Loss of chromosome Y in primary tumors

Meifang Qi; Jiali Pang; Irene Mitsiades; Andrew A Lane; Esther Rheinbay

doi:10.1016/j.cell.2023.06.006

Loss of chromosome Y in primary tumors

Cell. 2023 Jun 22:S0092-8674(23)00646-3. doi: 10.1016/j.cell.2023.06.006. Online ahead of print.

Authors

Meifang Qi¹, Jiali Pang², Irene Mitsiades³, Andrew A Lane⁴, Esther Rheinbay⁵

Affiliations

¹ Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02129, USA; Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
³ Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA.
⁴ Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital Department of Pathology, Boston, MA 02114, USA. Electronic address: erheinbay@mgh.harvard.edu.

PMID: 37385248
DOI: 10.1016/j.cell.2023.06.006

Abstract

Certain cancer types afflict female and male patients disproportionately. The reasons include differences in male/female physiology, effect of sex hormones, risk behavior, environmental exposures, and genetics of the sex chromosomes X and Y. Loss of Y (LOY) is common in peripheral blood cells in aging men, and this phenomenon is associated with several diseases. However, the frequency and role of LOY in tumors is little understood. Here, we present a comprehensive catalog of LOY in >5,000 primary tumors from male patients in the TCGA. We show that LOY rates vary by tumor type and provide evidence for LOY being either a passenger or driver event depending on context. LOY in uveal melanoma specifically is associated with age and survival and is an independent predictor of poor outcome. LOY creates common dependencies on DDX3X and EIF1AX in male cell lines, suggesting that LOY generates unique vulnerabilities that could be therapeutically exploited.

Keywords: Y chromosome; cancer genomics; sex chromosome; somatic copy number variation; uveal melanoma.