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Molecular Genetics of Cancer

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It has been established that cancer is a genetic disease, characterized by interplay of mutant form of the oncogenes and tumour suppressor genes leading to the uncontrolled growth and spread of cancer cells. While some of the mutant genes may be inherited, others occur in the somatic cells of the individuals, which can divide and form tumour. Completion of Human Genome Sequencing Project has generated a wealth of new information about the mutations that trigger a cell to become cancerous. It has now been possible to understand to great extent the relationship between genes and cancer, and how mutations, chromosomal changes, viruses and environmental agents play a role in the development of cancer. In this chapter current understanding of the nature and cause of cancer has been presented.


During mitotic cell division, in every cell, all chromosomes must duplicate faithfully and a copy of the each has to be distributed to progeny cells. Progression through the cell cycle is controlled by the activities of many genes. At different stages in the cell cycle there exist control points (G1, G2, S, and M stages) at which the cell cycle is arrested if there is damage to the genome or cell-cycle machinery. Such mechanism helps to repair the damage or destroy the cell. Through this process it is possible to prevent the possibility of dividing a defective cell and from becoming cancerous.

Proteins and enzymes called cyclines and cycline-dependent kinases (Cdks) respectively are the key components that are involved in the regulation of events in the checkpoints. At the G1-to-S checkpoint, two different G1 cycline/Cdks complex forms, resulting in activation of the kinase. The kinase catalyzes a series of phosphorylations (addition of phosphate group) of cell-cycle control proteins, affecting the functions of those proteins and leading to translation into the S phase. Similarly, at the G2-to-M checkpoint, a G2 cycline binds to a Cdk to form a complex. Phosphorylation of the Cdk by another kinase keeps the Cdk inactive. Removal of a phosphate group from Cdk by a phosphataes enzyme activates the Cdk. Thereafter, the cell moves from S to M phase, due to phosphorylation of proteins by Cdk.

13.2.1 Regulation of Cell Division in Normal Cells

Division of normal cells is regulated by both extracellular and cellular molecules that operate in a complicated signal system. Steroids and hormones made in other tissues are extracellular molecules, which influence the growth and division of some other tissues. These extracellular molecular are known as growth factors, which bind to specific receptors on their target cells. The receptors are proteins that span the plasma membrane, and the growth factor binds to the part of the receptor which lies outside of the cell. The signal is then transmitted to an intracellular part through the membrane-embedded part of the receptor. Thereafter, the signal is relayed through a series of proteins, which ultimately activate nuclear genes involved in stimulation and division of cells through transcription factors (Fig 13.1a). In the opposite direction, inhibition of cell growth and division is regulated by growth-inhibiting factors (Fig 13.1b). The process which involves either growth-stimulatory or growth-inhibitory signal after binding of the extracellular factor to the receptors is called signal transduction, and the proteins involved in such process are called signal transducers. Cell division in normal cells takes place only when there exist balance between stimulatory and inhibitory signals from outside the cells. Any mutation either in the stimulatory or inhibitory genes or genes encoding cell surface receptors involved in cell cycle control may cause imbalance and loss of control of cell division.


Clinically, cancer is defined as a large number of complex diseases that behave differently depending on the cell types from which they originate. However, at the molecular level, all cancers exhibit common characteristics, and thus they can be grouped as a family. All cancer cells share two fundamental properties: unregulated cell proliferation, characterized by abnormal growth and division, and metastasis, a process that allow cancer cells to spread and invade other parts of the body. When a cell loses its genetic control over its growth and division, it may give rise to a benign tumour, a multicellular mass. Such tumours may cause no serious harm and can often be removed by surgery. However, if cells of the tumour also acquire the ability to break loose, enter the blood stream, invade other cells, they may induce formation of secondary tumours elsewhere in the body. Such tumours are called malignant, which are difficult to treat and may become life threatening. A benign tumour may become malignant through multiple steps and genetic mutations.

Mutations in three kinds of genes can leads to cancer. These are proto-oncogenes, tumour suppressor genes and mutator genes. Mutant proto-oncogenes are called oncogenes, are usually more active than normal cells. The product of oncogenes stimulates cell proliferation. The normal tumour suppressor genes inhibit cell proliferation, while the mutants found in tumour cells have lost their inhibitory function. The normal mutator genes are required to ensure fidelity of replication and maintenance of genome integrity, while mutant mutator genes in cancer cells make the cells prone to accumulate mutational errors.


Most cancer causing animal viruses are RNA viruses known as retroviruses, and the oncogenes carried by RNA tumour viruses are altered forms of normal animal host cell genes. Infection with retroviruses can transform normal host cells to the neoplastic state, and such cells proliferate in an uncontrolled manner to produce tumour. Examples of retroviruses include human immunodeficiency virus (HIV-1), mouse mammary tumour virus, felin leukemia virus, and Rous sarcoma virus. A typical retrovirus particle has a protein core, which often is icosahedral in shape, with two copies of plus-sense (means directly translatable) single stranded RNA molecule (7kb and 10 kb). The core is surrounded by an envelope with virus-encoded glycoproteins inserted into it (Fig 13.2). The virus enters the host cell by interacting with the host cell surface receptor through its glycoproteins present in the envelope.

To understand how retroviruses cause cancer in animals, it is essential to know their life cycle. Rous sarcoma virus (RSV) is one of the earliest retrovirus studied on induction of cancer. When a retrovirus like RSV infect a cell, the RNA genome is released from the viral particle, and a double stranded DNA copy of the genome is made by reverse transcriptase (Fig 13.3). This is known as proviral DNA. The proviral DNA then enters the nucleus of the infected cell, and integrates into the host chromosome at random locations. The integrated DNA copy is called provirus. At the left end of all retroviral RNA genomes consists of the sequence R and U5, and U3 and R at the right end. Powerful enhancer and promoter elements are located in the U5 and U3 sequences (Fig 13.3). During proviral DNA synthesis by reverse transcriptase, the end sequences are duplicated to produce long terminal repeats of U3-R-U5 (LTRs in Fig 13.3), which contain many of the transcription regulatory signals for the viral sequence. The two ends of the proviral DNA are ligated to produce a circle, a double stranded molecule in which the two LTRs are next to each other. Staggered nicks are made in both viral and cellular DNAs, and integration of the viral DNA begins. The viral DNA ends joined through recombination. Integration occurs at this point, and single stranded gaps are ligated. The integration of retrovirus proviral DNA results in a duplication of DNA at the target site, producing short, direct repeats in the host cell DNA flanking the provirus.

The proviral DNA is transcribed by host RNA polymerase II, after integration into the host DNA. The retroviruses have three protein- coding genes for the virus life cycle: gag, pol, and env (Fig 13.3). The gag gene encodes a precursor protein that is cleaved to produce virus particle protein. The pol gene encodes a precursor protein which produces an enzyme called reverse transcriptase, required for the integration of the proviral DNA into the host chromosome. The env gene encodes the precursor to the envelop glycoprotein. The progeny virus particles are produced when transcription products of the entire integrated viral DNA are packed into new viral particles. The new virus particles are released and can infect new host cells.

A retrovirus may induce cancer in the host cells through two different ways. First, the proviral DNA may integrate by chance near one of the cell’s normal proto-oncogenes. The strong enhancers and promoters in the provirus then stimulate transcription of proto-oncogenes present in the host cell at high levels or at inappropriate timing. This leads to stimulation of host-cell proliferation. Second, a retrovirus may pick-up a copy of a host proto-oncogene and integrates it into its genome (Fig 13.4). The integrated oncogene may mutate during the process of transfer into the virus, or it may be expressed at abnormal levels, due to action of the viral promoters. Retroviruses that carry these viral oncogenes can infect and transform normal cells into tumour cells.

Different oncogenic retroviruses carry different oncogenes. Most oncogenic retroviruses cannot replicate as they do not have a full set of life-cycle genes. Thus they cannot change growth properties of the host cells. They are called nononcogenic retroviruses. HIV-1 is a nononcogenic retrovirus. On the contrary, RSV is an oncogenic retrovirus as it can replicate its oncogenes and can affect the growth and division of the infected host cells. Viral oncogenes, genetically called v-oncs are responsible for many different cancers. The v-oncs of RSV is called v-src.

Unlike RNA tumour viruses, DNA tumour viruses do not carry oncogenes. Their mechanism for transforming cells is completely different. They transform normal cells to cancerous state through the action of genes present in the viral chromosome. DNA tumour viruses are found in five major families of DNA viruses which include: papovaviruses, pox viruses, hepatitis B viruses, herpes viruses and adenoviruses.

After infection, the DNA tumour viruses produce a viral protein that activates DNA replication in the host cell. Then, utilizing host proteins, the viral genome is replicated and transformed. After producing large number of progeny viruses, they lyses the host cell and the viruses thus released can infect other cell. Rarely, the viral genome instead of replicating gets integrated into the host genome. Thereafter if the viral protein that activates DNA replication of the host cell is synthesized, this will lead to division and proliferation of the host cell converting normal cell to cancerous state. Basically, the cells move from G0 phase to the S phase of the cell cycle.

The DNA viruses which induces cancers are papillomaviruses (HPV 16 and 18), human T-cell leukemia virus (HTLV-1), hepatitis B virus, human herpesvirus 8, and epstein-barr virus. Some of these viruses cause benign tumours such as skin and venereal warts in humans. Transformation is caused by the key viral genes, E6 and E7, which encode proteins that activate progression through the cell cycle. However, in most of the cases, virus infection alone is not sufficient to trigger human cancers. Other factors like DNA damage, accumulation of mutants in cell’s oncogenes and tumour suppressor genes, are required to induce cancer in multiple pathways. Some transducing retroviruses, their viral oncogenes, viral protein and type of cancer induced is presented in Table 13.1.


Cancer cells are characterized by the presence of chromosomal translocations, deletions, aneuploidy, and DNA amplification. Cultured cancer cells also show similar genomic instabilities. Study of the specific chromosomal defects can be used to diagnose the type and stage of the cancer. For example, chronic myelogenous leukemia (CML) gene C-ABL from chromosome 9 is translocated to the chromosome 22 in the region of gene BCR. The fused ABL-BCR gene encodes for a chimeric ABL-BCR protein, which produces an abnormal signal transduction molecule that stimulates the CML cells to proliferate. The normal ABL protein (protein kinase) acts within signal transduction pathway, transferring growth factor signals from the external environment to the nucleus, thereby control cell division.

Defect in the DNA repair genes can also induce cancer. For example, Xenoderma pigmentosum (XP), a disease in which the skin becomes extremely sensitive to UV light and other carcinogens. Patients with XP often develop skin cancer. Cells of XP are defective in nucleotide excision repair, with mutations appearing in any one of the seven genes whose products are required to carry out DNA repair. Hereditary nonpolyposis colorectal cancer (HNPCC) is also caused by mutations in genes controlling DNA repair. Patients affected by HNPCC have an increased risk of developing colon, ovary, uterine, and kidney cancers. At least eight genes are associated with HNPCC, and four of these genes (MSH2, MHS6, MLH1, and MLH3) control DNA mismatch repair. Mutations in any one of these genes can lead to development of cancer.


Epigenetics includes those factors that affect heritable gene expression but do not alter the nucleotide sequence of DNA. Examples of epigenic modifications are DNA methylation, acetylation and phosphorylation of histones etc. Modifications caused through these processes can be inherited and affect gene expression. X-chromosome inactivation, heterochromatin gene expression are such examples. Cancer cells contain major alterations in DNA methylation. In general, there is much less DNA methylation in cancer cells compared to normal cells. On the other hand promoters of some genes are highly methylated in cancer cells. Apparently these changes lead to the release of transcription repression over the bulk of genes that would otherwise remain silent, while at the same time repressing transcription of genes that would normally regulate functions such as DNA repair, cell cycle, and cellular differentiation. The genes MLH1 and BRCA1, involved in DNA repair mechanism, are transcriptionally silenced by hypermethylation in many cancer cells. Methylation profiles can be used to diagnose types of tumours and their possible course of development.

It has also been observed that histones are also modified in the cancer cells. These modifications are due to mutations in the genes that encode histone acetylases, deacetylases, methyltransferases, and demethylases. Since the epigenetic modifications are reversible, epigenetic- based therapies may be useful for cancer treatments.


If a normal cell encounters defective processing in DNA replication, DNA repair or chromosome assembly, they do not allowed to continue through the cell cycle, till the conditions are corrected and thereby reduces the chances of accumulation of defective cells. In case the damage of the DNA is irreparable, the cell may go through a second line of defence called programmed cell death or apoptosis. Apoptosis is controlled genetically, and is an inherent process to eliminate certain cells that are not required for by the final adult organism. In this process, the nuclear DNA becomes fragmented, internal cellular structures are disrupted, and cell dissolves into small spherical (apoptotic) bodies. Thereafter, these bodies are engulfed by the phagocytic cells of the immune system. The products of the genes Bcl2 and BAC can trigger or prevent apoptosis. In the cancer cells these genes are mutated, and as a result normal checkpoints in the cell cycle are inactivated. Such cells remain defective and cannot undergo apoptosis.


Henry Harris in late 1960’s observed that some cell lines, derived from the somatic hybrid of normal rodent cells and cancer cells, did not form tumours, instead established a normal growth pattern. He speculated that products of some genes present in the normal cells had the ability to suppress the uncontrolled proliferation of cancer cells. These genes are called tumour suppressor genes. Inactivation of tumour suppressor genes has been linked to the development of a wide variety of human cancer, including colon, lung and breast cancers.

With the development of positional cloning technique, it has become possible to isolate tumour suppressor genes. In this technique, variations in the genetic characters present in the cancer cells and/or in cells of patients with inherited cancer predisposition are identified. Existence of variations indicate occurrence of mutations and help to study such mutations through cloning. Through this technique several tumour suppressor genes are identified in humans (Table 13.2).

13.8.1 The p53 Tumour-Suppressor Gene

In human cancer cells p53 is the most frequently mutated gene. The nuclear protein encodes by the gene p53 acts as a transcription factor. It can stimulate transcription or repress more than 50 different genes. Although the p53 protein is continuously synthesized, it is rapidly degraded and thus is present in low levels. When p53 protein binds to another protein called Mdm2, it induces degradation and sequesters the transcriptional activation domain of p53. It also prevents conversion of inactive p53 protein to active form. In case Mdm2 protein gets dissociated from p53 protein then rapid increase in the activated p53 protein takes place at nuclear level. Such dissociation is induced due to creation of dsDNA breaks, chemical damage in DNA and presence of DNA-repair intermediates. Increase in the level of p53 protein leads to increased protein phosphorylation, acetylation, and other post translational modifications.

The products of p53 gene control the movement of the normal cells through different phases of the cell cycle. Activated p53 proteins can: i) stimulate transcription of p21 protein (which arrests progression from G1-S checkpoint of mitotic cycle), ii) regulate gene expression that retard replication of DNA (this helps in repair of the damaged DNA before replication), and iii) block damaged cells (DNA damage occurred during S phase) from progression from G2 to M checkpoint by regulating expression of other genes.

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