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Men have higher cancer incidences than women. Lifetime risk for men is 50% and for women 30% and an incidence quote of 1.8 for men/women has been shown for cancer in non-sex organs. Calculations suggest that a third of all cancer cases should be possible to eliminate if causes were known and could be eliminated. Further support for differences is that men have worse survival statistics and that boys have worse cancer prognosis. We have found that skin carcinogens inactivate androgen receptor (AR) in human stem cells. In the present project we will study if carcinogen-induced inactivation of androgen receptor (AR) in human stem cells can explain men’s susceptibility to cancer, and in particular the high incidence for older men. We will 1) investigate how environmental carcinogens inactivate AR, 2) analyze the consequences of AR inactivation concerning DNA damage and repair, 3) study if carcinogens interact with age-dependent decline in testosterone levels and increase DNA damage and mutation burden, and 4) analyze differences in tumor-specific mutational burden between genders. Our study will hopefully explain a major risk factor behind melanoma and perhaps also men´s cancer susceptibility for several other tumors. Our study may also suggest tools to decrease men´s cancer incidence, as well as the total cancer incidence, via a development of new risk assessment strategies.