A team of scientists, led by researchers at The Wistar Institute, has identified a possible explanation for why middle-aged adults were hit especially hard by the H1N1 influenza virus during the 2013-2014 influenza season. The findings offer evidence that a new mutation in H1N1 viruses potentially led to more disease in these individuals. Their study suggests that the surveillance community may need to change how they choose viral strains that go into seasonal influenza vaccines, the researchers say.

“We identified a mutation in recent H1N1 strains that allows viruses to avoid immune responses that are present in a large number of middle-aged adults,” said Scott Hensley, Ph.D., a member of Wistar’s Vaccine Center and an assistant professor in the Translational Tumour Immunology program of Wistar’s Cancer Center.

Historically, children and the elderly are most susceptible to the severe effects of the influenza viruses, largely because they have weaker immune systems.  However, during the 2013-2014 physicians saw an unusually high level of disease due to H1N1 viruses in middle-aged adults—those who should have been able to resist the viral assault. Although H1N1 viruses recently acquired several mutations in the haemagglutinin (HA) glycoprotein, standard serological tests used by surveillance laboratories indicate that these mutations do not change the viruses’ antigenic properties.

However, Wistar researchers have shown that, in fact, one of these mutations is located in a region of HA that allows viruses to avoid antibody responses elicited in some middle-aged adults. Specifically, they found that 42 percent of individuals born between 1965 and 1979 possess antibodies that recognize the region of HA that is now mutated. The Wistar researchers suggest that new viral strains that are antigenically matched in this region should be included in future influenza vaccines.

“Our immune systems are imprinted the first time that we are exposed to influenza virus,” Hensley said. “Our data suggest that previous influenza exposures that took place in the 1970s and 1980s influence how middle-aged people respond to the current H1N1 vaccine.”

The researchers noted that significant antigenic changes of influenza viruses are mainly determined using anti-sera isolated from ferrets recovering from primary influenza infections. However humans are typically re-infected with antigenically distinct influenza strains throughout their life.  Therefore, antibodies that are used for surveillance purposes might not be fully reflective of human immunity. Wistar Institute

Tumour cells isolated from the blood of patients with triple negative breast cancer reveal similar cancer-driving mutations as those detected from standard biopsy, suggesting that circulating cells could one day replace tissue biopsies
The genetic fingerprint of a metastatic cancer is constantly changing, which means that the therapy that may have stopped a patient’s cancer growth today, won’t necessarily work tomorrow. Although doctors can continue to biopsy the cancer during the course of the treatment and send samples for genomic analysis, not all patients can receive repeat biopsies. Taking biopsies from metastatic cancer patients is an invasive procedure that it is frequently impossible due to the lack of accessible lesions.  Research suggest that tumour cells circulating in the blood of metastatic patients could give as accurate a genomic read-out as tumour biopsies.

“Counting the number of circulating tumour cells (CTCs) can tell us whether a patient’s cancer is aggressive, or whether it is stable and responding to therapy,” says the article’s first author Sandra V. Fernandez, Ph.D., assistant professor of Medical Oncology at Thomas Jefferson University. “Our work suggests that these cancer cells in the blood also accurately reflect the genetic status of the parent tumour or its metastases, potentially giving us a new and easy to source of genomic information to guide treatment.”

First discovered for their diagnostic potential in 2004, circulating tumour cells are beginning to be used in the clinic to help guide treatment decisions and track a patient’s progress as the cancer progresses. Although other studies have pooled the collected CTCs and compared their collective genetic signature to that of the primary tumour, this is the first study to look at the genomic signature of individual tumour cells in circulation. In order to isolate single tumour cells from the blood, the authors used a new technology, DEPArrayTM , in their laboratory.
The researchers compared tissue biopsies surgically removed from two patients with inflammatory breast cancer with circulating tumour cells (CTCs). Breast tissue samples from both patients showed a specific mutation in a region of a cancer-driving gene, p53. The authors studied this mutation in several CTCs isolated from both patients. They found that in several of the CTCs collected, the mutations matched with the tumour biopsy, however in one patient, some of circulating tumour cells had an additional mutation. “Since inflammatory breast cancer is a very rapidly changing disease, we think this additional mutation may have been acquired after the original surgical biopsy was taken,” said Dr. Fernandez. In the case where an additional p53 mutation was found, the blood to isolate CTCs were drawn one year later than the breast tissue biopsy was taken.
Although further work analyzing a greater number of genes and samples is needed, the work shows that CTCs offer the possibility of capturing the most current genomic information in an easy-to-obtain sample such as blood, thus helping guide treatment decisions. It also suggests that it may be necessary to test more than one cell for the most accurate reading, as the CTC population appears to be heterogenous. Thomas Jefferson University (TJU)

Age-related loss of the Y chromosome (LOY) from blood cells, a frequent occurrence among elderly men, is associated with elevated risk of various cancers and earlier death.

This finding could help explain why men tend to have a shorter life span and higher rates of sex-unspecific cancers than women, who do not have a Y chromosome, said Lars Forsberg, PhD, lead author of the study and a geneticist at Uppsala University in Sweden.

LOY, which occurs occasionally as a given man’s blood cells replicate – and thus takes place inconsistently throughout the body – was first reported nearly 50 years ago and remains largely unexplained in both its causes and effects. Recent advances in genetic technology 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 colleagues studied blood samples from 1,153 elderly men aged 70 to 84 years, who were followed clinically for up to 40 years. They found that men whose samples showed LOY in a significant fraction of their blood cells lived an average of 5.5 years less than men whose blood was not affected by LOY. In addition, having undergone LOY significantly increased the men’s risk of dying from cancer during the course of the study. These associations remained statistically significant when results were adjusted for men’s age and other health conditions.

“Many people think the Y chromosome only contains genes involved in sex determination and sperm production,” said Jan Dumanski, MD, PhD, co-author on the study and a professor at Uppsala University. “In fact, these genes have other important functions, such as possibly playing a role in preventing tumours.” When LOY takes place, Y chromosome genes are not expressed, and this tumour prevention would be reduced.

Interestingly, LOY in blood cells is associated with many different cancers, including those outside of the blood system. This may be because Y chromosome genes enable blood cells to assist with immunosurveillance, the process by which the immune system detects and kills tumour cells to prevent cancer.

“Our hypothesis is that LOY disrupts the immunosurveillance normally conducted by blood cells, allowing tumours 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 researchers are currently exploring LOY in more detail, including the effects of various lifestyle factors and other health conditions. They are also examining the frequency and consequences of LOY in different types of cells and throughout the life course. The American Society of Human Genetics

Down syndrome is the most common chromosomal abnormality in humans, involving a third copy of all or part of chromosome 21. In addition to intellectual disability, individuals with Down syndrome have a high risk of congenital heart defects. However, not all people with Down syndrome have them – about half have structurally normal hearts.

Geneticists have been learning about the causes of congenital heart defects by studying people with Down syndrome. The high risk for congenital heart defects in this group provides a tool to identify changes in genes, both on and off chromosome 21, which are involved in abnormal heart development.

Researchers at Emory University School of Medicine, with colleagues at Johns Hopkins University, Oregon Health Science University, and University of Pittsburgh, report results from the largest genetic study of congenital heart defects in individuals with Down syndrome.

The team found that infants with congenital heart defects, in the context of Down syndrome, were more likely to have rare, large genetic deletions. Those deletions tended to involve genes that affect cilia, cellular structures that are important for signalling and patterning in embryonic development.

These new findings, along with other recent studies, suggest that the risk for congenital heart defects in Down syndrome can come from several genes and environmental factors, in addition to the substantial risk from the extra chromosome 21.

“In Down syndrome, there’s a 50-fold increase in risk for heart defects, which is enormous,” says senior author Michael Zwick, PhD, associate professor of human genetics and paediatrics at Emory. “Studying congenital heart defects in the ‘at risk’ Down syndrome population can make it possible to reveal genes that impact the risk of heart defects in all children, including those with typical number of chromosomes.”

“Understanding the origin of heart disorders in individuals with Down syndrome may reveal aspects of biology that would allow better personalization of their health care, since genetic alterations that affect the heart may also affect other organs, such as the lungs or gut,” Zwick says.

“Our partnership with families who have a child with Down syndrome and our investment in a comprehensive clinical data and biorepository will continue to provide resources to study not only heart defects, but also other Down-syndrome associated medical conditions such as cognitive function, leukaemia,  and dementia,” says co-author Stephanie Sherman, PhD, professor of human genetics at Emory University School of Medicine.

The study included 452 individuals with Down syndrome. 210 had complete atrioventricular septal defects (AVSDs), a serious heart defect that is relatively common among those with Down syndrome (about 20 percent). The remaining 242 had structurally normal hearts. The Emory team used high density microarrays to probe more than 900,000 sites across the human genome to detect structural variation, including deletions or duplications of DNA.

An atrioventricular septal defect means that the central region of the heart separating the atria from the ventricles has failed to form properly. Such defects increase the workload on the heart, and a complete AVSD leads to heart failure: fluid buildup in the lungs and difficulty breathing, requiring surgery in the first year of life.

The team’s results add to evidence for a connection between AVSDs and cilia. Ciliopathies are a class of genetic disorders that include kidney, eye, and neurodevelopmental disorders. Cells in the airways have mobile cilia which sweep mucus and dirt out of the lungs, but almost every cell in the body has a primary (sensory) cilium.

“The finding that ciliome genes may be disrupted in children with Down syndrome and AVSD may indicate differences in life-time care for these individuals,” Zwick says. “This is a suggestive result that needs replication in a larger group.”

To confirm and strengthen the findings, Zwick and his team are currently performing an independent study of individuals with Down syndrome, using whole genome sequencing to further delineate alterations in genes that perturb heart development in children. Emory Health Sciences