As far as our genetic library goes, the Y chromosome seems like a mere pamphlet. Just ask any cell with a pair of X chromosomes if it feels overly bothered by that trivial loss of DNA.
Yet the departure of the male sex chromosome in tissues has been linked with the progression of numerous health problems, raising questions over why losing the Y is associated with our biology going rogue.
An investigation led by University of Arizona researchers has now found evidence of a genetic domino effect that lays the foundations for carcinomas to form, making the loss of the Y chromosome a new hallmark of pending cancer.
None of us should get too attached to our flimsy little Y chromosome. Roughly 40% of men in their 70s have tissues that no longer have a copy, having dropped it along the way as if it were as important as a receipt for last month’s groceries. If you make it to your 90s, those chances jump to nearly 60%.
This loss creates a mosaic effect throughout the body, where every cell that loses the chromosome can generate its own desert island of unique tissue.
Outside sperm production and determining sexual characteristics at critical stages through life, losing the Y chromosome’s few dozen genes shouldn’t make much difference to our body. Male bandicoots even destroy their copy intentionally in some body tissues as they grow. C’est la vie!
But humans aren’t bandicoots, and over the years, this mosaic effect has become associated with various health conditions, including chronic kidney disease, fibrosis, and an increased risk of severe COVID.
With signs of mosaic loss of the Y chromosome prevalent in renal cell and esophageal cancers, researchers have been keen to map its appearance in tissues surrounding tumors to determine how they may be related to the disease’s progress.
An analysis of 1,000 tissue samples representing 11 major organs in just over 400 male donors has now delivered a clear map and expression profile of missing Y chromosomes in typical, pre-cancerous, and malignant tumors.
The findings reshape current understanding of Y-chromosome loss in cancer development, suggesting that as the Y-chromosome becomes increasingly scarce in tissues, tumors become progressively more likely.
"We are now thinking of this as a gradient, similar to a hillside that slowly gets steeper," says urologic oncologist and senior author Dan Theodorescu. "The closer the tissue is to a cancer, the more Y chromosome loss we see.”
By measuring the degree of transcription carried out in the tissues, the researchers found that the more Y chromosomes a tissue has, the more likely it is to express genes on those chromosomes.
This dose-dependent relationship could create a “field effect” that permeates tissues, exposing them to environmental effects that predispose cells to turning cancerous.
It was already known that this gradient increased the odds of adverse outcomes arising in other conditions. Fewer Y chromosomes in individuals with heart failure made it more likely they’d have cardiovascular problems, for example.
Taken in context with previous research, the new findings suggest that the steady loss of Y chromosomes in a space creates localized inflammation, triggering tissues to go into a mode that predisposes them to cancer.
While this makes mosaic Y chromosome loss a less benign part of life for us humans, it gives cancer specialists a new signpost indicating the edges of a potentially deadly tumor.
“That gradient could one day help doctors suspect trouble in biopsies that miss a smaller cancer," says Theodorescu.
This research was published in JCI Insight
Source: The University of Arizona
