological carcinogens like bacteria, viruses and parasites (WHO 2009).
Aging is a factor for cancer; it means old people are more affected than young ones because the cell cycle repair mechanisms became less effective (WHO 2009).
Cancer affecting the cellular processes:
Cell cycle: In cancer development two types of control mechanisms are found. They are protein phosphorylation's that occur serially and a regular of checkpoints (Kathleen Collins 1997). Checkpoint 1 and checkpoint 2 are disrupted in both sporadic and hereditary forms of cancer. Cyclin dependent kinase cause the cell cycle to move from G1-S phase or G2-M phase. Maturation promoting factor activates cell cycle.p53 stops the cell cycle (Jiri Bartek 1 2003).
Apoptosis: Reduced cell death is called apoptosis.it is caused by damaged cell or during tumor development. Two mutations are initiating apoptosis.p53 gene is inactivated by mutation cause cell death normally. Other mutation is on bcl-2 which is a proto-oncogene, when mutated it inhibits apoptosis being triggered that stops cell death. B lymphocytes act as bcl-2 protein.bcl-2 alteration is due to chromosomal translocation (C. S. Potten 2004).
Angiogenesis: Blood vessels which are formed newly are called angiogenesis which is responsible for growth of a tumor and survival. They supply oxygen and nutrients for the tumor (Dieter Marme 2007).
CANCER AS A GENETIC DISEASE:
Cancer is a genetic disease fundamentally, due to mutations and epigenetic changes. In DNA sequences the genes get altered then the information is altered which is passed to the next generation when cancer cell is divided. Majority are somatic mutations, which is caused in body cells. Germ line mutations are that occur in germ cells (fertilized egg) can pass through hereditary (Nussbaum 2008). Usually for cancer cells single mutations are not enough they only influence malignant growth. Further mutations cause malignant transformation (Blakeslee 2008).
INHERITED VERSUS AQUIRED MUTATIONS:
Inherited mutations are also called germ line mutations because mutations are carried by germ lines and it affects to the next generation. Acquired mutations are called somatic mutations these are not inherited because it is caused in body cell. Almost 90% of the mutations are somatic (21).
GROUPS OF GENES INVOLVED IN CANCER:
These genes are responsible for cancer.
Oncogenes: Proto-oncogenes are normally present in cells. When a mutation occur it develop into oncogene which leads to formation of growth of cells without control (Ford 1991).
Tumour suppressor genes: These genes supresses the uncontrolled growth of cells. Thus it retards the cancer formation. When a mutation occurs normal growth can develop into tumour (Ford 1991).
Care taker genes: These genes are called DNA repair genes. These are a form of tumour suppress genes because they guard the damaged DNA by repairing (Ford 1991).
INHERITANCE OF COLON CANCER (FAP AND HNPCC):
Microevolution is a process that occurs through series of stages. Two types of hereditary colon cancer are there:
1. Familial Adenomatous polyposis (FAP)
2. Hereditary Nonpolyposis Colon Cancer (HNPCC) (Miriam Komaromy 2000,2001).
In colorectal cancers these changes are observed:
Loss or mutation of APC expression in Ts gene (5q) is the key to detect the early lesions (Read.A 2004).
In early adenomas due to DNA hypo methylation in CpG islands become hyper methylated in specific of the promoters (Read.A 2004).
KRAS oncogene becomes active due to mutations (12 p) this cause to develop early stage to intermediate stage of adenomas (Read.A 2004).
Colorectal cancer is best developed in evolution because it can be clearly observed at all stages in restricted colon who are suffering with familial adenomatous polyposis (FAP). It is inherited by autosomal dominant pattern (Miriam Komaromy 2000,2001). In colon the epithelium is differentiated as normal epithelium (microscopic crypt foci) and benign epithelium (named as polyps or adenomas). Depending on the length of foci the adenomas are early (<1cm), intermediate (>1cm without foci) and late (>1cm with foci).Later on these stages eventually become metastasize. Many tumors are caused due to loss or mutation or activation of certain genes (Read.A 2004).
FAP is caused due to mutation of mutation of chromosome 5 on APC gene it is considered as first step. One mutation does not cause colon cancer; there are several intermediate mutations which will develop into final stage form. Due to mutation of chromosome5q on APC causes normal colon epithelium to develop adenomas. Then mutation on k-ras 12p form intermediate adenoma. In both allele mutation is caused in 18q DCC by deletion which will develop adenoma with villi. Finally, mutation on both alleles by deletion of 17p p53 cancerous adenoma is formed which is a stage of colon cancer (Cummings 2006).
Many mutations are gathered in a single cell. Each mutation develops a change in a cell. Growth and division of cells form a begnin tumor, then enlarging and transforming progressively escapes from cell cycle controls to become metastatic tumor. Later mutations develop to form tumors at several places (Cummings 2006).
APC: Adenomatous polyposis coli are represented as APC (Miriam Komaromy 2000,2001). Mutation occurs mostly on exon 15 which contains coding sequence, and then FAP is caused (Ross 1998). In APC gene both copies are mutated so heterozygosity loss is caused and time is also a factor for development of colon cancer (Ross 1998). The function of APC is to prevent Wnt signalling by degrading beta catenin and by nuclear localization. The component of destruction complex (APC bound to Axin) degrades beta catenin by proteolysis as shown in figure 1. In Wnt signalling, beta catenin oncogene attaches with nuclear patterns that produces a transcription signal initiate's cellular activation as in figure 2. The activation of Wnt signal is the first step to form colorectal cancer. If a specific mutation occurs in APC gene, beta catenin releases and activated. In sporadic cancers APC is inactivated through somatic mutations in which both alleles are mutated. In germ line the cancer is caused through carriers, there is a chance of 100% to get FAP at age of 40 (Sanford D. Markowitz 2009).
It is also called as Lynch syndrome. HNPCC is caused due to mutations in any one of the DNA mismatch repair genes (Miriam Komaromy 2000,2001). They are MLH1, MSH2 and MSH6. The genes involved like tumour suppressor genes and DNA repair genes. In HNPCC patient's microsatellite instability is observed. Microsatellite is a repeat sequence of base pairs in a DNA. If there a loss in mismatch repair gene the microsatellite length is not conserved. This produces a mutation in neighbouring genes affecting the action of tumour suppressor gene and oncogene (Ross 1998). Primary mutations in MLH1, MSH2 cause defects in germ line lead to colorectal cancer. About 80% develops in this pattern. The germ line mutations in MSH6 contribute about 1%. Non familial colon cancer is due to somatic inactivation of MLH1mismatch repair gene, in which both genes silencing occurs in promoter region by inactivating methylation of promoter (Sanford D. Markowitz 2009). In few patients it was observed in genes like MLH3 and PMS2 in HNPCC with microsatellite instability (Asad Umar 2004). Rarely PMS1 also involved in HNPCC.
In carries with mutations in MSH2 has greater risk than MSH1 (H. F.A. Vasen 2001). The reason for this is two complexes are formed with mutS homologues like MSH6 and MSH3; these protein complexes identify DNA mispaired bases. MLH1forms a complex with PMS2 and interacts with protein complex attached to mispaired DNA. Then attachment of protein complexes causes removal of mispaired DNA and DNA resynthesis occurs (H. F.A. Vasen 2001). The similarity and difference in both is the result of loss of function completely, In DNA strands homologous recombination is controlled by MSH2 respectively (H. F.A. Vasen 2001). Also, MSH2 play role in transcription-receptor coupled pathway.
Due the mutations two forms of syndromes are observed in colon cancer through hereditary. STK11 gene 19q13.3-q13.4 chromosome is mutated then syndrome is called "peutz-jehers". Another mutation is on SMAD4 or DPC4 18q21.1 chromosome then syndrome is named as juvenile polyposis (JPS). Sometimes the mutation is caused on PTEN 10q23.3 chromosome (Sensen 2002).
Finally it was noticed that HNPCC and APC mutations about 60% follow different route. In multi-step evolution process early mutations are more important than later mutation because the normal cell behavior can be changed. Gate keeper hypothesis by Kinzler and Vogelstein discovered that a particular gene in a cell population is responsible for a constant cell number should be maintained which is called gate keeper. Mutation in gatekeeper leads to permanent imbalance in cell division and cell death. Other mutations in other genes have no effect if gate keeper is function is correctly working. People inherited with FAP will be healthy and normal up to cell is prone to second mutation occurs (Read.A 2004).