Lars Forsberg's research on LOY

Loss of chromosome Y (LOY) - a new biomarker for cancer and Alzheimer’s disease in men

Men live on average 6 years shorter compared to women in the developed countries. This difference has been recognized for centuries but the underlying factor(s) have been unknown. As a male specific genetic risk factor - LOY could help explain this sex difference.

Loss of chromosome Y is the most common during life acquired human mutation and can be observed in up to 20 % of men older than 80 years of age, and it also occurs in younger men. The peripheral blood of men affected with LOY consists of a mixture of cells with or without the Y chromosome and using standard molecular methods the condition can readily be detected when >5-10% of the blood cells lack the Y chromosome.

LOY is associated with increased disease risk

LOY was first described more than half a century ago but its phenotypic consequences have been elusive with a prevailing consensus that this mutation was phenotypically neutral and related to normal aging.

However, our recent discoveries show that during life acquired LOY in blood is associated with risk for all-cause mortality and risk for non-hematological cancers (Nat. Genet. 2014, PMID:24777449) as well as Alzheimer’s disease (AJHG 2016, PMID:27231129). We have also shown that LOY is induced by smoking and that the fraction of cells with LOY decreased in smokers with LOY after smoking cessation (Science 2015, PMID:25477213).

We have now established that LOY in blood is associated with disease processes in other tissues. But how can a mutation in blood cells be associated with risk for disease in other organs? This is a still open question and one hypothesis is that a defective immunosurveillance function of immune cells without the Y chromosome could be involved.

Ongoing projects

The possible link between defective immunosurveillance function and LOY is now studied in several ongoing projects in my group with focus on three objectives:

  1. Expanding the study of LOY and associations with disease risks in still larger cohorts.
  2. Investigating functional aspects of LOY.
  3. Developing improved technology for LOY detection.

For example, we are now collecting and sorting blood cells from men affected with various types of cancer, Alzheimer’s disease as well as controls, to investigate what subset of immune cells, when affected by LOY, is responsible for the phenotypic consequences observed. Furthermore, we are working to understand what happens in cells without the Y chromosome by for example study changes in gene expression in cells with LOY. The overall goal is to develop LOY as a new, strong and predictive biomarker.