Cancer cells erase sections of Y chromosome to trigger tumor growth in men

A new study found that cancer cells selectively chip away gene-rich sections of the Y chromosome, triggering ripples that regulate tumor growth. 

Co-led by University of Arizona Cancer Center physician-scientist Dr. Dan Theodorescu, the paper, "Recurrent deletions and regulatory disruption of the Y chromosome in cancer," was published in the journal Communications Biology.

Each cell in men's bodies usually contains one X and one Y chromosome. The Y chromosome has long been known to determine male sex, but researchers are learning its genes also play other roles in cells throughout the body. "Loss of Y" is a common genetic change in aging men, often found in blood cells. Y loss also occurs in cancer cells themselves, which is the focus of this study.

A research team of cancer specialists and computational biologists analyzed genome sequencing and gene expression data from 160 male cell lines in the Cancer Cell Line Encyclopedia. Researchers focused on cancer cell lines to eliminate non-cancerous background cells that can obscure genetic signals in tumor samples.

Using a novel scoring system called the Y EroSion Score, or YES, the team mapped Y chromosome loss as a continuous spectrum of erosion rather an all-or-nothing state.

Traditionally, researchers looked at losing the Y chromosome in a cancer cell as an all-or-nothing event. It was either there or completely gone. By zooming in with high-coverage genome sequencing, we discovered that cancer cells are actually wearing down specific, gene-rich regions of the Y chromosome to help tumor growth while keeping other regions intact."

Dr. Dan Theodorescu, study's senior author and Nancy C. and Craig M. Berge endowed chair and Director, University of Arizona Cancer Center

Researchers identified 24 protein-coding genes on the Y chromosome that were recurrently lost. Fifteen of these genes were also found to be lost in at least one of two external datasets: single-nucleus sequencing of bladder tumors and a pan-cancer clinical sequencing panel.

When the team compared the findings to genome sequencing data from healthy men in the 1000 Genomes Project, they found no evidence of the same Y chromosome deletions. The findings show that these Y chromosome losses are acquired over time rather than inherited traits.

"When specific parts of the Y chromosome are lost, the effects reverberate through the entire cell, affecting pathways that determine stress, growth and immune responses," said Theodorescu, who is also a professor at the U of A College of Medicine – Tucson. "Understanding which parts are lost gives us a clearer map of how tumors evolve and could eventually lead to targeted therapies for patients."

Theodorescu's previous related research found that loss of the Y chromosome in cancer cells in men as they age can help tumors evade the immune system, which helps explain why the loss of the chromosome has been linked to increased mortality from carcinomas[CO1] and other cancers. The groups other research suggests that loss of the Y chromosome in normal-appearing tissues acts as an early warning sign and may mark a hidden zone of genetic vulnerability for cancer to develop.

Theodorescu's co-authors on the new research paper included Trini Nguyen, Aditi Kuchi and Nicholas Tatonetti of Cedars-Sinai Medical Center.

This research was funded by the National Institutes of Health under grant mumbers R35GM131905 and R35CA294022.