Understanding how Y chromosome loss affects lung cancer treatment outcomes can help guide treatment decisions.
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Men with the most common form of lung Cancer appear to be uniquely susceptible to the loss of the Y chromosome from their cells, which may have its advantages and disadvantages. On the one hand, it protects tumors from destruction by the immune system, but on the other hand, it increases the effectiveness of a widely used cancer drug.
As they age, many of their cells are prone to mutations and loss of Y chromosomes. It happened with immune cells associated with heart disease and shorter life expectancy. There is also accumulating evidence that cancer cells that lose their Y chromosomes influence disease progression, with bladder cancer being the best-studied example.
For a cell, the loss of Y is a binary event: it either happens or it doesn’t. But what seems important to health The results are the proportion of a particular cell type that lacks a Y chromosome.
Recent research began with Demeo Dawn at Brigham and Women's Hospital in Boston, Massachusetts, and her colleagues are analyzing Y chromosome gene expression levels in a public database of samples of lung adenocarcinoma, the most common type of lung cancer that begins in the mucus-producing cells lining the airways. New connections between Y loss and various conditions have led researchers to evaluate it in more detail through gene expression studies, DeMeo said.
They found that cancer cells often lack Y chromosomes, unlike healthy lung cells and immune cells. This occurred regardless of whether the tissue donors smoked or not, a behavior known to cause lung cancer and lead to Y loss.
Y's losses also accumulated. “There is a group of people who are losing more and more Y chromosomes in more and more cells, so a large proportion of tumors show Y loss,” says a team member. John Quackenbush at Harvard University.
To find out why this accumulation occurs, the team looked at other genetic changes in cells without Y. This linked the loss to decreased expression of a common set of antigens that cancer cells often produce and that normally signal immune system cells called T cells tell you that these cancer cells are abnormal and should be attacked. This reduction in expression then allows cancer cells lacking Y to proliferate unchecked.
“This suggests that as tumor cells lose their Y chromosomes, they are increasingly able to evade immune surveillance, and this may indicate that they are selected for this,” says Quackenbush. T cells were less common in Y-losing samples than in Y-sparing tumors.
More positive news came when researchers looked at data from 832 people with lung adenocarcinoma who were treated with the immune checkpoint inhibitor pembrolizumab, a drug that boosts a person's natural immune response to tumors, reversing T-cell suppression. They saw that loss of Y was associated with better treatment outcomes.
“When you have LOY [loss of Y]you are more sensitive to checkpoint inhibitors,” says Dan Theodorescu at the University of Arizona, which discovered same result for bladder cancer in 2023. “This is confirmed here in a completely different set of data.”
However, although Y loss is associated with a shorter life expectancy for men than women, existing data suggests it does not affect the survival rate of people with lung adenocarcinoma. “Research needs to explore how the effect of such mutations and their impact on survival differs depending on the type of cancer,” Teodorescu says. With this better understanding, Y loss could one day be used as a biomarker to guide clinical decisions, he said.
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