Genetics of cancer

DEFINITION: The genetics of cancer can be defined as the study of heredity and variation in the development of cancer.

Description: Inheritance of characters or traits occurs through basic units of heredity called genes. Each human cell consists of twenty-three pairs of chromosomes containing genes inherited from both biological parents. Some genes are dominant, requiring only one copy to exert their effects, while others are recessive, requiring both copies to be in place to cause any changes. Aberrations in chromosomes or mutations in specific genes without chromosomal modifications could lead to cancer development. However, only 5 to 10 percent of cancers are attributed to heredity. Most cancers are acquired because of changes (called mutations) that occur in normal genes. Exposure to chemicals (for example, in smoking) and radiation (emitted by various sources, including the sun) poses a high risk of inducing gene mutations. Chromosomal aberrations such as deletion of an entire chromosome, multiplication of specific chromosomes, or translocation of certain parts of chromosomes are probable causative agents for cancer.

A normal cell transforms into a cancer cell in a multi-step process due to a concatenation of events leading to modifications in many genes. These changes primarily enable normal cells to acquire uncontrolled growth potential, resulting in the formation of tumors. Tumor development culminates in metastasis, a process in which cancerous cells travel through blood vessels and invade other body organs. Genetic changes suggested as hallmarks of cancer include:

• Self-sustained growth that is independent of the availability of external growth factors
• Resistance to signals controlling cell growth and proliferation
• Methods to evade mechanisms of the programmed cell death pathway (apoptosis)
• Uncontrolled capacity to replicate
• Sustained capability to produce new blood vessels (angiogenesis) required for growth and survival of tumors and resistance to antiangiogenesis factors
• Capability to overcome stringent physiological barriers and get transported to other regions of the body and spread (metastasis)

Broadly, these properties encompass three categories of gene mutations—mutations occurring in proto-oncogenes, mutations of tumor-suppressor genes, and mutations in deoxyribonucleic acid (DNA) repair genes.

Mutations of proto-oncogenes:Proto-oncogenes are genes responsible for and required for normal growth and development. Average growth and development are complex physiological processes that require the activation of several genes, which is made possible by signal transduction mechanisms inherent in cells. Signal transduction is a process whereby a signal the cell receives from its external environment is processed and transduced to the internal milieu, activating various genes. Many signal transduction pathways initiate physiological processes such as cell division and proliferation.

Many proto-oncogenes have been identified in the human genome, including RAS, HER2, MYC, and Cyclin D. Mutated or damaged proto-oncogenes are called oncogenes. The presence of oncogenes in cells correlates with the development of cancers. Humans have a wide array of oncogenes called gain-of-function genes, as they gain the capacity to induce tumor development due to mutations. They become hyperactivated in the mutated state and initiate multitudes of cell signal transduction pathways, ultimately resulting in uncontrolled cell division and growth.

The mitogen-activated protein kinase (MAPK) pathway is a signal transduction pathway implicated in most cancers. Mutations in genes involved in this signal transduction cascade impede communication within and between cells, resulting in abnormal growth and tumor development. Specific examples include the RAS and BRAF gene families. About 25 percent of all cancers have recorded some kind of mutation in RAS family members. The MAPK signal transduction cascade is initiated by activating cell-surface receptors such as tyrosine kinase and epidermal growth factors that traverse cell membranes. Inhibitors of receptor activation are being tried as possible therapeutic agents for cancer.

Mutations of tumor-suppressor genes:Tumor-suppressor genes are a class of recessive genes whose protein products control cell division and death. Most often, the protein products of these genes act directly on cells to usher them to the apoptotic pathway. In cancer cells, entry into the apoptotic pathway is impossible because of mutations in tumor-suppressor genes. Tumor-suppressor genes are called loss-of-function genes because mutations in these genes result in the loss of their normal tumor-suppression function. This is significant because a single copy of a normal tumor-suppressor gene is enough to exert a beneficial effect. Mutations in both copies of the genes could result from hereditary or environmental factors or aging. Most tumor developments document mutations in tumor-suppressor genes.

A classic example of a tumor-suppressor gene is TP53. Most cancers reported in human cells exhibit either an abundance of abnormal TP53 genes or the absence of normal TP53 genes and signaling pathways. There is also overwhelming evidence to show that mutant TP53 protein acquires novel oncogenic traits that provide a favorable environment for tumor cells' development, sustenance, and resistance. Replacement of the normal, wild-type TP53 gene using a retroviral TP53 expression vector is an attempt to control cancer cell growth in gene therapy. In addition to the TP53 gene, its homologs TP73 and TP63 have also been identified in cancer induction.

Mutations in DNA-repair genes: Exposure to certain types of radiation, such as ultraviolet (UV) light, can induce damage in DNA. Cells have evolved standard repair mechanisms that can detect and correct such damage through specific genes called DNA-repair genes. Therefore, most mistakes usually go unnoticed. However, when mutations occur in DNA-repair genes, damaged and malfunctioning DNA accumulates in cells, interfering with normal processes and inducing tumor development. Mistakes in tumor-suppressor genes can lead to cancer if not repaired in time. DNA-repair genes are recessive genes, so it is imperative to have mutations in both copies of the gene to have visible effects. Examples of these mutations occur in the skin cancer xeroderma pigmentosum and some forms of colon cancer. In these colon cancers, DNA-repair genes MLH1 and MSH2, located on chromosomes 3 and 2, are mutated and damaged.

Chromosomal aberrations: In other cases, the number of chromosomes may not be different from the normal forty-six, but portions of chromosomes may be deleted, added, or translocated to a different chromosome. Some of these modifications could shuffle relevant genes, leading to cancer development. Chronic myeloid leukemia (CML) Chromosomes have distinct sizes and characteristics, and accordingly, each chromosome has been designated a unique number and can be distinguished easily in modern karyotyping tests. Sometimes, for various reasons, including being fertilized by more than one sperm, cells can acquire an abnormal number of chromosomes, a condition called aneuploidy. In other cases, the number of chromosomes may not differ from the normal forty-six, but portions of chromosomes may be deleted, added, or translocated to a different chromosome. Some modifications could shuffle relevant genes, leading to cancer development. For example, in chronic myeloid leukemia (CML), a small portion of genetic material from chromosome 22 is translocated to chromosome 9 and vice versa—a condition called reciprocal translocation.

A consequence of this translocation is the transfer of a normal proto-oncogene called ABL1 from chromosome 9 to chromosome 22. Movement of ABL1 to chromosome 22 is responsible for its conversion to an oncogene and, ultimately, malignancy. Other cancers resulting from a similar translocation between chromosomes 9 and 22 include acute lymphoblastic leukemia and adult acute myelogenous leukemia. Burkitt lymphoma, a B-lymphocyte malignancy most common in Africa, is induced by the translocation of genetic materials between chromosomes 8 and 14, activating the oncogene MYC.

Heritability of cancer: Whether cancer incidence results from alterations of whole chromosomes or specific genes, its inheritance is variable. In cancers such as retinoblastoma, a childhood eye cancer, tumor development occurs only with deletions in both copies of chromosome 13. Children with a deletion in one copy of the chromosome are at risk for the disease because every cell in these patients possesses this deletion. Still, a second mutation in the remaining complete copy of the chromosome is required for disease development. Similar is the case of Wilms’ tumor, a childhood kidney cancer condition, in which the abnormality in chromosome 11 is inherited in one copy, but a second mutation is necessary for tumor expression. Other cancers with genetic predispositions include xeroderma pigmentosum, Paget disease of bone, ataxia telangiectasia, and Fanconi anemia.

There are several common examples of familial cancer syndromes that predispose subsequent generations of patients to cancer. Typical examples are colon cancers, breast cancers, and prostate cancers. Colon cancers occur because of two kinds of hereditary conditions: familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC). FAP involves mutations of a tumor-suppressive gene called APC and interactions between TP53 and KRAS genes. HNPCC occurs as a result of mutations in MLH1 and MSH2 genes that are involved in DNA repair.

Approximately 80 percent of patients with familial early-onset breast and ovarian cancers exhibit mutations in a tumor-suppressor gene called BRCA1. BRCA1 and another gene called BRCA2 are examples of mutations that have penetrated the reproductive cells (germ-line mutations) and, therefore, are inherited, predisposing women to these cancers. Similarly, mutations in the gene HPC1 (hereditary prostate cancer 1), located on chromosome 1, are responsible for most familial cases of prostate cancer.

Epigenetics and cancer: Epigenetics can be defined as the study of factors other than traditional DNA sequences inherited during cell division. These can be monogenic (involving a single gene) or multigenic (involving multiple genes). The most prevalent epigenetic disease is due to loss of phenotypic plasticity (the ability of cells to alter their behavior as a response to alterations in internal or external environments). This loss of genomic imprinting is the first reported molecular evidence that epigenetics plays a role in cancer. Considerable attention is therefore being focused on epigenetic aspects of cancer development.

Progress and perspectives: Progress in discovering, analyzing, and profiling genetic determinants of cancer has been excellent. Advances in molecular biological techniques and the cracking of the human genome have enabled forays into various aspects of cancer. Techniques such as array comparative genomic hybridization (aCGH), which can measure DNA copy number alterations (CANs), contribute to correlating genetic factors with human diseases. The advent of therapeutic strategies such as gene therapy has advanced researchers’ ability to overcome various impediments posed by traditional treatment strategies. Previously unimaginable approaches—like supernumerary artificial chromosomes with relevant genes to cure cancer and other diseases—have begun to be attempted. However, gene therapy encounters multitudes of social and ethical concerns because of its ability to alter genes, which are the basic units of heredity and variation. Similarly, other benefits of diagnostic tools, such as genetic testing, should be handled cautiously. Statistics show that only about 5 percent of cancers are inherited or due to heredity. Awareness of and caution about various risk factors, such as carcinogens and viruses, remains recommended to prevent cancer.

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