Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer

• Published in: Nature genetics Vol. 46; no. 6; pp. 624 - 628
• Main Authors: Forsberg, Lars A, Rasi, Chiara, Malmqvist, Niklas, Davies, Hanna, Pasupulati, Saichand, Pakalapati, Geeta, Sandgren, Johanna, de Ståhl, Teresita Diaz, Zaghlool, Ammar, Giedraitis, Vilmantas, Lannfelt, Lars, Score, Joannah, Cross, Nicholas C P, Absher, Devin, Janson, Eva Tiensuu, Lindgren, Cecilia M, Morris, Andrew P, Ingelsson, Erik, Lind, Lars, Dumanski, Jan P
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2014; Nature Publishing Group
• Subjects: 45; 45/23; 45/61; 45/77; 631/208; 692/308/2056; 692/699/67; 692/700/478/174; Age; Aged; Aged, 80 and over; Agriculture; Animal Genetics and Genomics; Biomarkers, Tumor - blood; Biomedicine; Cancer; Cancer Research; Carcinogenesis; Chromosome Aberrations; Chromosomes; Chromosomes, Human, Y - genetics; Cohort Studies; Councils; Deoxyribonucleic acid; Disease susceptibility; DNA; Gene Deletion; Gene Function; Genetic research; Genetic Variation; Genomes; Genotype; Health risks; Hematology; Human Genetics; Humans; letter; Loy; Male; Middle Aged; Mortality; Mosaicism; Neoplasms - blood; Neoplasms - genetics; Neoplasms - mortality; Oncology, Experimental; Phenotype; Properties; Proportional Hazards Models; Risk; Risk factors; Sex Factors; Sex factors in disease; Studies; Survival analysis; Y chromosome
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2966

Lars Forsberg, Jan Dumanski and colleagues report that age-related loss of chromosome Y in peripheral blood is associated with increased risks of all-cause mortality, cancer mortality and non-hematological cancer mortality. Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained 1 , 2 . Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells 3 , 4 , but the phenotypic consequences of LOY have been elusive 5 , 6 , 7 , 8 , 9 , 10 . From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17–3.13; 637 events) and non-hematological cancer mortality (HR = 3.62, 95% CI = 1.56–8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all-cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis.