Researchers at Boston University School of Medicine (BUSM) have discovered a molecule that could help lead to the non-invasive detection of lung cancer as well as its treatment. Using RNA sequencing, the team looked at airway epithelial cells and identified a regulatory molecule that was less abundant in people with lung cancer and inhibits lung cancer cell growth. The findings suggest that this molecule may aid in diagnosing lung cancer in earlier stages and could potentially, when at healthy levels, aid in treating the disease.
According to the National Cancer Institute (NCI), lung cancer is the leading cause of cancer death among both men and women in the United States, and 90 percent of lung cancer deaths among men and approximately 80 percent of lung cancer deaths among women are due to smoking. The NCI also estimates that approximately 373,489 Americans are living with lung cancer and its treatment costs approximately $10.3 billion in the United States each year.
MicroRNA’s are a new class of molecules classified as important regulators of the activity of other genes. In this study, the research team used a next-generation RNA sequencing technology and identified that a microRNA named miR-4423 in epithelial airway cells plays a major role in how these cells develop. In epithelial cells from the airway of smokers with lung cancer, levels of miR-4423 were decreased.
‘These results suggest measuring the levels of microRNAs like miR-4423 in cells that line the airway could aid in lung cancer detection through a relatively non-invasive procedure,’ said Avrum Spira, MD, MSc, the Alexander Graham Bell professor of medicine and chief of the division of computational biomedicine at BUSM, one of the study’s senior authors.
Using experimental models in vitro and in vivo, the research team demonstrated that miR-4423 can both promote the development of the normal airway cells and suppress lung cancer cell growth. This suggests that miR-4423 plays a major regulatory role in cell fate decisions made by airway epithelial cells during maturation and low levels of miR-4423 contributes to lung cancer development. Interestingly, throughout the body, miR-4423 seems only to be present in high levels in the airway epithelium, suggesting this could be a very specific process occurring only in the lungs.
‘Our findings open up the option to study whether returning miR-4423 levels to normal in the airway could help stop cancer growth and potentially be a way to treat lung cancer,’ said Catalina Perdomo, PhD, a researcher in the division of computational biomedicine at BUSM who is the paper’s lead author.
‘Interestingly, when we examined the genomes of other species for microRNAs that might function like miR-4423, we did not find anything in non-primates,’ said Marc Lenburg, PhD, an associate professor in computational medicine and bioinformatics at BUSM who is one the study’s senior authors. ‘It makes us wonder what it is different about lung development in primates and excited that this could be a very specific process to target for lung cancer treatment.’ EurekAlert

A 30-year-old woman with a history of upper respiratory infections had no idea she carried an immunodeficiency disorder – until her 6-year-old son was diagnosed with the same illness.
After learning she has common variable immunodeficiency (CVID), a disorder characterised by recurrent infections, such as pneumonia, and decreased antibodies, the woman, her husband, their three children and parents joined a multidisciplinary University of Utah study and researchers identified a novel gene mutation that caused the disease in the mom and two of her children. The researchers discovered that a mutation in the NFKB2 gene impairs a protein from functioning properly, which interferes with the body’s ability to make antibodies and fight infection. The children’s father did not have the mutation, nor did a third sibling or the woman’s parents.
Another 35 people with CVID were tested for the gene mutation, and one other unrelated person was found to have it. His father wasn’t tested, but no one else in his family immediate family had the mutation, so the researchers don’t know whether he could have inherited the disorder from his father or developed the gene mutation sporadically.
CVID typically doesn’t present with symptoms until adulthood and it’s not uncommon for someone to reach their 20s, 30s or beyond before being diagnosed, according to Karin Chen, M.D., co-first author of the study published Thursday, Oct. 17, 2013, in the American Journal of Human Genetics online. Identifying the NFKB2 mutation will make it easier to recognise and treat the disorder, particularly after a test developed in conjunction with the study by ARUP Laboratories becomes available as early as next May.
‘If we can screen patients for genetic mutations, we can identify disease complications associated with that gene, start looking for them and treating them sooner,’ says Chen, instructor of pediatric immunology at the University’s School of Medicine.
There’s no cure for CVID, but it can be treated with monthly infusions of antibodies at a cost of $5,000 to $10,000 per treatment.
Identifying the gene mutation and developing the test for it took approximately two years, a fast turnaround made possible because of the multidisciplinary research that the University of Utah Health Sciences encourages and is known for doing. The study involved researchers from the U School of Medicine’s Departments of Pediatrics, Pathology, Human Genetics and Program in Molecular Medicine and ARUP, which is a University-owned, nationwide testing laboratory.
Emily M. Coonrod, Ph.D., a research scientist with the ARUP Institute for Clinical and Experimental Pathology, is co-first author with Chen. Karl V. Voelkerding, M.D., also of the Institute for Clinical and Experimental Pathology and a U professor of pathology, is the senior author.
CVID probably is underdiagnosed, making it hard to know how common it is. But the disorder is estimated to occur in one in 10,000 people to one in 50,000 people, meaning it is one of more common types of immunodeficiency disorders, according to Chen. University physicians currently treat about 150 CVID patients in the Intermountain Region. Historically, CVID has been diagnosed clinically by doctors who are aware of the symptoms and then have individuals tested for low levels of antibodies.
No mutation had been identified in NFKB2 before this study. But Attila Kumánovics, M.D., assistant professor of pathology and co-author on the study, had perused the medical literature and found that a mouse model had been developed that carried a similar mutation in the NFKB2 gene and also had immunodeficiency. That was a key development, according to Voelkerding. ‘This meant that the finding in our patients could be correlated to literature.’ University of Utah Health Care

Miraca Holdings Inc., a Japan-based holding company in the healthcare sector, recently announced that its affiliate Innogenetics N.V. in Ghent (Belgium) had changed its name to Fujirebio Europe N.V. The name change is the next logical step in an integration process that was launched by the acquisition in September 2010 of Innogenetics N.V. by Fujirebio Inc., a subsidiary of Miraca Holdings. Fujirebio is recognized as a key player in oncology for routine and novel IVD markers. Th e name change confirms Fujirebio’s strong commitment to the introduction of the Lumipulse immunoanalyser range in laboratories across Europe. The Lumipulse G1200 was presented to the European market for the first time in Italy in November 2011 and this fully automated chemiluminescent enzyme immunoassay (CLEIA) system is now available to laboratories in Spain and will soon be available in Germany and France.

For more than 100 years, researchers have been unable to explain why cancer cells contain abnormal numbers of chromosomes, a phenomenon known as aneuploidy. Many believed aneuploidy was simply a random by-product of cancer.

Now, a team at Harvard Medical School has devised a way to understand patterns of aneuploidy in tumours and predict which genes in the affected chromosomes are likely to be cancer suppressors or promoters. They propose that aneuploidy is a driver of cancer rather than a result of it.
‘If you look at a cancer cell, it looks like an unholy mess with gene deletions and amplifications, chromosome gains and losses, like someone threw a stick of dynamite into the cell. It seems random, but actually previous work has shown that there is a pattern to which chromosomes and chromosome arms are altered—and that means we can understand that pattern and how or if it drives cancer,’ said senior author Stephen Elledge, Gregor Mendel professor of Genetics and of Medicine at HMS and professor of medicine at Brigham and Women’s Hospital.

‘What we have done is to propose a new theory about how this works and then prove it using mathematical analysis,’ he said.
For decades since the ‘oncogene revolution,’ cancer research has focused on mutations—changes in the DNA code that abnormally activate genes that promote cancer, called oncogenes, or deactivate genes that suppress cancer. The role of aneuploidy—in which entire chromosomes or chromosome arms are added or deleted—has remained largely unstudied.

Elledge and his team, including research fellow and first author Teresa Davoli, suspected that aneuploidy has a significant role to play in cancer because missing or extra chromosomes likely affect genes involved in tumour-related processes such as cell division and DNA repair.

To test their hypothesis, the researchers developed a computer program called TUSON (Tumour Suppressor and Oncogene) Explorer together with Wei Xu and Peter Park at HMS and Brigham and Women’s. The program analysed genome sequence data from more than 8,200 pairs of cancerous and normal tissue samples in three pre-existing databases.

They generated a list of suspected oncogenes and tumour suppressor genes based on their mutation patterns—and found many more potential cancer drivers than anticipated. Then they ranked the suspects by how powerful an effect their deletion or duplication was likely to have on cancer development.

Next, the team looked at where the suspects normally appear in chromosomes.

They discovered that the number of tumour suppressor genes or oncogenes in a chromosome correlated with how often the whole chromosome or part of the chromosome was deleted or duplicated in cancers. Where there were concentrations of tumour suppressor genes alongside fewer oncogenes and fewer genes essential to survival, there was more chromosome deletion. Conversely, concentrations of oncogenes and fewer tumour suppressors coincided with more chromosome duplication.

When the team factored in gene potency, the correlations got even stronger. A cluster of highly potent tumour suppressors was more likely to mean chromosome deletion than a cluster of weak suppressors.
Since 1971, the standard tumor suppressor model has held that cancer is caused by a ‘two-hit’ cascade in which first one copy and then the second copy of a gene becomes mutated. Elledge argues that simply losing or gaining one copy of a gene through aneuploidy can influence tumour growth as well.

‘The loss or gain of multiple cancer driver genes that individually have low potency can add up to have big effects,’ he said.

‘It’s a terrific study,’ said Angelika Amon, a professor of biology at Massachusetts Institute of Technology who was not involved in the project. ‘These novel algorithms of identifying tumour suppressors and oncogenes nicely provide an explanation of how aneuploidies evolve in cancer cells, and the realisation that subtle changes in the activity of many different genes at the same time can contribute to tumorigenesis is an exciting and intriguing hypothesis.’

These findings also may have answered a long-standing question about whether aneuploidy is a cause or effect of cancer, leaving researchers free to pursue the question of how. Harvard Medical School

A study by researchers in Nottingham has identified seven distinct types of breast cancer, a discovery which could lead to new and improved prognostic tests for patients with the disease.
The findings could revolutionise the way in which breast cancer patients are treated by giving clinicians more detailed information about a patient’s breast cancer type and helping them create a more personalised treatment plan, avoiding over or under-treatment.
Dr Green said: ‘With an increasing number of treatment options available for breast cancer patients, decision making regarding the choice of the most appropriate treatment method is becoming increasingly complex. Improvements in care and outcome for patients with breast cancer will involve improved targeting of effective therapies to appropriate patients.
‘Equally important should be improvement in parallel strategies to avoid unnecessary or inappropriate treatment and side effects.’
Breast cancer is a biologically complex disease and each tumour can have very different properties, so the more information that doctors have about each patient’s cancer, the better they can plan treatments. Currently just two proteins are tested for as standard in breast cancer cells (known as biomarkers): the oestrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2), alongside information about the tumour size, spread and grade.
Dr Green and colleagues, who also included Professor Ian Ellis in the Division of Oncology and Jon Garibaldi and Daniele Soria in the University’s School of Computer Science, wanted to see if, by testing for more biomarkers, but keeping the number of biomarkers as low as possible to make an affordable test a realistic proposition, they could devise categories that better reflect the diversity of breast cancer and, importantly, better predict how a patient’s cancer is likely to progress.
Using tissue that now forms part of the Breast Cancer Campaign Tissue Bank, the team tested 1073 tumour samples and from these, 997 (93%) fitted perfectly into one of seven classes, whereas 76 (7%) had mixed characteristics and couldn’t be put into a distinct category. They then verified these classes in another 238 tumour samples.
The seven classes are defined by different combinations and levels of ten biomarkers found in breast cancer cells. These biomarkers include ER and HER2, the two biomarkers currently tested for in clinics, but also others that are not currently tested for, such as p53, cytokeratins, HER3 and HER4.
To test whether the new classes could give doctors more information about prognosis, Dr Green’s team compared the classes to survival outcomes from the patient samples. Each of the seven classes was found to have its own unique survival outcome. This indicates that the classes can tell us more about prognosis and help doctors to fine-tune treatment plans to improve survival.
Importantly, the technology required to measure protein biomarkers in tumour samples is already in place in most pathology laboratories across the UK, whereas newly developed genetic profiling tests such as Oncotype DX need to be sent to specialist laboratories, which brings additional costs. University of Nottingham