Mosaic loss of chromosome Y (LOY) in blood cells is associated with shorter survival and higher risk of cancer in men. L. A. Forsberg1,2, C. Rasi1,2, N. Malmqvist1,2,3, H. Davies1,2, S. Pasupulati1,2, G. Pakalapati1,2, J. Sandgren4, T. Diaz de Ståhl4, A. Zaghlool1,2, V. Giedraitis5, L. Lannfelt5, J. Score6, N. C. P. Cross6, D. Absher7, E. Tiensuu Janson3, C. Lindgren8,9, A. P. Morris8, E. Ingelsson2,3, L. Lind3, J. P. Dumanski1,2 1) Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; 2) Science for Life Laboratory, Uppsala University, Uppsala, Sweden; 3) Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 4) Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden; 5) Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden; 6) Faculty of Medicine, University of Southampton, Southampton, UK; 7) HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA; 8) Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; 9) Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
It is well known that men have an overall shorter life expectancy compared with women. However, it is less well recognized that incidence and mortality for sex-unspecific cancers are higher in men, a fact that is largely unexplained. Age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells and it was first described more than 50 years ago, but the phenotypic consequences of LOY have been elusive. Our latest results suggest that LOY could be a key factor to explain the higher mortality of men. Survival analyzes performed in the Swedish ULSAM-cohort (Uppsala Longitudinal Study of Adult Men) with >1100 participants analyzed on 2.5M Illumina SNP-array indicated that LOY in peripheral blood could be associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) as well as non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). Among the elderly men in this cohort, followed clinically for up to 20 years, at least 8.2% of the subjects were affected by LOY in a significant fraction of blood cells. The median survival time in men affected with LOY was half, i.e. 5.5 years shorter, compared to the men without mosaic LOY in blood cells. The association of LOY with risk of all-cause mortality was validated (HR = 3.66, 95% CI = 1.27-10.54; 59 events) in the independent PIVUS-cohort (Prospective Investigation of the Vasculature in Uppsala Seniors) in which 20.5% of men showed LOY. Our discovery of a correlation between LOY and all-cause mortality as well as non-hematological cancer mortality will be published in Nature Genetics. These results illustrates the impact of post-zygotic mosaicism such as loss of chromosome Y (LOY) on disease risk, could explain why males have a higher mortality compared to females, are more frequently affected by cancer and suggests that chromosome Y is important in processes beyond sex determination and sperm production. LOY in blood could become a predictive biomarker of male carcinogenesis.
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