Abstract 4683: Smoking is associated with mosaic loss of chromosome Y

Abstract Smoking of tobacco is a major preventable environmental risk factor related to human health. Smoking killed about 100 million people during the 20th century and is projected to kill one billion people during this century, assuming that the current frequency of smoking is maintained. Lung cancer is the prime cause of cancer-associated death in relation to smoking. However, it is less well appreciated that smoking also causes tumors outside the respiratory tract, which are predominant in men, and cumulatively roughly as common as lung cancer. Moreover, it is known that males have a higher incidence and mortality from most sex-unspecific cancers, regardless of smoking status, and this fact is largely unexplained by known risk factors. We have recently shown that a male specific risk factor, acquired mosaic loss of chromosome Y (LOY) in non-cancerous blood cells, is associated with an increased risk of non-hematological tumors among aging males. Median survival among men with LOY was 5.5 years shorter [1]. We demonstrate here that smoking is associated with LOY in blood cells in three independent cohorts (TwinGene: odds ratio [OR] = 4.3, 95% CI = 2.8-6.7; ULSAM: OR = 2.4, 95% CI = 1.6-3.6; and PIVUS: OR = 3.5, 95% CI = 1.4-8.4) encompassing in total 6014 men. Our data also support a transient and dose-dependent mutagenic effect from smoking on LOY-status [2]. Thus, smoking may induce LOY, linking the most common acquired human mutation with a severe preventable risk factor. Our results could explain the observed sex differences and why smoking seems a greater risk factor for cancer in men than women. The molecular mechanisms behind these observations are not well understood, but LOY appears a strong and male-specific risk factor. Follow up studies are required to understand how cellular Y chromosome deficiency in normal blood cells might cause risk for cancer. We hypothesize that the Y-chromosome loss may be skewed towards, and exert negative effect on, a specific population of immune cells that are responsible for immunosurveillance. Selected references: 1. Forsberg LA, Rasi C, Malmqvist N, Davies H, Pasupulati S, Pakalapati G, Sandgren J, de Stahl TD, Zaghlool A, Giedraitis V, Lannfelt L, Score J, Cross NC, Absher D, Janson ET, Lindgren CM, Morris AP, Ingelsson E, Lind L, Dumanski JP: Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer, Nature Genetics 2014, 46:624-628. 2. Dumanski J, Rasi C, Lönn M, Davies H, Ingelsson M, Giedraitis V, Lannfelt L, Magnusson P, Lindgren C, Morris A, Cesarini D, Johannesson M, Tiensuu Janson E, Lind L, Pedersen N, Ingelsson E, Forsberg L: Smoking is associated with mosaic loss of chromosome Y, Science 2014, in press. Citation Format: Jan P. Dumanski, Chiara Rasi, Mikael Lönn, Hanna Davies, Martin Ingelsson, Vilmantas Giedraitis, Lars Lannfelt, Patrik KE Magnusson, Cecilia M. Lindgren, Andrew P. Morris, David Cesarini, Magnus Johannesson, Eva Tiensuu Janson, Lars Lind, Nancy L. Pedersen, Erik Ingelsson, Lars A. Forsberg. Smoking is associated with mosaic loss of chromosome Y. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4683. doi:10.1158/1538-7445.AM2015-4683