What Causes Cancer? Cancer, Genes, and Epigenetics

There are multiple causes of cancer. It is a very complicated process but can be simplified to lifestyle choices, chronic inflammation, infections, and genes.

Lifestyle choices are the most important predictors of risk of diseases, metabolic syndrome, diabetes, hypertension, heart disease, stroke and cancer. What we eat, drink, or smoke are instrumental in what kind of diseases we suffer from. Likewise, failure to exercise will affect our health.

Tobacco use is the most common preventable cause of cancers. It is associated with many cancers including mouth cancer, head and neck cancer, esophageal cancer, stomach cancer, and lung cancer among others.

The World Health Organization (WHO) warned in February 2008 that 1billion people worldwide could die of tobacco-related causes this century unless urgent action is taken. The WHO’s report includes these global statistics on tobacco deaths:

  • 100 million people died of tobacco-related causes during the 20th century.
  • Tobacco currently kills 5.4 million people per year.
  • Tobacco use makes six of the World’s eight leading causes of death — including heart disease, stroke, and cancer — more likely

Another cause of cancer is chronic inflammation. Some examples of chronic inflammatory conditions that lead to cancer include ulcerative colitis, Crohn’s disease, and Barrett’s esophagus.

Inflammation stimulates tumor development at all stages; initiation, progression, and metastasis. Tumor recruited leukocytes secrete cytokines that enhance DNA damage and encourage growth of the cancer cells through production of blood vessels (proliferation and angiogenesis).

Infections are well documented to lead to malignancy. Some examples include:

  • Helicobacter pylori; Gastric lymphoma
  • Schistosomiasis; gallbladder and bladder
  • Epstein Barr Virus; lymphoma
  • Human Herpes Virus 8; Kaposi’s sarcoma
  • Chlamydia species; ocular lymphoma, lung cancer, and cervical cancer
  • Human Papilloma Virus; cervical cancer, oral cancer, and anal cancer

GENES AND CANCER

Genes are the blueprint to the body. There are 20,500 protein encoding genes (exons) in the human genome (Human Genome Project) and many more non-encoding sections (introns). There are 2-3 meters DNA/cell, 2 X 1013 meters per human body. There are two major types of cancer genes, tumor suppressor and oncogenes.

Tumor Suppressor Genes have multiple functions. Some slow down cell division such as the retinoblastoma gene (RB1). Others are involved in DNA repair such as the mismatch repair genes in hereditary colon cancer (hMSH2, hMLH1). Finally, some genes are involved in regulating natural cell death. This is called apoptosis and the p53 tumor suppressor gene works in this area.

Proto-oncogenes control normal growth, mutated, they become oncogenes. These cause normal cells to grow out of control and become malignant. Oncogenes can exert their effect on a wide array of cellular processes including growth factors, growth factor receptors, signal transducers, transcription factors, and programmed cell death regulators. There are more than 100 known oncogenes. Common oncogenes and their function appear below.

Common Oncogenes

Growth factors: sis (PDGF)

Growth factor receptor: erb B-1, erb B-2

Signal transducer: abl, ras

Transcription factor: myc

Apoptosis: bcl-2

There is no inevitability between presence of genes and cancer (or disease). For instance, protein transcripts for the bcr-abl gene involved in chronic myelogenous leukemia (CML) are present in up to 69% of the population but only 1:100,000 people will ever get CML. Many of us have cancer genes in our bodies, but the majority of us will not get the diseases because the genes are turned off. The process by which genes are turned on or off is called epigenetics and it is a growing field of study in cancer and other diseases.

EPIGENETICS

Epigenetic changes are modifications to the genome that are heritable during cell division but do not involve a change in DNA sequence. Expression of genes is not regulated by the DNA sequence, which is the same in every cell, but by epigenetic marking and packaging. This process regulates chromatin structure through DNA methylation, histone variants, post-translational modifications, nucleosome positioning factors or chromatin loop and domain organization.

How can this cause cancer? Well, if a tumor suppressor gene is abnormally turned off, or an oncogene is turned on, then carcinogenesis can occur. One key to abnormal gene expression is methylation of the genome. To go further, some explanation of terms is necessary.

DNA contains four bases: adenine, guanine, cytosine, thymidine, but there is a fifth base methylated cytosine. DNA methyl-transferase (DNMT), produces methyl-cytosine where cytosines precede guanine (CpG). The CpG areas are not symmetric but clustered in CpG islands located at promoter regions. The promotor region is the region at the beginning of a gene and it controls the start of gene transcription. If the promotor is off, then the gene nevers is expressed. Abnormal methylation in cancer has been known for 20 years. Hypo-methylated areas turn on normally silent areas such as virally inserted genes or inactive X-linked genes. Hyper-methylated areas silence tumor suppresser genes. Both of these processes can mean trouble.

In conclusion, many factors lead to cancers. Probably the most important is our lifestyle choices such as what we eat or smoke. Other factors include chronic inflammation, infections or abnormal gene function. The study of how genes cause cancer by being turned on or off is called epigenetics. It is a fascinating area of research and will surely change our whole perception of cancer and disease in the future.