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INTRODUCTION TO CANCER
Cancer is a disease in which group of cells show uncontrolled growth, invasion, undesirable cell division and sometimes it may lead to metastasis.
In cancer, cells constantly become old and will die. Normally New cells are produced to replace them in an orderly and controlled manner. Cancer is formed due to damage of DNA and the cells cannot be repaired. All types of cancers will be started due to out of controlled growth of abnormal cells, and develops in to a lump which is called a Tumor.
Tumor can be either Benign Tumor (OR) Malignant Tumor. Benign tumor is not a cancerous; they do not grow and spread to the extent of cancerous tumor. On the other hand Malignant tumor grows and spread to the other parts of the body and it is also called as METASTASIS.
Mutations involved in cancer:
Mutations are the fundamental cause of cancer. One of the main important characteristics of cancer is deregulated cell proliferation and the loss of cell differentiation. There are different types of genes which controls cell behavior, cell growth and death. The cell with such types of mutations leads to tumors.
Mutations may occur in genes when a cell divides. Since the mutations that only occur in the cancer cells cannot be passed to be one to one. So mutations in cancer genes are inherited.
Mutations are not only inherited but majority are sporadic. There are different types of mutations present in cancer. They are Point mutations, deletions, amplification and chromosomal rearrangements.
There are two main important types of cancer genes are.
1. Oncogenes and
2. Tumor suppressor gene.
Oncogenes and proto-oncogene:.The mutated forms of normal genes are called as proto-oncogenes. Proto-oncognes are derived from normal cellular genes which often divides cells and further differentiates. When mutation is done the cell divides too fast which leads to the cancer. In order to have a oncogen effect one allele of proto-oncogen need to be over active.
Functions of proto-oncogenes are:
1. Growth factor
2. Signal transducers
3. Amplification and for control the transcription of genes..
Some examples of the oncogenes are:
B-RAF, which is used for the intracellular signaling. when the gene is mutated it leads to the melanoma.
HER2 is used for the growth factor receptor .when the gene is mutated it leads to the breast cancer.
RAS is the most important signal transducer gene. The main members of RAS family HRAS, KRAS, and NRAS which are coded for a protein, P21, which binds to the GTP and has activity. When RAS protein is bound to the GDP it is in inactive position when it bound to the GTP it gets activated. When it is mutated in certain cancer like colorectal cancer.
Some more genes like APC, MLH1, MLH2, which are used for the DNA repair and also acts as a scaffold protein .when the gene is mutated it leads to the colorectal cancer.
TUMOR SUPPRESSOR GENE:
These are the genes that help to protect against cancer by controlling cell proliferation, trigger apoptosis pathway and repairing damage to genetic code (or) DNA. when the inactivation of the suppressor gene, it leads to cancer due to out of cell control. TSG which gives information to provide different proteins which involves in preventing cancer and also it is referred as" GATEKEEPER" because they control the cell division and the growth of the cancer. When the loss of function leads to the mutation and cancer. This type of silencing gene is called as "EPEGENETIC" because no mutation sequence of gene occurs.
EXAMPLES OF TUMOR SUPPRESSOR GENES:
One of these is p53 gene which frequently inactivated gene in human cancers. The p53 genes can initiate DNA repair, cell-cycle arrest and importantly apoptosis. Particularly p53 itself regulates MDM2 in cancer cells proven that which is useful in the development of targeted therapies.
RB which is a tumor suppressor gene located on the chromosome 13q14 which regulates transcription factor and translation factor. The mutation occurs due to the loss of g1/s and s phase check point functions so it leads to the retinoblastoma, osteosarceoma and breast cancer.
HEREDITARY AND SPORADIC FORMS OF CANCER:
Hereditary cancers also called as germ line mutation or Inherited mutation are caused by a gene change passed from parent to their children .where as Sporadic form of cancer often occurs earlier than hereditary cancer .
People with hereditary cancer inherits a mutated gene from their parents. Every cell in the body contains the mutation and can pass the altered gene along to the children .
Mostly 75% of cancers are Sporadic cancers. Generally this type of cancer will occur due to mutations. Sporadic cancers doesn't carry any high risk mutations and not having any familial history.
Sporadic form of cancer will be caused due to any exposure to sun, radiation or by any chemicals or any random events in the cell, causes the cancer cell mutation. .
For example TUMOR SUPPRESSOR GENE is implicated in sporadic cancer. In the sporadic breast cancer, a mutation occurs in the genes like BRCA1 and BRCA2 when the copies of both are lost or mutated.
TP53 is the most common gene seen in sporadic form of cancer. The result of mutations in the gene leads to a wide range of cancers which includes breast, ovarian, colon and rectal, skin, lung, liver cancers and cancers of the bone.
FORMS OF HEREDIATRY COLON CANCER:
Colorectal cancer is the most important among all the cancers and it is the 2nd largest cancer which is mostly seen in western countries. About 5-10% of colon cancers are believed to be hereditary. Mainly this cancer will be seen in younger age due to the dietary factors.
The best known hereditary colon cancer syndromes are:
1. HNPCC (HEREDIATRY NONPLYPOSIS COLORECTAL CANCER).
2. FAP (FAMILIAL ADENOMATOUS POLYPOSIS).
HNPCC (HEREDIATRY NONPLYPOSIS COLORECTAL CANCER).
HNPCC is also called as LYNCH SYNDROME. Both sporadic and hereditary colorectal cancer are shown due to the mismatch repair of genes. This mismatch repair gene leads to a mutation and which allows accumulation of mutation lead to the tumor or colon cancer HNPCC represents 20% of colorectal cancers. HNPCC is a disease of an autosomal dominant mode of inheritance. It simultaneously develops synchronous and metachronous colorectal neoplasms and extra colonic tumors.
Genes involved in the HNPCC:
The different types of genes which associated with HNPCC are MLH1, MSH2, PMS1, PMS2, MSH6, in which MLH1, MSH2 cause mutations and lead to the colon cancer, Mutations of any genes can prevent repair of DNA mistakes. As the cells continue to divide in an uncontrolled manner which causes cancer.
Mostly genes like MLH1, MSH2, PMS1, and PMS2 which causes colon cancer frequently.
MLH1 is also called as "mutl homolog 1". The MLH1 gene gives the information about making a protein and also plays an important role in DNA repair. In the preparation of cell division some mistakes may appear in DNA and they can be minimized by this protein. This protein form complex with PMS2 protein is used for the repair in misleading during replication of DNA. The mismatch of the DNA will be replaced with corrected DNA sequence.
MLH1 gene is located on chromosome 3p21. The mutations in MLH1 occurs due to the alteration of protein sequence which may lead to the colon cancer. If the MLH1 protein is absent during the cell division, the cell divides continuously and accumulates in DNA which leads to the tumor in colon cancer or any other part of the body.
The other name of the gene is "mutS homolog 2". This is located on the chromosome 2p21. The MSH2 gene plays an essential role in making a protein sequence and for DNA repair. MSH2 protein joins with 2 proteins and forms active protein complex with MSh6 or MSH3, which is used for the mistakes made during DNA replication.
During the cell division, if the MSH2 protein is absent or inactivated the cell division becomes uncontrolled. So it cannot produce the protein sequence correctly, leading to the mutation which further turns to tumor in the colon or any other part of the body.
The other name of this gene is "Post meiotic segregation". This is located on the chromosome "7p22". It gives instructions to make a new protein and also plays an important role in DNA repair which fix problems encountered during the cell division. PMS2 protein combines with MLH1 to form a active protein complex which is used to repair made by during replication of DNA.
Mutation in the PMS2 is reported only 2%. When the protein is inactivated it cannot repair the mistakes during DNA replication and leading to uncontrolled cell division which leads to the formation of tumor in colon or other part of the body.
FAP (FAMILIAL ADENOMATOUS POLYPOSIS).
FAP is an "AUTOSOMAL DOMINANT INHERITENT" occurs for 1-2% of colorectal cancers. It is characterized significantly by the presence of hundreds or thousands of polyps or adenomas throughout the colon and rectum.
This gene is also called as "APC GENE OR ADENOMATOUS POLYPOSIS COLI". APC is a tumor suppressor gene which is located on the chromosome 5q21. This region is divided in to 15 exons and which encodes a big protein (contains 2843aa). This APC protein contains various domains which is used for oligomerization and for different intracellular proteins .
FUNCTIONS OF APC GENE:
It plays an important role in the "cell adhesion, signal transduction, transcriptional activation".
APC is a tumor suppressor protein plays an important role in "WNT signaling pathway".
It also regulates the degradation of" beta-catenin".
WNT signals influence the stability of protein complex which contains beta-catenin, and glycogen synthesis kinase 3.
Absence of WNT or presence of inactivated APC protein leads to the degradation of beta-catenin.
Mutation Analysis OF APC GENE:
Mostly mutations will be seen in FAP due to the "insertions, deletions, and nonsense mutations, loss of APC gene". Some of the genes affected in the syndrome are "P53 gene", "RB1 gene" and "P16gene" respectively. Germ line mutation in the APC gene are found mostly in FAP where 70-80% of sporadic colorectal adenomas and somatic APC mutations. Mutations in APC lead to stop codons there by truncated proteins will be produced which lose their beta-catenin binding sites. The mutations in colon cancer are due to the loss of APC function or microsatellite instability which results loss of mismatch repair function. Loss of normal APC function is seen in both familial and sporadic colon cancer.
MiRNA is also plays an important role in cell development, differentiation, proliferation, and apoptosis. Several mi RNA expression lead to the colorectal cancer specific WNT pathway might lead to the crc.
Inactivation of APC tumor suppressor gene also initiates colon cancer. The down regulation of the APC protein mediated by beta-catenin and T cell transcription factor 4. The activated mutation of beta-catenin alters the functional phosphorylation sites, which results in the mutations of tumor.