It’s long been known men fare worse with colon cancer than women. The presumption was male smoking habits, extra meat consumption and maybe hormones made the difference.
But a pair of studies out Wednesday in the journal Nature finds genetics can sometimes explain why sex matters.
When tumor cells lose the Y chromosome that characterizes male cells, men with bladder cancer fare worse and those with colon cancer fare better.
“What sets these studies apart is really that they’re able to assign a mechanism (to explain sex differences),” said Kevin Haigis, a cancer biologist and chief scientific officer of the Dana-Farber Cancer Institute in Boston, who was not involved in the research. “And that mechanism is linked to the Y chromosome.”
Identifying sex differences in cancer can call attention to patients at higher risk for recurrence and therefore in need of closer surveillance and potentially additional therapies, said Dr. Ronald DePinho, who led one of the studies.
To best target cancer care, researchers have to study how genetics operate in the context of a patient’s sex, race, age and lifestyle, said DePinho, a professor of cancer biology at MD Anderson Cancer Center in Houston.
“These are all things we have to pay attention to if we are going to realize the full potential of precision oncology.”
Sex differences and cancer
Males typically have one Y chromosome and one X, while females have two Xs. But with advancing age, some male cells can lose their Y chromosome.
Men with few Y chromosomes in their blood cells, for instance, are more prone to heart disease, neurological conditions and cancer.
David Page, a biologist at the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology, has devoted his career to exploring ways the Y chromosome impacts human health. He’s excited other researchers are investigating the role of the Y in cancer.
“The attention that’s being drawn to the role of the Y chromosome is fabulous,” Page said. “What I find most striking is the idea that one can work the Y chromosome into a conversation about cancers without blinking an eye. That’s a pretty big change.”
Haigis said he’s also happy to see scientists exploring something other than hormones to explain sex differences in cancer. “What these studies really reveal is that there are molecular mechanisms beyond hormones that can account for sex differences, and maybe we need to consider these non-hormone-related mechanisms when we’re thinking about outcomes,” he said.
Colon cancer: Men fare worse if they have a mutation in KRAS gene
The study led by DePinho showed male mice with a mutation in a gene called KRAS have worse colon cancer outcomes than either females with a KRAS mutation or males without one. The same is true in people.
KRAS regulates a gene on the Y chromosome, the study showed, and when a KRAS mutation makes the KDM5D gene more active, cancer is more likely to spread and escape the immune system’s ability to recognize and attack tumors, the study showed.
This suggests that men with colon cancer and a KRAS mutation ‒ which occurs at least 30% of the time ‒ should be followed more carefully after surgery and perhaps receive extra treatment to improve their outcomes, DePinho said.
“The knowledge of genetic alterations that confer a poor or favorable prognosis is very helpful to physicians to be able to enlist those patients into more aggressive or not surveillance,” DePinho said, as well as to consider additional therapies.
“You don’t want to carpet-bomb. You don’t want to treat colon cancer in general just to treat the KRAS-mutant colon cancers,” DePinho said, “so this story is helpful because it tells you that specifically KRAS-mutant colorectal cancer in men are the ones we really have to shine a spotlight on.”
Page urged caution in assuming what happens in mice will happen in people, but he said the findings are compelling and worth exploring further.
Bladder cancer: role of lost Y
Bladder cancer is more common in men than women, even after correcting for male lifestyles, but women tend to have a worse outcome, said Dr. Dan Theodorescu, a bladder cancer specialist and co-author of the other study. Male patients whose bladder cancers have lost the Y chromosome fare just as badly as women, said Theodorescu, who directs the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai in Los Angeles.
He and his team showed that in bladder cancers lacking Y chromosomes, the immune system doesn’t function as well. Immune soldiers known as T cells were “paralyzed and tired,” he said. “The natural thing to ask when you know that is what can we do to make them hearty and able to destroy the cancer?”
Existing immunotherapy drugs that take the brake off T cells are more effective in bladder cancers that have lost their Y chromosomes than in those that still have it. This suggests but needs to be shown in clinical trials that the drugs might help men whose bladder cancer has lost their Y chromosomes, he said.
In other tumor types, anywhere from 2% to 78% of cancer cells have lost their Y chromosomes, Theodorescu said. “We now know this is not unique to bladder cancer.” The team plans to study whether the lost Y in other cancers has the same effect as it seems to have in bladder cancer and therefore whether those patients could benefit from immune therapy.
“I’m hoping that this paper is going to trigger an avalanche of (other) studies,” because I think it’s fascinating,” he said.
Contact Karen Weintraub at kweintraub@usatoday.com.
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