The Mutational Basis Of Hereditary Colon Cancer Biology Essay


Colon cancer is one of the sever types of cancer. It is the third most commonly diagnosed cancers in United States with about 150,000 men and women are newly affected each year and among this 50,000 Americans die each year because of this dreadful disease. Life time risk of an individual affected by colon cancer is about six percent. Because of its dreadful nature it has been a special interest in the scientific area to prevent its dangerous effects. The present topic depicts the mutational basis of hereditary colon cancer.

The human body consists of large number of cells and each cell consists of 46 chromosomes and these chromosomes contain large stranded DNA. This DNA consists of thousands of genes and these genes carry the genetic information. The different genes perform different functions like cell division, growth, body colour etc. The genes which are involved in cell multiplication and growth when mutated cells may multiply and grow without control. This continuous growth leads to formation of Polyp. These polyps in turn grow into cancer if additional genetic changes occur and this defines the cancer as genetic disease. These cancers may be monoclonal (derived from one mutated cell) or polyclonal (multiple cells are transformed independently).

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This accounts for about 15% of colorectal cancer. The unique repeated segments of DNA are called Microsatellites consisting of cytosine and adenine nucleotides. In tumour there is an alteration of these nucleotides found indicating formation of new alleles and failure of DNA replication. This DNA replication failure is known as microsatellite instability (Aaltonen et al., 1993) .The major changes include large intact chromosome compliment as a result of defect in the DNA mismatch repair system. This is involved in Lynch syndrome.

The loss of single APC gene does not leads to complete formation of carcinoma. The various genes like 5q, 12p, 18q and 17p when mutated are involved in various stages of colon cancer. The diagram below represents the various stages of colon cancer and the various genes involvement.

These are normal genes involved in tumour suppression in somatic cell hybrids. These genes show dominant pattern of inheritance in general and in the case of somatic cells they show recessive behaviour. Mutations in these genes results in loss of function. These are the most important class of genes responsible for both Familial Adenomatious Polyposis and Juvenile Polyposis. (Markowitz et al., 1995)



Hereditary Pattern  

Predominant Cancer  




Colon, intestine,etc




Multiple (including intestine)


Attenuated polyposis



TP53 (p53) 



Multiple (including colon)


Juvenile polyposis




Oncogenes are normal genes which function in dominant fashion, when activated or expressed results in the development of disease (Duesberg, 1983). Oncogene products are involved in the control of cell cycle, growth and differentiation (Bishop, 1981). When these genes are activated forms cancer.

The various Oncogenes and their role are presented below

Sis-oncogene- Involved in cell growth and division

fms-oncogene-Receptor for colony-stimulating factor 1

erB1-oncogene-gene for epidermal growth factor receptor

RAS-oncogene-Acts in signal transduction pathway

MYC and FOS-oncogenes-Codes for proteins which are involved in the regulation of DNA transcription or replication

Stability genes:

This consists of mainly mismatch repair genes which are involved in Lynch syndrome. The other genes of this category is depicted below

Repair/stability genes


Hereditary pattern

Predominant cancer




Multiple (including colon, uterus, and others)

MYH (MutYH) 

Attenuated polyposis






Multiple (including colon)

Epigenetics of Colon cancer:

Epigenetic events do not happen as a result of changes in the DNA sequence but changes occur during cell division. Apart from genetic changes, epigenetic changes like DNA methylation results in the initiation and progression of colorectal cancer. In the case of hereditary colon cancer syndromes the susceptibility is inherited dominantly and the cancer develops only when the genetic and epigenetic alterations accumulate in a progressive way.


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DNA methylation:

It plays a significant role in the development of tumours .Hypo-methylation causes increase in gene expression and plays a role in the activation of oncogenes such as K-ras. Hypermethylation and Hypomethylation coexist in different areas of genome in various tumours.

Types of Colon cancer:

Colon cancer is mainly divided into three types. They are

Sporadic Colon Cancer

Familial Colon Cancer and

Hereditary Colon Cancer

Among the above three classes of Colon cancer, Hereditary colon cancer is the most sever and common form of colon cancer.

Hereditary Colon cancer:

The two primary types of hereditary colon cancer are

1. Familial Adenomatous Polyposis (FAP) and

2. Hereditary Non Polyposis Colon Cancer (HNPCC)

These hereditary colon cancer syndromes are caused by specific inherited mutations .These can affect multiple members of a family and the patients who have inherited one of these syndromes are likely to get 90-100% of colon cancer. In US 5% of all colon cancers are due to these syndromes.

1. Familial Adenomatous Polyposis (FAP) and

It is an autosomal dominant disorder affecting one in 13,000 births. FAP is characterised by large number of small adenomatous polyps develop on colon. The gene responsible for this syndrome is Adenomatous Polyposis Coli (APC) gene, which is present on chromosome 5 with about 19 exons 16 are alternately expressed. This gene acts as a tumour suppressor and regulator of other genes when functions normally. The characteristic future of FAP is presence of more than 100 polyps in the colon.

The APC protein along with glycogen synthase kinase-3β, phosporylate cytoplasmic β-catenin. β-catenin is in contact with E-cadherin to facilitate cell -cell contact. Mutation of APC genes leads to stabilization of β-catenin resulting in nuclear translocation and in concert with T-cell factors (TCF) activate target genes like C-myc, cyclin D11, MMP-7, Axin2/conductin and EphB/ ephrin B

The p53 gene located on chromosome I7 acts as tumour suppressor type gene and produces protein P53 containing 393 amino acids. P53 is involved in cell cycle arrest, stimulation of DNA repair and promotion of cell death. Point mutation in p53 results in loss of its function and development of colon cancer (Kern et al., 1992).


3. Hereditary Non Polyposis Colon cancer:

It is also known as Lynch Syndrome. This inherited colon cancer is the most common type of colon cancer accounting of about 3-5% of all colon cancer cases. It is an autosomal dominant inheritance affecting right colon at 30's-40's with 80% life time risk. Germline mutations in DA mismatch repair genes are found in HNPCC patients.

DNA mismatch repair genes:

These genes are involved in repair and recognization of DNA mismatches, by binding to mismatches, separating, destroying and resynthasizing new DNA strands. Germline mutations in these genes develop cancer. These cause the Lynch syndrome. The various DNA mismatch genes involved in HNPCC are

hMSH2 present on chromosome 2, accounting for about 60 percent of HNPCC colon cancer cases.

hMLH1 present chromosome 3, accounting for about 30 percent of HNPCC colon cancer cases.

hPMSI present chromosome 2, accounting for about 5 percent of HNPCC colon cancer cases.

hPMS2 present chromosome 7, accounting for about 5 percent of HNPCC colon cancer cases.

C - A - G - C - T

G - T - C - A - C - A

C - A - G - C - T C - A - G - C - T Nucleotide added DNA not repaired and

G - T - C - G - A G - T - C - G - A copied on incorrectly in new cells

C - A - G - C - T

G - T - C - G - A

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