Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer.
Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells, but the phenotypic consequences of LOY have been elusive. 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.
1] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Lars A
LA
Forsberg
1] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Chiara
C
Rasi
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.
Niklas
N
Malmqvist
1] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Hanna
H
Davies
1] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Saichand
S
Pasupulati
1] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Geeta
G
Pakalapati
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Johanna
J
Sandgren
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
Teresita
T
Diaz de Ståhl
1] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Ammar
A
Zaghlool
Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
Vilmantas
V
Giedraitis
Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
Lars
L
Lannfelt
Faculty of Medicine, University of Southampton, Southampton, UK.
Joannah
J
Score
Faculty of Medicine, University of Southampton, Southampton, UK.
Nicholas C P
NC
Cross
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
Devin
D
Absher
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Eva Tiensuu
ET
Janson
1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. [2] Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
Cecilia M
CM
Lindgren
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Andrew P
AP
Morris
1] Science for Life Laboratory, Uppsala University, Uppsala, Sweden. [2] Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Erik
E
Ingelsson
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Lars
L
Lind
1] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. [2] Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Jan P
JP
Dumanski
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood; D002869:Chromosome Aberrations; D041322:Chromosomes, Human, Y / Q000235:genetics*; D015331:Cohort Studies; D017353:Gene Deletion; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009030:Mosaicism; D009369:Neoplasms / Q000097:blood* / Q000235:genetics* / Q000401:mortality; D010641:Phenotype; D016016:Proportional Hazards Models; D012306:Risk; D012737:Sex Factors
D014408:Biomarkers, Tumor