Mosaic loss of chromosome Y is associated with common variation near TCL1A

Zhou, Weiyin; Machiela, Mitchell J.; Freedman, Neal D.; Rothman, Nathaniel; Malats, Núria; Dagnall, Casey; Caporaso, Neil E.; Teras, Lauren T.; Gaudet, Mia M.; Gapstur, Susan M.; Stevens, Victoria L.; Jacobs, Kevin B.; Sampson, Joshua N.; Albanês, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Berndt, Sonja I.; Hoover, Robert N.; Black, Amanda; Silverman, Debra T.; Figueroa, Jonine D.; García-Closas, Montserrat; Real, Francisco X.; Earl, Julie; Marenne, Gaëlle; Rodríguez-Santiago, Benjamín; Karagas, Margaret R.; Johnson, Alison; Schwenn, Molly; Wu, Xifeng; Gu, Jian; Ye, Yuanqing; Hutchinson, Amy; Tucker, Margaret A.; Pérez-Jurado, Luís A.; Dean, Michael; Yeager, Meredith; Chanock, Stephen J.

doi:10.1038/ng.3545

Cited by 141 publications

(210 citation statements)

References 35 publications

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“…1b). Corroborating previous studies1314, the observed LOY was associated with older age in patients ( P = 0.04); the average age of patients with LOY in the peripheral blood was 68.9 year in comparison to 58.8 year in those without this abnormality. Notably, we did not observe any association between age of patients and extent of somatic LOY in tumors of the affected patients.…”

Section: Resultssupporting

confidence: 86%

Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

Arseneault

Monlong

Vasudev

et al. 2017

Sci Rep

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Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively.

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Section: Resultssupporting

confidence: 86%

Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

Arseneault

Monlong

Vasudev

et al. 2017

Sci Rep

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“…LOY is the most common known acquired human mutation in surveyed populations 96 , and its frequency increases with age ( Figure 3A), and is associated with smoking 97 . It has also been associated with decreased survival time from all causes ( Figure 3B), including cancer ( Figure 3C) 96 , and with increased risk of Alzheimer disease ( Figure 3D) 98 ; these associations have been replicated in some but not all studies [99][100][101][102] . The SNP rs2887399 near TCL1A on chromosome 14 is associated with LOY risk (OR = 1.55, 95% CI = 1.36-1.78; P = 1.37 x 10 -10 ) 101 and more recently 18 additional associated genomic regions have been identified 102,103 .…”

Section: Y-chromosomal Aneuploidymentioning

confidence: 80%

Human Y-chromosome variation in the genome-sequencing era

2017

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The properties of the human Y chromosome -male-specificity, haploidy, and escape from crossing-over -make it an unusual component of the genome, and have led to its genetic variation becoming a key part of studies of human evolution, population history, genealogy, forensics and male medical genetics.Next-generation sequencing (NGS) technologies have driven recent progress in these areas. In particular, NGS has yielded direct estimates of mutation rates and an unbiased and calibrated molecular phylogeny of unprecedented detail. Moreover, the availability of direct-to-consumer NGS services is fuelling a rise of 'citizen scientists', whose interest in resequencing their own Y chromosomes is generating a wealth of new data.

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“…A recent genome-wide approach identified TCL1A that is associated to hematological malignancies as a genetic susceptibility locus for LOY at chromosome 14. 17 It might be that LOY chromosome reflects general genomic instability of which the small and last to be replicated Y chromosome is the first victim. Rapidly dividing cells might not take their time to replicate its telomeres, and this may lead eventually to loss of the entire chromosome.…”

Section: Discussionmentioning

confidence: 99%

Loss of Y Chromosome in Blood Is Associated With Major Cardiovascular Events During Follow-Up in Men After Carotid Endarterectomy

Haitjema

Kofink

Setten

et al. 2017

Circ Cardiovasc Genet

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L oss of the Y chromosome (LOY) in blood cells was already described in the 1960s and affects ≈15% of the male population of older age.1 Only recently, LOY was associated with a higher risk of (nonhematological) cancer and overall mortality. 2,3 This relationship was speculated to be because of smoking and a disrupted tumor immunosurveillance. See Editorial by Dumanski et al See Clinical PerspectiveThe Y chromosome exhibited an immuneregulatory function by acting as a global transexpression quantitative trait locus in mice. 8 The Y chromosome directly mediated changes in the transcriptome of CD4 + T cells and macrophages, contributing to altered gene expression and alternative splicing. A role in global immune response was also found in the monocyte and macrophage transcriptome results of males with haplotype I that exhibited a 50% greater risk of myocardial infarction. 9 Comparison of gene expression data between haplotype I and other haplotypes revealed pathways that are related to inflammation and immunity, revealing downregulation of adaptive immunity and upregulation of inflammatory response in haplotype I carriers.Background-Recent studies found an immune regulatory role for Y chromosome and a relationship between loss of Y chromosome (LOY) in blood cells and a higher risk of cancer and mortality. Given involvement of immune cells in atherosclerosis, we hypothesized that LOY is associated with the severity of atherosclerotic plaque characteristics and outcome in men undergoing carotid endarterectomy. Methods and Results-LOY was quantified in blood and plaque from raw intensity genotyping data in men within the Athero-Express biobank study. Plaques were dissected, and the culprit lesions used for histology and the measurement of inflammatory proteins. We tested LOY for association with (inflammatory) atherosclerotic plaque phenotypes and cytokines and assessed the association of LOY with secondary events during 3-year follow-up. Of 366 patients with carotid endarterectomy, 61 exhibited some degree of LOY in blood. LOY was also present in atherosclerotic plaque lesions (n=8/242, 3%). LOY in blood was negatively associated with age (β=−0.03/10 y; r 2 =0.07; P=1.6×10 -7 ) but not with cardiovascular disease severity at baseline. LOY in blood was associated with a larger atheroma size (odds ratio, 2.15; 95% confidence interval, 1.06-4.76; P=0.04); however, this association was not significant after correction for multiple testing. LOY was independently associated with secondary major cardiovascular events (hazard ratio=2.28; 95% confidence interval, 1.11-4.67; P=0.02) in blood when corrected for confounders. Conclusions-In this hypothesis-generating study, LOY in blood is independently associated with secondary major cardiovascular events in a severely atherosclerotic population. Our data could indicate that LOY affects secondary outcome via other mechanisms than inflammation in the atherosclerotic plaque. (Circ

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Mosaic loss of chromosome Y is associated with common variation near TCL1A

Cited by 141 publications

References 35 publications

Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma

Human Y-chromosome variation in the genome-sequencing era

Loss of Y Chromosome in Blood Is Associated With Major Cardiovascular Events During Follow-Up in Men After Carotid Endarterectomy

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