Inherited genetic disorders result in gene alterations in virtually every cell in our body. As a result, these disorders tend to affect many tissues, organs, and body systems. When genetic screening identifies an inherent risk in one’s genome (e.g., a known cancer gene such as BRCA1, BRCA2, or PALB2 gene for breast cancer), management may include counseling, more frequent cancer screening, or even preventive (prophylactic) surgery to remove the tissues at highest risk of becoming cancerous (e.g., preventive mastectomy). In our immunology and genetics discussions, we have discussed environmental factors (carcinogens) and radiation-caused mutations that may contribute to the development of cancer. The damage to our DNA through both injury and chronic irritation (remember our previous comments on smoking in Blog #18?) all can lead to cumulative mutations and resultant “cancering.” But up to now, we haven’t considered the possibility of a random mistake (oncogenesis) in one of those trillions of normal DNA replications that escape apoptosis and result in a cancer-causing mutation. A series of these mutations (carcinogenesis) in a specific gene (oncogene) class can “de novo” transform a normal cell into a neoplastic (cancer) cell.
Beyond “a random genetic mistake” producing cancer, there are several other genetic irregularities that can create carcinogenesis. Epigenetics (see Blog #10) is the study of changes in organisms (humans included) caused by modification of gene expression (protein production) rather than alteration of the genetic code itself. As with all genetic activity, epigenetics can turn gene expression on or off by the DNA genetic code or by environmental factors. Such abnormalities can produce unpredictable cancers.
Proto-oncogenes are genes that promote cell growth and cellular division, whereas tumor suppressor genes discourage cell growth, or briefly halt the process of DNA repair. A series of many mutations to these protooncogenes are needed before a standard cell transforms into a neoplastic cell. This phenomenon is referred to as “oncoevolution” (another paradox). Tumor suppressor genes that are activated by cellular stress or injury that produce free-floating genetic material can trigger enzymes and pathways that result in the activation of a tumor suppressor gene, p53. This tumor suppression protein arrests the progression of the abnormal cell cycle (apoptosis), preventing mutations from being passed on to subsequent cells. This p53 protein has been named the “guardian of the genome.”
It is estimated that about 20% of cancers are caused by infectious agents. Organisms of the microbiome and its dysbiosis (an imbalance between the types of organisms) can induce carcinogenesis through direct DNA damage and inflammation, indirectly through modulation of immune responses, or by chronic inflammatory responses induced by bacterial metabolites. Among infectious agents, viruses tend to have a higher risk as carcinogens, although bacteria and parasites may also be implicated. Some viruses can disrupt signaling that normally keeps cell growth and proliferation in check. Also, infections can weaken the immune system or cause chronic inflammation that may lead to mutations and subsequent cancers. The most significant viral risks for cancers include the following:
Epstein-Barr Virus (EBV): Risk of lymphoma and cancers of the nose and throat;
Hepatitis B Virus and Hepatitis C Virus (HBV and HCV): Risk of liver cancer;
Human Immunodeficiency Virus (HIV): Risk of Kaposi sarcoma, lymphomas (including both non-Hodgkin’s lymphoma and Hodgkin’s disease), and cancers of the cervix, anus, lung, liver, and throat;
Human Papillomaviruses (HPVs): Risk of all cervical cancers and penile cancers;
Human T-Cell Leukemia/Lymphoma Virus Type 1 (HTLV-1): Risk of adult T-cell leukemia/lymphoma ATLL);
Merkel Cell Polyomavirus (MCPyV): Risk of Merkel cell carcinoma;
Helicobacter pylori (H. pylori): Risk of stomach cancer.
Discussion Questions:
The word “cancer” is not a noun but rather a verb. Can you explain the logic in this “flummoxed” statement?
This phenomenon is referred to as “oncoevolution” is a bit of a paradox. Can you explain its meaning and its paradoxical nature?
Comments