Mutagenesis. Smoking is associated with mosaic loss of chromosome Y

Abstract

Tobacco smoking is a risk factor for numerous disorders, including cancers affecting organs outside the respiratory tract. Epidemiological data suggest that smoking is a greater risk factor for these cancers in males compared with females. This observation, together with the fact that males have a higher incidence of and mortality from most non-sex-specific cancers, remains unexplained. Loss of chromosome Y (LOY) in blood cells is associated with increased risk of nonhematological tumors. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts [TwinGene: odds ratio (OR) = 4.3, 95% confidence interval (CI) = 2.8 to 6.7; Uppsala Longitudinal Study of Adult Men: OR = 2.4, 95% CI = 1.6 to 3.6; and Prospective Investigation of the Vasculature in Uppsala Seniors: OR = 3.5, 95% CI = 1.4 to 8.4] encompassing a total of 6014 men. The data also suggest that smoking has a transient and dose-dependent mutagenic effect on LOY status. The finding that smoking induces LOY thus links a preventable risk factor with the most common acquired human mutation.

Fig. 1

The association between smoking status and the level of LOY (i.e. mLRR-Y) in three independent cohorts. In all cohorts, these unadjusted analyses indicate that the current smokers (Yes) (table S5) had a significantly higher degree of mosaic loss of chromosome Y (LOY) in blood, compared to non-current smokers (No), composed of never- and previous-smokers. *** and * denotes p-values lower than 0.001 and lower than 0.05, respectively (Kolmogorov–Smirnov tests: TwinGene D=0.15 p=1.131e-11; ULSAM D=0.15 p=0.0006; PIVUS D=0.23 p=0.0203). The definitions used for LOY-scoring and the entire ranges of mLRR-Y data observed in each cohort are shown in figs. S3-S5.

Fig. 2

Differences in degree of LOY between different smoking categories within TwinGene (A) and ULSAM (B) as defined in table S5. In TwinGene (A) there was a significant difference between four smoking categories (ANOVA; F_(3,4137)=22.2, p-value=3.028e-14) and results from post-hoc analysis adjusting p-values for multiple testing using a Tukey HSD test are displayed. In ULSAM (B) there was also a significant difference between three smoking categories (ANOVA; F_(2,1107)=12.2, p=5.812e-06) and post-hoc analysis is shown. In both cohorts, the current smokers had a significantly higher degree of LOY compared to all other categories. The average degree of LOY in the previously regular smokers was not significantly different from the average degree of LOY in the never smokers in both cohorts. Panel C visualize a dose response effect within current smokers in TwinGene with men smoking the most packyears also being associated with higher degree of LOY, as defined in fig. S5 (Kolmogorov–Smirnov test: D=0.2244, p=0.0010).