the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). When expression of DNA repair genes is reduced, this causes a DNA repair deficiency. This is shown in the figure at the 4th level from the top. With a DNA repair deficiency, DNA damage persists in cells at a higher than typical level (5th level from the top in figure); this excess damage causes an increased frequency of mutation and/or epimutation (6th level from top of figure). Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair or in Homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR-defective cells During repair of DNA double-strand breaks, or repair of other DNA damage, incompletely-cleared repair sites can cause epigenetic gene silencing. The somatic mutations and epigenetic alterations caused by DNA damage and deficiencies in DNA repair accumulate in field defects. Field defects are normal-appearing tissues with multiple alterations (discussed in the section below), and are common precursors to development of the disordered and over-proliferating clone of tissue in a cancer. Such field defects (second level from bottom of figure) may have numerous mutations and epigenetic alterations. It is impossible to determine the initial cause for most specific cancers. In a few cases, only one cause exists: for example, the virus HHV-8 causes all Kaposi's sarcomas. However, with the help of cancer epidemiology techniques and information, it is possible to produce an estimate of a likely cause in many more situations. For example, lung cancer has several causes, including tobacco use and radon gas. Men who currently smoke tobacco develop lung cancer at a rate 14 times that of men who have never smoked tobacco: the chance of lung cancer in a current smoker being caused by smoking is about 93%; there is a 7% chance that the smoker's lung cancer was caused by radon gas or some other, non-tobacco cause. These statistical correlations have made it possible for researchers to infer that certain substances or behaviors are carcinogenic. Tobacco smoke causes increased exogenous DNA damage, and this DNA damage is the likely cause of lung cancer due to smoking. Among the more than 5,000 compounds in tobacco smoke, the genotoxic DNA-damaging agents that occur both at the highest concentrations, and which have the strongest mutagenic effects are acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide