Cancer Genetics

views updated

Cancer genetics


A continuous process in which multiple alterations occur in genes that control cell division and differentiation that leads to cancerthe uncontrolled division and proliferation of cells. These genetic alterations are referred to as mutations, which are changes in the normal DNA sequence of a particular gene. Mutations may include deletions, chromosomal translocations, inversions, amplifications, or point mutations.

Cancer genetics is the understanding of the genetic processes underlying the actual disease occurrence. This understanding plays a significant role in early detection, therapy, prevention, and prognosis.


Nearly all cancers originate from a single cell and are the result of genetic alterations, although most of them are not inherited. Individuals who are genetically predisposed to a particular cancer will not necessarily develop the disease in the absence of somatic mutations. Somatic mutations occur in non-sex determining cells, meaning they will not be passed on to offspring. These mutations can be influenced by environment and other causes, such as an individual's habits (i.e. smoking). A single genetic error or mutation in a cell does not typically induce malignancy; instead it develops after a series of mutations over a period of time.

Regulation of cell death and survival

A balance between cell division and death of the old, degenerated cells is essential for proper cellular functioning of any organism. Cells that can no longer replicate or that have sustained injuries (like hypoxia, heat, extreme cold, or ultraviolet radiation) are candidates for cell death. Alternatively, cells can be killed if infected by intracellular organisms (pathogens), or damaged cells may be engulfed by a host's lymphocytes (white blood cells involved in cellular defense mechanisms). Another form of cell death in the disease process is a suicide mechanism initiated by cells known as apoptosis. In this process, extracellular or intracellular signals may trigger the degradation of nuclear material resulting in cell death. Some of the apoptotic genes like bcl2 family members (bcl-X, A1, bax, bad) are shown to be involved in various cancers. Studies to alter the activity of bcl2 family members and related genes will be of potential use in designing cancer therapies.

Oncogenes and tumor suppressor genes

The incessant cell proliferation in cancer may either be due to over-activation of a specific gene that promotes cell division or due to the improper functioning of a gene that will otherwise restrain growth. Genes that promote cell division are proto-oncogenespositive regulators of cell division. Overexpression of proto-oncogenes results in uncontrolled cell growth. Genes that suppress or restrain growth are tumor suppressor genes and loss of their function results in unregulated cell division. An alteration in the function of genes in each of these classes is due to a change, or mutation, in the DNA within the cell. The different types of mutations include point mutations, amplifications, and chromosomal alterations.

Point mutations

DNA is composed of a string of nucleotides, each containing a phosphate group, deoxyribose, and one of four bases; adenine (A), guanine (G), cytosine (C), and thymine (T). These bases are paired as either A-T or C-G and these pairs compose the "rungs" in the double helix structure of DNA. The order of the bases creates the genetic code for development. A sample genetic code is CAG-TAA-CCA-GCG, etc. These triplets code for synthesis of specific proteins.

A point mutation is a single nucleotide change in a DNA strand. This may alter the genetic code, thus altering the function of the protein. In the above example, a point mutation in the thymine base of the second triplet would look like: CAG-AAA-CCA-GCG. Changing the code from TAA to AAA could alter the function of a protein and thus could cause a predisposition to disease such as cancer. One example of a point mutation that has been identified is the ras family of oncogenes (such as H ras, K-ras, N-ras ), present in 15% of all human cancers.

DNA amplification

Another mechanism of oncogene activationDNA amplificationresults in an increase in the amount of DNA in the cell. A large number of genes are amplified in human cancers.

DNA amplification can be detected by cytological staining (a method in which the amplified DNA is stained), or by another fluorescent technique called comparative genomic hybridization (CGH). CGH allows the specific recognition of regions of gene amplifications in tumor DNA and is a more sensitive diagnostic tool.

Chromosomal alteration

Chromosomal alteration may involve translocations and is often seen in lymphoid tumors. Translocation is the transfer of one part of a chromosome to another chromosome during cell division and may involve transcription factors (i.e., nuclear factors), signal transduction proteins, and cellular regulatory molecules.

DNA repair genes

In addition to oncogenes and tumor suppressor genes, DNA repair genes may lead to cancer. DNA repair genes are capable of correcting the errors that occur during cell division. Malfunction of these repair genes, either through inherited mutation or acquired mutation, may affect cell division resulting in malignancies.

RNA and DNA viruses

Malignancies are known to be associated with RNA or DNA viruses. A retrovirus is an RNA virus that possesses a single-stranded RNA as its genetic material, in contrast to the double-stranded DNA. Retroviruses are known to induce malignancies in animals, and one known human

Childhood cancers associated with congenital syndromes or malformations
Syndrome or AnomalyTumor
AniridiaWilms' tumor
HemihypertrophyWilms' tumor
Adrenocortical carcinoma
Genito-urinary abnormalities (including undescended testicles)Wilms' tumor
Ewing's sarcoma
Testicular cancer
Beckwith-Wiedmann syndromeWilms' tumor
Adrenocortical carcinoma
Dysplastic nevus syndromeMelanoma
Nevoid basal cell carcinoma syndromeBasal cell carcinoma
Poland syndromeLeukemia
Trisomy-21 (Down syndrome)Leukemia
Bloom syndromeLeukemia, gastrointestinal carcinoma
Severe combined immune deficiency diseaseEBV-associated B-lymphocyte lymphoma/leukemia
Wiscott-Aldridge syndromeEBV-associated B-lymphocyte lymphoma
Ataxia telangiectasiaEBV-associated B-lymphocyte lymphoma
Gastric carcinoma (stomach cancer)
RetinoblastomaWilms' tumor
Ewing's sarcoma
Fanconi anemiaLeukemia
Squamous cell carcinoma
Multiple endocrine neoplasia syndromes (MEN I, II, III)Adenomas of islet cells, pituitary, parathyroids, and adrenal glands
Submucosal neuromas of the tongue, lips, eyelids
Medullary carcinoma of the thyroid (thyroid cancer, a specific type)
Malignant schwannoma
Non-appendiceal carcinoid
Neurofibromatosis (von Recklinghausen syndrome)Rhabdomyosarcoma
Optic glioma

malignancy is T-cell lymphoma or leukemia caused by human T-cell lymphotropic virus (HTLV) type I.

DNA viruses are implicated in human malignancies more often than RNA viruses. Human papilloma virus is related to human cervical cancer , and hepatitis B and C are related to hepatocellular carcinoma (liver cancer). In addition, the Epstein-Barr virus that causes the commonly known infectious mononucleosis also causes Burkitt's lymphoma in Africa and nasopharyngeal carcinoma in parts of Asia.

Mendelian cancer syndromes

Some forms of cancer are classified as hereditary cancers, or familial cancers, because they follow the Mendelian pattern of inheritance, the more familiar form of inheritance in which genetic material is passed from the mother or father to the offspring during reproduction. Cancer-related genes may be inherited as autosomal dominant, autosomal recessive, or x-linked traits.

About 100 syndromes have been identified as hereditary cancers although not all of them are common. Some of the known tumor suppressor genes responsible for familial cancer syndromes are BRCA1, which is associated with breast, ovarian, colon, or prostate cancers; BRCA2 involved in breast cancer , male breast cancer, and ovarian cancer ; TSC2 associated with angiofibroma; and RB associated with retinoblastoma and osteosarcoma . The discovery of these genes that are associated with hereditary cancer syndromes is also beneficial in understanding the normal control of cell growth.

Complex inherited cancer syndromes

Several types of cancer do not follow a simple Mendelian pattern of inheritance. In many instances, environmental factors can affect the outcome of disease expression in conjunction with genetic alterations. One such example is lung cancer. Cigarette smoke is an environmental factor that may result in lung cancer for individuals frequently exposed to the toxins in the smoke. However, individuals who possess a gene that predisposed them to lung cancer are genetically more susceptible than the rest of the population to these toxins, and may develop cancer with less exposure or none at all. Individuals without a predisposing gene may not develop the cancer as readily.

It is estimated that less than 10% of the breast and ovarian cancers are the result of mutations in the BRCA1 or BRCA2 genes. The remaining 90% of breast cancer incidences are not usually dependent on inherited factors, although family history should be investigated.

Genetic counseling

Genetic counselors comprehend the medical aspects of hereditary cancer syndromes and can educate the affected family regarding available management options. The counselors communicate the risk for disease development to individuals and their families and actively participate in guiding the course of action from an unbiased perspective. Genetic counselors also aid in providing updated information regarding genetic testing for cancer risk, especially with the discovery of hereditary cancer-associated genes. Genetic counseling efforts may involve a team of health professionals anchored by the genetic counselor which includes a medical geneticist with appropriate background, mental health professional, a physician specializing in cancer (oncologist), and a surgeon (if the type of cancer requires surgery).

Genetic testing

Genetic testing examines the genetic information contained inside an individual's DNA, to determine if that person has a certain disease, is at risk to develop a certain disease, or could pass a genetic alteration to his or her offspring. Individuals who seek genetic testing are usually family members believed to have a predisposition or susceptibility to cancer as known from the personal family medical history. The identification of genes associated with certain types of cancers such as BRCA1, BRCA2, HNPCC (colon cancer ), and RB improves the accuracy of DNA testing to predict cancer risk.

Often a positive test result indicates that the individual does carry the abnormal gene and is more likely to get the disease for which the test was performed than the rest of the population. A negative test result can signify the absence of the abnormal gene and a lesser chance of developing the disease. However, a negative test result cannot guarantee that the person will never develop cancer at any point in his or her lifetime. This is because

Chromosomes and cancer
Cancer typeAssociated gene mutation
Chronic myelocytic leukemiatranslocation resulting in the Philadelphia chromosome (Ph)
Burkitt's lymphomatranslocation involving the c-myc proto-oncogene
Retinoblastomamutation in chromosome 13; mutation can be inherited
Wilms' tumormutation in chromosome 11; mutation can be inherited
Colon cancer (occurs sporadically, butmutation in adenomatous polyposis coli (APC) gene followed by further mutations
also occurs as a familial
cancer syndrome)
Breast cancer (occurs sporadically andmutation affecting the gene BRCA1, or mutation in BRCA2
also as a familial cancer syndrome)

many mutations are induced by environmental factors and accumulate over a period of time.

It is necessary for the individual undergoing genetic testing to know that assessing the mutations is challenging and false-positive results are possible. False-positive results are those that indicate the presence of an abnormal gene that may not really exist, or the abnormal gene may result in a disorder other than the one for which the testing was performed. If the tests administered are not sensitive and specific, they may detect sequence variations that could be benign variants rather than the disease-causing mutations.

Genetic testing is recommended for individuals of higher risk of cancer based on the family medical history.

Genetic testing is also performed for individuals who have survived cancer at an earlier time in their lives. It may be performed to determine one or more of the following:

  • risk to offspring
  • necessity of prophylactic surgery in appropriate cases
  • surveillance purposes
  • personal cancer etiology (cause of disease)

Genetic counseling professionals can assist in the decision to perform genetic testing and in understanding the associated risks. Some individuals find it difficult to cope with the knowledge of their own genetic predisposition. These patients should consider addressing these issues with appropriate health care professionals.

Future potential of genetics in cancer

In 2000, researchers finished successfully sequencing the draft of the entire human genome, in which 30,000 to 40,000 genes have been identified. Each gene codes for a specific protein with a unique function in cellular metabolism. Genomic scientists are examining the draft sequence to identify novel genes in an attempt to decipher their functionality. This research to understand the role of a particular gene in cancer development may lead to improved early diagnostic tools and advancements in therapeutic intervention.

See Also Cancer biology; Carcinogenesis; Chromosome rearrangements



Harrison's Principles of Internal Medicine, Volume 1, 14th edition. New York: McGraw-Hill, 1998.

DeVita Jr., Vincent T., et al. (Eds). Cancer: Principles and Practice of Oncology. J.B. Lippincott Company, 1997.


"Hereditary common cancers: molecular and clinical genetics."Anticancer Research 20 (November-December 2000): 4841-4851.

Venter, J. Craig, et al. "The sequence of the Human Genome."Science 291 (February 16, 2001): 1304-1351.


American Academy of Family Physicians. Genetic Testing: What you should know. <>. (Rev. June 2001).

National Cancer Institute. "Cancer genetics." CancerNet. <>. (December 1999).

Kausalya Santhanam, Ph.D.


Autosomal recessive

A pattern of genetic inheritance where two copies of an abnormal gene must be present to display the trait or disease.

Autosomal dominant

A pattern of genetic inheritance where only one abnormal gene is needed to display the trait or disease.


A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.


Lack of oxygen to the cells that may lead to cell injury and ultimately cell death.

Infectious mononucleosis

A common viral infection caused by Epstein-Barr virus with symptoms of sore throat, fever, and fatigue. This infection is not in any way related to cancer.


A tumor growth that spreads to another part of the body, usually cancerous.


Building blocks of genes, which are arranged in specific order and quantity.


Genes that allow the uncontrolled division and proliferation of cells that lead to tumor formation and usually cancer.


The transfer of one part of a chromosome to another chromosome during cell division. A balanced translocation occurs when pieces from two different chromosomes exchange places without loss or gain of any chromosome material. An unbalanced translocation involves the unequal loss or gain of genetic information between two chromosomes.

X-linked traits

Genetic conditions associated with mutations in genes on the X chromosome. A male carrying such a mutation will contract the disorder associated with it because he carries only one X chromosome. A female carrying a mutation on just one X chromosome, with a normal gene on the other chromosome, will not be affected by the disease.