Non-Small Cell Lung Cancer - Causes

There is considerable debate over the lung cancer risk posed by depleted uranium used in military weapons (e.g., in the Gulf and Balkan conflicts). A 2001 study estimated that it would cause an additional 8 deaths from lung cancer out of every 10,000 people or soldiers who were highly exposed to this substance. The study was based on a mathematical model, however, and the issue is not settled.

Other lung carcinogens include asbestos, arsenic, certain petrochemicals, and other airborne byproducts of various mining and manufacturing processes.

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Genetic Mutations

Genetic mutations that cause cancer generally occur in two types of genes: tumor-suppressor genes, which prevent unlimited cell reproduction, and proto-oncogenes, which stimulate cell reproduction. (When a proto-oncogene becomes mutated, it is then called an oncogene.) Damage to either type of gene can cause a mutation that results in the uncontrolled division of cells that form tumors. No one genetic abnormality is likely to emerge as a single cause of lung cancer. It probably takes a variety of mutations to promote the devastating cascade of cellular events leading to cancer. The following mutations are among those under investigation:

Tumor-suppressor genes, including p53, PPP2R1B, and p16, and oncogene K-ras. The chemical benzo(a)pyrene diol epoxide (BPDE), a byproduct of tobacco smoke, is involved with a number of genetic mutations, including those to an oncogene called K-ras and to three tumor-suppressor genes known as p53, PPP2R1B, and p16. When normal, the tumor-suppressor genes are involved in cell repair and healthy replication. When they are impaired or blocked, rampant cell proliferation can occur, leading to cancer. (About 10% of the population may carry a gene that protects against lung cancer by reducing levels of BPDE.)
Chemotherapy resistance genes. Tumors that contain the p53 mutation may also be more resistant to chemotherapy. Another important contributor to lung cancer is a genetically defective protein called retinoblastoma (Rb), which is associated with very aggressive tumors. Specifically, low levels of the normal Rb gene may sometimes predict aggressive clinical behavior, especially in patients with small cell lung cancer.
Mutations to the FHIT gene. Another potentially important mutation may be an abnormality in the so-called FHIT gene that causes the cells lining the lung to become more vulnerable to the effects of tobacco smoke and other carcinogens.

Research continues on the puzzle of how genetic and environmental factors work together in the development of lung cancer. For example, some investigators are finding that variant genetic forms (polymorphisms) may actually change a person's metabolism to raise or lower the degree of biologic exposure to carcinogens, and ultimately influence the risk of cancer development.