Beginner's guide to genetics: Cancer genetics

In the fifth part of our series, Adrián J González and colleagues take you through the genetic basis of cancer

Cancer starts in a cell that loses genetic control. It always begins with one cell (an aberrant precursor) and then grows to give rise to a population of cells. This group of cells grow in a disorderly manner becoming different from the precursor. They have increased metabolism, divide rapidly, and develop certain characteristics, such as the ability to colonise new sites. These characteristics give cancerous cells an evolutionary advantage compared with normal cells.

DNA repair systems

Cells are constantly dividing. Genetic material is always duplicated and distributed in new cells. This high mobility of DNA increases the risk of mutations. Apart from the inherent risks involved in DNA duplication and cell division, carcinogens found in the environment--such as ultra violet radiation, hormones, or tobacco smoke--can disrupt the integrity of genetic information.

Often errors in DNA structure do not cause serious problems. Although changes in DNA occur every day, only one of 1000 accidental base changes remains as a mutation in DNA.1 This is thanks to DNA repair systems that detect errors and trigger enzyme mediated response that stop DNA duplication and repair the faulty section. Two of the most common DNA repair systems involve excision--one is the base excision repair and the other nucleotides excision repair. After recognition, both systems remove the deleterious base or segment, and using the other strand as a template, DNA polymerase adds corresponding nucleotides. DNA repair systems also induce some other responses to maintain healthy DNA--for example, they stimulate the cell cycle stop to allow DNA repair systems to act. They are also capable of provoking cell death (apoptosis) when DNA damage cannot be repaired. These systems mean that many errors are corrected and never represent a problem, but if these mechanisms do not function properly, cell cycle deregulation occurs.

Mutations in DNA repair systems can cause important medical conditions. In xeroderma pigmentosum, people have extremely sensitive skin to ultra violet light. This is because they are unable to repair DNA photoproducts (metabolites formed during exposure), as their base excision repair is absent. People with xeroderma pigmentosum are more susceptible to skin cancer than the normal population. Another example is ataxia telangiectasia syndrome, in which a mutation in the ATM gene is present. This protein is responsible for repairing double strand breaks in DNA. People with this condition are susceptible to leukemia, lymphoma, and are sensitive to g rays.

Important genes in carcinogenesis

Oncogenes

About 100 oncogenes have been described (table 1).² These are genes that stimulate cell growth and division or inhibit apoptosis. When present, oncogenes behave as dominant traits, so mutation is needed in only one of the copies of the gene for its function to alter.

Wild type oncogenes participate in normal cell function and are known as proto-oncogenes. When a mutation occurs, they transform into oncogenes. This also applies to their products. A proto-oncogene encodes a normal protein, and the product of an oncogene--anoncoprotein--has structural changes because of gene modifications.

The Ras protein is a signal transduction protein that, under proper stimulation (hydrolisation of guanosine triphosphate to guanosine diphosphate), induces the cell to continue its normal cycle. The Ras oncoprotein arises through a single base substitution--the amino acid glycine is changed for valine at site 12 of the protein. This single point mutation of the Ras gene results in the Ras oncoprotein, which maintains continuous cell stimulation and progression of the cell cycle in the absence of the proper stimulus.

Another example is the fusion occurring in the bcr/abl gene, known as Philadelphia chromosome. Neither of their respective chromosomes 9 (bcr) and 22 (abl) have any unusual activity except when translocation between chromosomes 9 and 22 occurs and bcr/abl is formed. This is an oncoprotein responsible for chronic myelogenous leukaemia.

Tumour suppressor genes

Tumour suppressor genes are the counterpart of oncogenes; instead of stimulating cells to grow and divide, they bring the cell cycle to a standstill when needed (table 2). They behave as recessive genes, because both copies of the gene need to be inactive for the gene to lose its function (loss of heterozygocity).

For example, if one of the two copies of the gene remains active, forming proteins, the disease does not occur. But if this functional gene mutates, the activity stops and the disease will occur.

The retinoblastoma (Rb) gene is a good example of a tumour suppressor gene. The Rb protein contains a transcription factor (signal molecule), E2F, that positively regulates the cell cycle, so Rb prevents stimulation that will lead to cell division. When Rb is phosphorylated, by proteins that control the cell cycle, a structural change is induced. As a result, E2F is liberated and stimulation of the cell cycle occurs. When mutations affect the Rb gene, the structure of the protein is also affected, and E2F is no longer controlled but continuouslystimulated.

"Guardian of the genome" or p53 is also a tumour suppressor gene. After DNA damage has been recognised, it triggers important events. It may inhibit progression of the cell cycle and start a cascade of events that leads to cell apoptosis if DNA damage cannot be resolved.

Loss of heterozygocity of p53 is the single most common change in cancer--an estimated 50% of cancers have it. Cells with DNA damage rest at the G1-S checkpoint of the cell cycle until the damage is corrected, but cells that lack p53 or have a mutant form do not stop at G1. Also cells that lack p53 do not undergo apoptosis.

Li-Fraumeni syndrome is a familial form of mutations at p53. Affected family members have multiple primary tumours, including soft tissue sarcomas; osteosarcomas; tumours of the breast, brain, and adrenal cortex; and leukaemia.

Familiar and sporadic forms of cancer

Cancer like other diseases can be sporadic or familiar (table 3). In sporadic forms, many changes in DNA occur, and most are related to the environment. In familiar forms, few mutations occur and the environment is not as important.

In the familiar form of retinoblastoma, a mutated copy of the Rb gene is inherited. Then, by an unknown mechanism this normal gene mutates and consequently there is loss of heterozygocity, and the retinoblastoma appears. Patients with the familiar form often have the disease bilaterally and at a younger age, compared with the sporadic form that only affects one eye and presents at a later age. The same occurs in people with multiple endocrine neoplasia type 1 (parathyroid hyperplasia or adenoma; islet cell hyperplasia, adenoma, or carcinoma, pituitary hyperplasia; or adenoma). Affected people inherit a mutated copy of the MEN1 gene, also a tumour suppressor gene, that codes for the menin protein, and later, by unknown mechanisms a "second hit" inactivates the remaining normal gene.

Sporadic or non-familiar forms of cancer are related to the environment and changes in genetic information. A good example is breast cancer, which in 10% of cases is familial and related to the BRCA1 and BRCA2 genes. In most affected people, however, breast cancer occurs through an interaction of environment factors--early menarche, late menopause, not giving birth or not breast feeding, and increased exposure to oestrogens.³ After a primary insult--inactivation of tumour suppressor gene or activation of proto-oncogenes--this exposure helps the progression of the disease, leading to the different histopathological stages of breast cancer.

In colorectal cancer, a model of progression has been described,⁴ in which subsequential errors or insults correlate to histological changes (figure). This is a good example of a sporadic cancer, in which multiple genetic disruptions are needed for a disease to appear.

CNRI/SPL

Adenoma-carcinoma model of progression of colorectal cancer

The multifactorial model applies to nearly all cancers in which genetic alterations and environmental exposures condition the appearance of the disease.

Knowledge about the origins of cancer is increasing daily, and the possibility of gene therapy to target specific genetic changes is becoming a real promise; this will be the central theme of our last article in the series.

Adrián J González, intern
Email: grangeroloco@hotmail.com

Juan J Morales associate, researcher

Leonora Luna, social worker

Jazmín Arteaga, third year resident in medical genetics

Osvaldo M Mutchinick, chief, Genetics Department, National Institute of Medical Sciences and Nutrition, Mexico


studentBMJ 2005;13:45-88 February ISSN 0966-6494

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3. Kufe DW, Pollock RE, Weichselbaum RR, Bast RC Jr, Gansler TS, Holland JF, et al, eds. Cancer medicine. 6th ed. Hamilton: BC Decker, 2003.
4. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-67.