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Gilbert’s syndrome, circulating bilirubin and lung cancer: a genetic advantage?

Cigarette smoking is the leading cause of lung cancer (all histological types), accounting for about 89% and 70% of lung cancer deaths in men and women, respectively, in Europe and other regions where cigarette smoking is common.1 Oxidative damage to DNA by free radicals and oxidants in cigarette smoke (figure 1) is one of the major pathways that can lead to lung cancer development.2 



Figure 1 
Causal pathways to lung cancer development. In this context, DNA alteration is influenced by ‘environment’, including cigarette smoke, (pathway 1a), and ‘genetic susceptibility’, including UGT1A1— uridine diphosphate-glucuronosyl-transferase—genotypes that are less susceptible to oxidants (and carcinogens) in cigarette smoke (pathway 2a), and their interaction. Pathways (1b) and (2b) refer to other possible effects of the environment and genetic susceptibility not through DNA alterations.



As the heme pathway plays an important role against oxidative stress, uridine diphosphate-glucuronosyl-transferase 1-1 ( UGT1A1 ) gene polymorphisms might be expected to protect against oxidative stress-induced cancer initiation.3 Congenital underexpression of hepatic UGT1A1 causes mild chronic unconjugated hyperbilirubinaemia, known as ‘Gilbert’s syndrome, GS’. Individuals with GS have mildly raised total bilirubin concentrations in the blood (>17 µmol/L) with normal serum activities of liver transaminases, biliary damage markers and red blood cell counts.4 The frequency of the Gilbert’s polymorphism is 30%–45%, however, phenotypic hyperbilirubinaemia is estimated to be 5%–10% in Caucasians.5 6 A remarkable body of evidence from experimental and clinical studies has demonstrated that bilirubin has substantial anti-inflammatory and antioxidative properties.4 The hypothesis that genetically raised bilirubin plays a role in lung …