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Men Lose Y Chromosomes With Age, And It Might Increase Their Risk Of Bladder Cancer
When urologic oncologist Dan Theodorescu thinks about his 25 years of research on bladder cancer, he remembers being in a flow. "When you hit something, you know in your gut that it's really important and everything works out because you're onto something." His latest study, published on June 21 in the journal Nature, provides a clearer picture on why men have a greater risk for bladder cancer.
The trailblazing findings draw a clear connection between the disease and damage to the Y chromosome—the genetic structure that largely distinguishes male from female in mammals at birth. Bladder cancer is a sexually dimorphic disease with men making up a disproportionate amount of cases. In fact, men have a 1 in 28 chance of developing the cancer, compared to women, who have a 1 in 91 chance. Theodorescu, now the director of Cedars-Sinai Cancer, sought to understand why men are more prone to developing this type of cancer. Beyond risk factors like smoking cigarettes, he narrowed his decades-long search to changes in hormones and chromosomes. Previous work in the field had found that an increase in androgens, which are produced in the testes and ovaries, interferes with the body's ability to fight off cancerous tumors. However, until this current study, few researchers focused on the role of chromosomes in bladder cancer.
As men get older, they naturally see the Y chromosome disappear in some cells. It's a common phenomenon—at least 40 percent of men partially lose their Y chromosome by age 70. Previous research has linked that loss with several health problems, including an increase in heart failure, Alzheimer's disease, and premature death.
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Theodorescu and his team started by studying several bladder cancer cell lines (a population of cells bred from a single common cell). They grew and isolated two sets of cells from male mice whose fathers had either kept or lost the Y chromosome. Tumor cells without a Y chromosome were more likely to exhibit aggressive growth than those with the Y chromosome.
The next step involved pooling together 16 cancer cells from mice containing a normal Y chromosome with 16 cells missing a Y chromosome. Both cell lines had a similar growth rate. However, when they studied the same cell lines in animals, the authors noticed the tumor cells containing a Y chromosome did not grow as well as cells without a Y chromosome.
While the cell models hint at the sex chromosome's role in cancer development, they don't explain why it makes bladder tumors grow more aggressively. One hypothesis is that tumor cells without a Y chromosome grow faster because they have an easier time evading a person's immune system. To test this possibility, the researchers injected Y-positive and Y-negative cells into mice bred without an immune system. Both tumor cells grew at the same rate, unlike in the cell lines where natural defenses were intact. "This was the clue that Y-negative cells were messing with the immune system somehow," Theodorescu says.
Another experiment used genetically engineered mice missing various pieces of their immune system and found that immune cells responsible for fighting infection, called T cells, were the ones most affected by the loss of the Y chromosome. "We compared T cells from Y-negative to Y-positive tumors and found Y-negative tumors are doing things to T cells to get them exhausted," Theodorescu explains. "An exhausted T cell can no longer destroy the tumor."
It's common for older men to have cells that lack a Y chromosome. One potential reason why is that when cells divide, they don't duplicate the Y chromosome because it's small. Jared Schafer for Cedars-Sinai Cancer The study might provide some insights on biological processes like adaptive immunity that are affected by disappearing Y chromosomes, says Chris Lau, a professor of medicine at the University of California, San Francisco who studies the human Y chromosome in his own research. "This could very well be the mechanism contributing to the disadvantage that seems to doom men with a mosaic loss of the Y chromosome in many other diseases, in which the immune system could play a role."
Of course, the million-dollar question is whether doctors can use this knowledge to help patients with bladder cancer. One option includes immune checkpoint inhibitors. This common form of immunotherapy blocks the receptors that tumors use to send signals that confuse T cells. It also teaches T cells how to recognize cancer cells. When Theodorescu's team administered immune checkpoint inhibitors to mice, they found those with Y-negative tumors responded better to treatment than Y-positive tumors.
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A new project Theodorescu and his colleagues are currently working on is seeing how many genes on the X chromosome are duplicates of genes found in the Y chromosome, also known as paralogs. Any mutations of these paralogs would cause a loss of gene function that could contribute to immune evasion in women, potentially adding to the risk of bladder cancer. Another issue the team is investigating is what happens to men who lose their Y chromosome and have mutations in Y-related genes on the X chromosome. "The loss may give you a worse cancer, but the response to immunotherapy could be even better," Theodorescu notes.
If all goes well, Theodorescu says he plans to use the data from his recent work to create a test that would predict a person's response to immunotherapy for any cancer. Additionally, the findings could help enhance immunotherapy and make it more effective against Y-negative tumors. Theodorescu is also not discounting the possibility of boosting immune response against other types of cancer. "If this pans out," he says, "we may be in a situation where we could use this platform to discover combination therapies that could potentially cure a significant number of patients than checkpoint inhibitor therapy alone."
No Impact Of Bladder Perforation On Tumour Recurrence In TUR Of Bladder Tumors
Egypt: A recent study published in International Urology and Nephrology found a 10% incidence of bladder perforation (BP) in patients who underwent transurethral resection of bladder tumours (TURBT) for non-muscle-invasive bladder cancer (NMIBC). Bladder perforation did not affect the probability of tumour progression, tumour recurrence, or radical cystectomy.
The symptoms were mild and needed only the prolongation of a urethral catheter in 86%. Abdominal drainage was the most common intervention required by the remaining 14%.
Bladder tumours are the most common malignancies of the urothelium, and 75–80% are non-muscle invasive. Trans-urethral resection of bladder tumours is the primary surgical management for NMIBC and is considered one of the most common endourologic procedures. It has been reported to be a reasonably safe procedure, with bladder perforation and bleeding being the most common complications. Bladder perforation, defined as any full-thickness resection of the bladder wall, is a concern; bleeding can be controlled during surgery.
Yasser Osman, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt, and colleagues reported the incidence, predictors, the impact of bladder perforation, and protocol of management in patients who underwent transurethral resection of bladder tumour in a retrospective study.
The study was conducted between 2006 and 2020 on patients who underwent TURBT for NMIBC. Based on their severity and type, bladder perforations were managed. Small BP with no or mild symptoms were controlled with urethral catheter prolongation. Those with significant extraperitoneal extravasations were managed with tube drain (TD) insertion.
Those with significant extraperitoneal extravasations were managed by inserting a tube drain (TD). Abdominal exploration was done for extensive BP and all intraperitoneal extravasations. The study included 1,570 patients (mean age 58 ± 11 years, 86% were males).
The study led to the following findings:
"We found a 10% incidence of bladder perforation with TURBT for NMIBC," the researchers wrote. "History of previous bladder resection and obturator jerk was the only independent risk factors for BP occurrence."
They revealed that the symptoms were mild in about 86% of the patients and did not need any active interventions, only prolonging the urethral catheter. For those who needed intervention, abdominal drainage was the most common procedure. There was no effect of bladder perforation on bladder tumour recurrence, progression or the probability of radical cystectomy.
Reference:
Osman, Y., Elawdy, M., Taha, DE. Et al. Bladder perforation as a complication of transurethral resection of bladder tumors: the predictors, management, and its impact in a series of 1570 at a tertiary urology institute. Int Urol Nephrol (2023). Https://doi.Org/10.1007/s11255-023-03638-6
Agent Orange Exposure Modestly Increases Bladder Cancer Risk In Vietnam Veterans
Vietnam veterans who were exposed to Agent Orange had a modestly increased risk for bladder cancer, although it did not alter the aggressiveness of the disease, according to recent study findings.
Results from this study, which were published in JAMA Network Open, may lead to more informed discussions between patients and health care providers.
"Agent Orange (exposure was) associated with an increased risk of bladder cancer, and patients should discuss this with their doctors," study author Dr. Stephen B. Williams, chief of the division of urology at The University of Texas Medical Branch in Galveston, said in an interview with CURE®.
In 2021, the VA added bladder cancer as a potential effect of Agent Orange exposure, which provided opportunities for veterans to apply for benefits.
"If (patients with bladder cancer) were in the Vietnam War (or potentially certain other places where Agent Orange was used or tested), it would be presumed that their bladder cancer was due to their service, and they could apply for benefits that could include compensation and increased health care eligibility in the Veterans Health Administration," a VA spokesperson told CURE® when the decision was made.
The researchers wrote in the published study that these findings support this VA designation.
"These results support prior investigations and further support bladder cancer to be designated as an Agent Orange-associated disease," they wrote.
In this current study, researchers analyzed data from 2,517,926 men who were veterans and were at a median age of 60 years when they entered the VA. Of these men, 629,907 (25%) were exposed to Agent Orange and 1,888,019 (75%) were not. There were several areas of interest in this study including the incidence and aggressiveness of bladder cancer.
Men who were exposed to Agent Orange had a significantly increased risk for bladder cancer compared with men who were not exposed. Findings demonstrated that the association between exposure and the risk for bladder cancer was "very slight," researchers wrote. In particular, exposure to Agent Orange was linked with a 4% increased risk for bladder cancer.
Researchers also sorted patient data by median age at VA entry, which determined that exposure to Agent Orange was not linked with the risk for bladder cancer in men older than the median age of 60 years. Despite this, the analysis found that exposure was associated with a 7% increased risk for bladder cancer in men who were younger than the median age.
"Thus, younger Vietnam veterans exposed to Agent Orange with potentially more life-years to develop bladder cancer were at greatest risk," the researchers wrote in the published study.
Veterans who were exposed to Agent Orange and were diagnosed with bladder cancer were less likely to have their disease develop into muscle-invasive bladder cancer.
"Although we cannot determine causality given the retrospective nature of our study design, this observation may be due to earlier bladder cancer detection in the group exposed to Agent Orange," the researchers wrote.
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