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Mutational signatures associated with tobacco smoking in human cancer

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Science  04 Nov 2016:
Vol. 354, Issue 6312, pp. 618-622
DOI: 10.1126/science.aag0299
  • Fig. 1 Comparison between tobacco smokers and lifelong nonsmokers.

    Bars are used to display average values for numbers of somatic substitutions per megabase (MB), numbers of indels per megabase, numbers of dinucleotide mutations per megabase (Dinucs), numbers of breakpoints per megabase (Breaks), fraction of the genome that shows copy-number changes (Aberr.), and numbers of mutations per megabase attributed to mutational signatures found in multiple cancer types associated with tobacco smoking. Light gray bars represent nonsmokers, whereas dark gray bars are for smokers. Comparisons between smokers and nonsmokers for all features, including mutational signatures specific for a cancer type and overall DNA methylation, are provided in table S2. Error bars correspond to 95% confidence intervals for each feature. Each q value is based on a two-sample Kolmogorov-Smirnov test corrected for multiple hypothesis testing for all features in a cancer type. Cancer types are ordered based on their age-adjusted odds ratios for smoking, as provided in Table 1. Data for numbers of breakpoints per megabase and fraction of the genome that shows copy-number changes were not available for liver cancer and small cell lung cancer. Adeno, adenocarcinoma; Esophag., esophagus. Note that the presented data include only a few cases (<10) of nonsmokers for small cell lung cancer, squamous cell lung cancer, and cancer of the larynx.

  • Fig. 2 Mutational signatures associated with tobacco smoking.

    (A) Each panel contains 25 randomly selected cancer genomes (represented by individual bars) from either smokers or nonsmokers in a given cancer type. The y axes reflect numbers of somatic mutations per megabase. Each bar is colored proportionately to the number of mutations per megabase attributed to the mutational signatures found in that sample. The naming of mutational signatures is consistent with previous reports (1618). (B) Each panel contains the pattern of a mutational signature associated with tobacco smoking. Signatures are depicted using a 96-substitution classification defined by the substitution type and sequence context immediately 5′ and 3′ to the mutated base. Different colors are used to display the various types of substitutions. The percentages of mutations attributed to specific substitution types are on the y axes, whereas the x axes display different types of substitutions. Mutational signatures are depicted based on the trinucleotide frequency of the whole human genome. Signatures 2, 4, 5, 13, and 16 are extracted from cancers associated with tobacco smoking. The signature of benzo[a]pyrene is based on in vitro experimental data (19). Numerical values for these mutational signatures are provided in table S6.

  • Fig. 3 Differentially methylated individual CpGs in tobacco smokers across cancers associated with tobacco smoking.

    Each dot represents an individual CpG. The x axes reflect differences in methylation between lifelong nonsmokers and smokers, where positive values correspond to hypermethylation and negative values to hypomethylation. The y axes depict levels of statistical significance. Results satisfying a Bonferroni threshold of 10−7 (above the red line) are considered statistically significant.

  • Table 1 Mutational signatures and cancer types associated with tobacco smoking.

    Information about the age-adjusted odds ratios for current male smokers to develop cancer is taken from (24). Odds ratios for small cell lung cancer, squamous cell lung cancer, and lung adenocarcinoma are for an average daily dose of more than 30 cigarettes. Odds ratios for cervical and ovarian cancers are for current female smokers. Detailed information about all mutation types, all mutational signatures, and DNA methylation is provided in table S2. Nomenclature for signature identification numbers is consistent with the COSMIC database (http://cancer.sanger.ac.uk/cosmic/signatures). The numbers of smokers and nonsmokers are unknown (i.e., not reported in the original studies) for acute myeloid leukemia, stomach, ovarian, and colorectal cancers. The patterns of all mutational signatures with elevated mutation burden in smokers are displayed in Fig. 2B. N/A denotes lack of smoking annotation for a given cancer type. Asterisks indicate that a signature correlates with pack years smoked in a cancer type. N.S. reflects cancer types without statistically significant elevation of mutational signatures. The odds ratio for all cancer types is not provided.

    Cancer typeOdds
    ratio
    NonsmokersSmokersTotal number of
    mutational signatures
    found in the cancer type
    Signature 4
    found in
    cancer type
    Mutational signatures
    with elevated
    mutation burden
    in smokers
    versus nonsmokers
    (q < 0.05)
    All cancer typesND 1062249026Y4, 5*
    Small cell lung cancer111.331456YN.S.
    Lung squamous103.571688Y4*, 5
    Lung adenocarcinoma21.91205587Y2*, 4*, 5*, 13*
    Larynx13.261175Y4*, 5
    Pharynx6.627495Y5*
    Oral cavity4.2982655Y5*
    Esophagus squamous3.9991939Y5
    Esophagus adenocarcinoma3.9671759Y N.S.
    Bladder3.81112885N5*
    Liver2.915723519Y4*, 5, 16
    Stomach2.147213NN/A
    Acute myeloid leukemia2.02022NN/A
    Ovary1.94583NN/A
    Cervix1.894748NN.S.
    Kidney1.71541036N5
    Pancreas1.611912011NN.S.
    Colorectal1.35594NN/A

Supplementary Materials

  • Mutational signatures associated with tobacco smoking in human cancer

    Ludmil B. Alexandrov, Young Seok Ju, Kerstin Haase, Peter Van Loo, Iñigo Martincorena, Serena Nik-Zainal, Yasushi Totoki, Akihiro Fujimoto, Hidewaki Nakagawa, Tatsuhiro Shibata, Peter J. Campbell, Paolo Vineis, David H. Phillips, Michael R. Stratton

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Supplementary Text
    • Figs. S1 to S10
    • Captions for Tables S1 to S6
    • References
    Table S1
    Table S1: Detailed information about each examined tobacco-associated cancer sample. Table S2: Comparison of features of tobacco smokers to the ones of lifelong non-smokers. Table S3: Relationships between mutational signatures and pack years smoked. Table S4: Individual CpGs with differential methylation in lung adenocarcinoma. Table S5: Individual CpGs with differential methylation in oral cancer. Table S6: Numerical patterns of mutational signatures associated with tobacco smoking.

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