Laird Harrison

October 31, 2014

SAN DIEGO — Men who lose chromosome Y in blood cells are more likely to get cancer and to die younger, a new study shows.

The finding could lead to a new screening tool, said researcher Lars Forsberg, PhD, from Uppsala University in Sweden. "Our ultimate goal is to treat tumors before they become metastatic," he told Medscape Medical News.

Dr Forsberg presented the results, which update a previous study by his team (Nat Genet. 2014;46:624-628), here at the American Society of Human Genetics 2014 Annual Meeting.

This association between loss of chromosome Y and cancer could help explain why men tend to have a shorter lifespan and higher rates of sex-unspecific cancers than women, who do not have a Y chromosome, Dr Forsberg said.

Loss of chromosome Y becomes more and more common as men age, he said. Although researchers have been aware of the phenomenon for nearly 50 years, they are only beginning to explore the causes and effects.

Recent advances in genetic technology have meant that a blood test can detect when only a small fraction of a man's blood cells have lost chromosome Y.

Dr Forsberg and colleagues studied blood samples from the Uppsala Longitudinal Study of Adult Men, which consisted of 1153 men, 70 to 84 years of age, who had been followed clinically for up to 40 years.

The researchers estimated that 15% of men in the sample fit the definition of chromosome loss, in which at least 18% of the nucleated cells in peripheral blood had lost chromosome Y.

They found that men who lost chromosome Y did not live as long as men without the condition (5.5 vs 11.0 years).

What is quite amazing is that we can use DNA collected from blood to predict cancer in the entire body.

In fact, the men who lost chromosome Y were twice as likely as those who did not to die during the median follow-up of 8.7 years (hazard ratio [HR], 1.91; 95% confidence interval [CI], 1.17 - 3.13). In addition, they were almost 4 times as likely to die from a nonhematologic cancer (HR, 3.62; 95% CI, 1.56 - 8.41.)

"What is quite amazing is that we can use DNA collected from blood to predict cancer in the entire body," Dr Forsberg said.

These associations remained statistically significant when results were adjusted for age, hypertension, exercise habits, smoking, diabetes, body mass index, low-density-lipoprotein cholesterol, high-density-lipoprotein cholesterol, and education level.

The researchers replicated the findings in a slightly younger cohort from the Prospective Investigation of the Vasculature in Uppsala Seniors. The 488 men ranged in age from 69.8 to 70.7 years.

They found that 20.5% of the men had loss of chromosome Y in more than 13% of nucleated blood cells.

As in the longitudinal study, men with loss of chromosome Y in this cohort were almost 4 times as likely to die during a median follow-up of 7.0 years (all-cause mortality HR, 3.66; 95% CI, 1.27 - 10.54; = .016).

The researchers also confirmed their results in a study of 4400 men in the TwinGene project.

The researchers speculate that chromosome Y plays some role in the immune system's surveillance for cancer.

In a continuation of this research, they are exploring the effects of various lifestyle factors and other health conditions on chromosome Y loss, and examining the frequency and consequences of the loss in other types of cells.

The presentation stimulated a lively discussion. One woman in the audience compared loss of chromosome Y to Turner syndrome, a congenital condition in which girls are born without complete pairs of X chromosomes in some cells and are at higher risk for cancer.

In response to a question from an audience member, Dr Forsberg explained that his team did not find any correlation between loss of chromosome Y and increased risk for autosomal copy-number variation.

These findings raise many questions, said session moderator Matt Deardorff, MD, from the Children's Hospital of Philadelphia, who was not involved in the study.

"What's going on to drive this?" asked Dr Deardorff. "What's the underlying mechanism? Should we be following up to identify people at risk?"

Dr Forsberg said he believes that people at risk should be identified. If men are found to have loss of chromosome Y, clinicians can follow-up with tests to detect various cancers, possibly catching tumors in the early stages of development, when they are easier to treat, he explained.

Dr Forsberg and a coauthor, Jan Dumanski, from Uppsala University, founded Cray Innovation to market screening tools to detect the loss of chromosome Y. Dr Deardorff has disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2014 Annual Meeting: Abstract 295. Presented October 21, 2014.


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