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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - DIALOY (Mosaic loss of chromosome Y (LOY) in blood cells - a new biomarker for risk of cancer and Alzheimerâ€™s disease in men)

Teaser

Summary

Mosaic loss of chromosome Y (LOY) is a during lifetime acquired mutation occurring when the Y chromosome have been lost from a percentage of the peripheral blood cells. LOY is the most common human mutation and about 10%, 20% and more than 50% of men in the ages of 70, 80 and 90 years of age, have lost the entire Y chromosome in more than 10% of the blood cells. LOY was first described more than 50 years ago and was long considered a neutral event related to normal aging. In contrast, recent results suggest that: men with detectable LOY in blood samples survives only half as long as age-matched controls. LOY can therefore help explain why men in the entire world lives shorter lives compared to females. Furthermore, the list of diseases associated with LOY are constantly growing and so far, LOY in blood has been found to be associated with outcomes such as non-hematological cancer, prostate cancer, bladder cancer, colorectal cancer, testicular germ cell tumors, myelodysplastic syndrome, Alzheimerâ€™s disease, major cardiovascular events as well as age-related macular degeneration (AMD). LOY is more common in elderly men but it also occurs and associate with cancer risk in younger men. In addition to age, smoking and genetic background are known risk factors. Smokers risk are fourfold larger compared to non-smokers and GWAS have identified 19 inherited genetic variants increasing the risk to be affected by LOY. How can LOY in blood cells increase the risk for disease in other organs and tissues? A likely explanation is that vital functions of immune cells in blood are compromized when affected with LOY. Ongoing research and preliminary data support this hypothesis. Regardless of the mechanism, LOY in blood could be used as a clinical biomarker to predict risk for various disease in middle-aged and elderly men.

The overall aim of the project is to explore and establish LOY as a new predictive biomarker for cancer and AD in men. To this end, the following three objectives are pursued:
â€¢ Objective 1 is to expand the studies of LOY as a biomarker by analyses of additional cohorts.
â€¢ Objective 2 is to investigate functional consequences of LOY through studies of changes of gene expression as a consequence of LOY and application of cell-sorting to understand the phenotypic effects from LOY in different cell-types in peripheral blood.
â€¢ Objective 3 is to develop improved methodology for LOY-detection with better sensitivity and specificity, compared to present methods, to promote the clinical utility of LOY.

Work performed

The goal of Objective 1 is to expand the studies of LOY as a biomarker by analyses of additional cohorts and additional diseases associated with LOY in leukocytes. This work is proceeding above expectation as we have now published a reproducible association between LOY and Alzheimerâ€™s disease
Furthermore, the list of diseases associated with LOY are constantly growing and so far, LOY in blood has been found to be associated with outcomes such as non-hematological cancer, prostate cancer, bladder cancer, colorectal cancer, testicular germ cell tumors, myelodysplastic syndrome, major cardiovascular events as well as age-related macular degeneration (AMD). The main goal of Objective 2 is to understand the functional consequences of LOY in blood cells. We are for example studying changes in gene expression as a consequence of LOY, both in different cell types sorted from blood by FACS and RNA-Seq, as well as by single-cell transcriptomic analyses using the 10X Chromium system, in an ongoing project which is close to submission. Hence, results from this project shows that cells without the Y chromosome have reproducible and systematic disturbances in expression in autosomal genes important for various biological functions. In another tier of this Objective we are investigating which cells types are mostly affected with LOY in patients diagnosed with cancer and Alzheimer\'s disease, compared to controls. We have recently generated remarkable and logic results from this project, which identifies specific cell-types that are leading to LOY-associated outcomes. Hence, previous findings and publications have been showing associations between LOY and various outcomes but these new results indicates, for the first time, causality. In Objective 3 we are developing improved methodology for LOY-detection with increased sensitivity and specificity, compared to present methods, to promote the clinical utility of LOY. This part of the project is also proceeding well beyond expectations. The planned custom Y-chip SNP-array is on the market and used by us and others. Furthermore, we developed a sensitive ddPCR protocol which will be published soon. The LOY-detection part of the project have also been expanded and will continue the coming years.

Final results

We are world leading in the field of single-cell transcriptomic analyses (scRNAseq). With this new method, which is gaining huge popularity in the field of human genetics, we can study gene expression in single-cells and thus, the effects of LOY at the most relevant and high resolution level. We will continue to generate data using scRNAseq and similar approaches during the rest of the project, which will give us the opportunity to understand in great details what acctually happens in cells after loosing the Y chromosome. The information gained from these analyses will also be used to identify targets for improved LOY-detection. Still today, most such analyses are based on DNA level technologies, but I envision that both RNA and protein level markers can be utilized for this purpose, which we aim to explore.