Molecular Genetics of Cancer

Molecular Genetics of Cancer

Cancer is a complex group of diseases all of which contain gene alterations in genes. A gene can be thought of as a unit of inheritance. It refers to a stretch of DNA (or RNA in some viruses) that occupies a specific position in a chromosome. Each gene codes for a specific protein that performs a particular function.

A combination of genetic and environmental factors can be held responsible for development of cancer. There are two common properties in all cancerous cells: 1) uncontrolled growth and 2) ability to metastasize. Cancer may be triggered by initial alterations in genes that control cell cycle and proliferation. This results in aberrant proliferation of the cells and formation of a tumor. Further, alterations in genes that code for cell surface proteins will result in loss of cell-to-cell contact. This allows the tumor cells to leave their site of origin and metastasize (spread) to other tissues and organs. Therefore, we can say that alterations in genes are responsible for the development of cancer.

What kind of alterations takes place in the gene?

The alterations in genes that lead to development of tumor or cancer are called mutations. A gene mutation is a permanent change in its DNA sequence. This can involve only a single base of DNA or a large segment of a chromosome. There are two kinds of gene mutations: 1) they can be inherited from a parent (called hereditary or germline mutations) or 2) acquired during a person’s lifetime due to environmental factors (somatic mutations). One or two mutations cannot cause cancer; rather many mutations in combination must accumulate to give rise to cancer.

The nucleotides of DNA are the building blocks of the genes and chromosomes.

The various kinds of mutations are as follows:

  • Point mutations: A single point mutation or a base substitution occurs when a single nucleotide is replaced with a different nucleotide.
  • Deletions: Mutations that result in missing DNA are called deletions. These can be small, such as the removal of just one part of the gene or longer deletions that affect a large number of genes on the chromosome.
  • Gene amplification: Multiple copies of a gene are erroneously produced in a cell. This usually results in increase of the RNA and protein of the particular gene.
  • Chromosomal translocation: This occurs when parts of chromosomes break and attach to another chromosome. This results in activation or inactivation of a number of genes that are present at the break and rejoining site. Such alterations can result in cancer development. Exposure to radiation for a prolonged time period can be the cause of chromosomal translocations.
  • Tumor viruses: Tumor viruses can be of two types: DNA tumor viruses and RNA tumor viruses or retroviruses. The DNA tumor viruses insert their genetic material into the DNA of the host cell and disrupt a gene. Disruption of a gene can either mean its inactivation or its excessive activation. RNA viruses (retroviruses) can activate a normally inactive gene. These viruses sometimes replicate their own DNA together with the host DNA (taken up by the virus). Since viral DNA replication is more error prone, mutations in the host gene are bound to happen. These mutated host genes when reinserted in the host cell can be the cause of cancer.

What Kinds of Mutated Genes Cause Cancer?

Mutations in three kinds of genes can cause cancer.

  • Oncogenes
  • Tumor suppressor genes
  • Cell death genes

Oncogenes: Oncogenes are mutated versions of the proto-oncogenes. The proto-oncogenes control cell growth normally, but when activated due to mutation their nature changes drastically. These altered genes or oncogenes behave badly and imposes no regulation over cell growth, hence resulting in tumor formation. There are more than 100 different types of proto-oncogenes. Each contains codes for a protein that plays a role in regulating normal cell behavior.

All genes including proto-oncogenes have two copies. Mutations in any one of them can lead to the conversion of a protooncogene to an oncogene.

Inherited and acquired mutations of proto-oncogenes

Mutations can either be inherited or acquired. Inherited mutations of proto-oncogenes are rare. One such inherited mutation of a gene causes the condition Li-Fraumeni. These mutations occur in the germ cells of the parents who pass them on to their children.

However, in most cases cancer-related mutations are acquired due to the effect of toxic chemicals, radiation and other random events. These mutations are not passed on to the next generation. Cancers formed due to acquired mutations are called sporadic cancers. Smoking can induce several mutations in proto- oncogenes, which may lead to lung cancer.

Tumor suppressor genes:

A tumor suppressor gene is a gene that protects a normal cell from turning into a tumor cell. Inactivation of these genes due to mutations can lead to unregulated cell growth and cancer.

A tumor suppressor gene regulates cell division. It stops the cells from proliferating too fast. Mutation in this gene will allow the cells to proliferate without any regulation. Mutations in tumor suppressor genes are mostly acquired. Mutations in both copies of a tumor suppressor gene pair are required before an effect is manifested.

Inherited and acquired mutations of tumor suppressor genes

Mutations in tumor suppressor genes are rarely inherited. One such rare condition is familial adenomatous polyposis (FAP) which arises due to mutation in the APC gene. This condition has been associated with an increased risk of colon cancer. Rare hereditary mutations in BRCA1 and BRCA2 can be a cause of breast cancer and ovarian cancer.

In majority of the cases, mutations in tumor suppressor gene are acquired. Acquired mutation of p53 is the cause of a wide array of cancers.

DNA repair genes:

The third type of genes implicated in cancer is called “DNA repair genes.” Every day, thousands of DNA-damaging events occur in each cell of our body, but efficient DNA repair systems have evolved to prevent such damage. Replication of DNA is a complex process during cell division in which many errors can occur. This can result in the formation of a gene which may not function properly. DNA may also be damaged by chemicals, reactive oxygen species, and radiation. Such errors or damage can cause a mutation in the cancer-related genes resulting in tumor growth and malignancy.

Genes which prevent such mishaps are called DNA repair genes. The protein products of the DNA repair genes not only correct the mistakes during DNA replication but also reduce the damage caused to DNA by the carcinogens. However, if these DNA repair genes are mutated, tumor formation cannot be prevented. Both copies of DNA repair genes need to be mutated for its inactivation.

Inherited and acquired mutations of DNA repair genes

Mutations in DNA repair genes can be inherited from a parent. Xeroderma pigmentosum is an example of a cancer in which mutated DNA repair genes are passed on to the next generation. Such mutations can also be acquired over time because of aging and environmental exposures.

Conclusion

Several genetic changes are required for the development of a malignancy. Cancer incidence increases in direct proportion to age. If only one mutation was needed for cancer to form, then the incidence of the disease would be unrelated to age. A comparison of inherited and non-inherited cancers reveals that the development of cancer is a multi-step process. This multistep process involves initiation, promotion, and progression. Studies of colon cancer have revealed an association between the accumulation of specific gene defects and the progressive development of a tumor.

References

  1. Wong KM, Hudson TJ, McPherson JD. (2011) Unraveling the genetics of cancer: genome sequencing and beyond. Annu Rev Genomics Hum Genet.;12:407-30.
  2. Charles J. Sherr (2004) Principles of Tumor Suppression. Cell, Vol. 116, 235–246
  3. S A Stass and J Mixson (1997) Oncogenes and tumor suppressor genes: therapeutic implications. Clin Cancer Res;3:2687-2695.
  4. P. L. Pearson & R. B. Van Der Luijt (1998) The genetic analysis of cancer. Journal of Internal Medicine; 243: 413–417
  5. JM Bishop (16 January 1987) The molecular genetics of cancer Science: Vol. 235 no. 4786 pp. 305-311
  6. Weinberg RA. (1995) Prospects for cancer genetics. Cancer Surv.;25:3-12.
  7. Knudson AG. (2002) Cancer genetics. Am J Med Genet. ;111(1):96-102.
  8. This article was originally published on September 3, 2012 and last revision and update was 9/4/2015.