Blood samples

Credit: William Weinert

SAN DIEGO—Age-related loss of the Y chromosome (LOY) from blood cells is associated with an elevated risk of cancer and mortality, a new study indicates.

This finding could help explain why men tend to have a shorter life span and higher rates of non-sex-specific cancers than women, said Lars Forsberg, PhD, of Uppsala University in Sweden.

He and his colleagues presented this research at the American Society of Human Genetics 2014 Annual Meeting and described it

in a letter to Nature Genetics.

LOY, which occurs occasionally as a man’s blood cells replicate, was first reported nearly 50 years ago and remains largely unexplained in both its causes and effects. Recent advances have allowed researchers to use a blood test to detect when only a small fraction of a man’s blood cells have undergone LOY.

Dr Forsberg and his colleagues studied the relationship between LOY, cancer, and mortality using blood samples from 1153 men aged 70 to 84 years who were followed for up to 40 years.

In survival analyses, the investigators studied 982 participants who did not have cancer prior to sampling. The team adjusted their analyses for age, hypertension, exercise, smoking, diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and ancestry.

The researchers calculated the degree of LOY for each subject from the median log R ratio values for approximately 2560 probes in the male-specific region of chromosome Y (mLRR-Y).

In a primary analysis, the investigators found that men with a higher degree of LOY had an increased risk of all-cause mortality (hazard ratio [HR]=2.13, P=0.029).

And LOY was a key risk factor for cancer-related mortality (HR=3.76, P=0.022), but it was not significantly associated with non-cancer-related mortality (P=0.245).

The researchers then scored participants on the basis of a defined threshold of mLRR-Y. Men with an mLRR-Y of –0.4 or less were scored as 1, and other subjects were scored as 0.

This analysis confirmed the effect of LOY on the risk of all-cause mortality (HR=1.91, P=0.010). It also showed that median survival times in men with LOY were 5.5 years shorter than for the other subjects, representing half the survival time.

In addition, the analysis confirmed the effect of LOY on the risk of cancer-related mortality (HR=3.29, P=0.003) and death from non-hematologic cancers (HR=3.62, P=0.003).

The investigators could not test the effect of LOY on mortality related to hematologic malignancies, as only one man with an mLRR-Y of –0.4 or less died from a hematologic malignancy.

However, the team did find that the risk of any cancer diagnosis was higher in men with an mLRR-Y of −0.4 or less (HR=2.47, P=0.014). And the same was true for the risk of developing a non-hematologic cancer (HR=2.68, P=0.008).

“Many people think the Y chromosome only contains genes involved in sex determination and sperm production,” said Jan Dumanski, MD, PhD, also of Uppsala University. “In fact, these genes have other important functions, such as possibly playing a role in preventing tumors.”

The researchers noted that LOY in blood cells is associated with many different cancers, and this may be because Y chromosome genes enable blood cells to assist with immunosurveillance.

“Our hypothesis is that LOY disrupts the immunosurveillance normally conducted by blood cells, allowing tumors to grow unchecked and develop into cancer,” Dr Forsberg said.

These findings suggest a new approach to early detection of cancer risk in men: a blood test to assess LOY.

“LOY is not very dangerous in a small fraction of blood cells but becomes increasingly predictive of cancer as more cells lose their Y chromosome,” Dr Forsberg explained. “This takes years, so you’d have a window of time to do something to reduce your risk.”

The investigators are currently exploring LOY in more detail, including the effects of various lifestyle factors and other health conditions on LOY. They are also examining the frequency and consequences of LOY in different types of cells and throughout life.

LOY linked to higher risk of cancer, mortality in men