Understanding how Y chromosome loss affects lung cancer treatment outcomes could guide treatment decisions
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Men with the most common form of lung cancer appear to be particularly susceptible to losing the Y chromosome in their cells, which could have both advantages and disadvantages. On the one hand, this protects their tumors from destruction by the immune system, but on the other hand, it enhances the effectiveness of a commonly used cancer drug.
As men age, many of their cells are likely to mutate and lose their Y chromosomes. In the case of immune cells, this has been linked to heart disease and a shorter lifespan. Evidence is also accumulating that loss of Y chromosomes from cancer cells affects disease progression, with bladder cancer being the best-studied example.
For a cell, the loss of Y is a binary event: either it occurs or it does not occur. But what appears to be important for health outcomes is the fraction of cells of a particular type that lack a Y chromosome.
The latest research began with Dawn DeMeo of Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues analyzing the expression levels of Y chromosome genes in a public database of lung adenocarcinoma samples, the most common type of lung cancer, which begins in the mucus-producing cells lining the airways. Emerging links between Y loss and various conditions have required researchers to evaluate this in more detail via gene expression studies, DeMeo says.
They found that cancer cells often lacked Y chromosomes, while healthy lung cells and immune cells did not. This occurred regardless of whether tissue donors smoked, a behavior known to cause lung cancer and induce Y loss.
The loss of Y has also accumulated. “There is a group of people who are losing more and more Y chromosomes in more and more cells, so a greater proportion of the tumor has Y loss,” says team member John Quackenbush from Harvard University.
To find out why this buildup occurs, the team looked at other genetic changes in cells without Y. This linked the loss to reduced expression of a common set of antigens that cancer cells often produce, which usually signal immune system cells called T cells that these cancer cells are abnormal and should be attacked. This reduced expression then allows cancer cells lacking Y to proliferate out of control.
“What this suggests is that as tumor cells lose their Y chromosomes, they are increasingly able to evade immune surveillance, which suggests that they are being selected,” says Quackenbush. T cells were consistently less frequent in samples characterized by Y loss than in Y-retaining tumors.
The most positive news came when researchers looked at data from 832 people with lung adenocarcinoma who had been treated with the immune checkpoint inhibitor pembrolizumab, a drug that reinvigorates a person’s natural immune response to tumors by reversing the suppression of T cells. They found that loss of Y was associated with better treatment outcomes.
“When you have LOY [loss of Y]you’re more responsive to checkpoint inhibitors,” says Dan Theodorescu of the University of Arizona, who discovered the same result in bladder cancer in 2023. “It’s validated here in a completely different data set. »
However, although loss of Y is linked to men having shorter lifespans than women, existing data suggest that it does not affect the survival of people with lung adenocarcinoma. Research needs to uncover how the actions of these mutations and their effects on survival vary across cancer types, Theodorescu says. With this better understanding, Y loss could one day be used as a biomarker to inform clinical decision-making, he says.
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