Researchers from Yale School of Medicine and Celera Diagnostics have confirmed and extended the significance of a genetic variant that substantially increases the risk of a frequently fatal thoracic aortic dissection or full rupture.
Thoracic aortic aneurysms, or bulges in the artery wall, can develop without pain or other symptoms. If they lead to a tear — dissection — or full rupture, the patient will often die without immediate treatment. Therefore, better identification of patients at risk for aortic aneurysm and dissection is considered essential.
The research team, following up on a previous genome-wide association study by researchers at Baylor College of Medicine, investigated genetic variations in a protein called FBN-1, which is essential for a strong arterial wall. After studying hundreds of patients at Yale, they confirmed what was found in the Baylor study: that one variation, known as rs2118181, put patients at significantly increased risk of aortic tear and rupture. In addition, the Yale team was able to show that this increased risk of tear was powerful enough to be significant even independently of aortic size.
‘Although surgical therapy is remarkable and effective, it is incumbent on us to move to a higher genetic level of understanding of these diseases,’ said senior author Dr. John Elefteriades, the William W. L. Glenn Professor of Surgery (Section of Cardiac Surgery) at Yale School of Medicine, and director of the Aortic Institute at Yale-New Haven Hospital. ‘Such studies represent important steps along that path.’
The researchers hope their confirmation of the earlier study may help lead to better clinical care of patients who may be at high risk of this fatal condition. ‘Patients with this mutation may merit earlier surgical therapy, before aortic dissection has a chance to occur,’ Elefteriades says. Yale cardiothoracic surgeons will now begin assessing this gene in clinical patients with aneurysm disease. Yale University

A study done by researchers at Fox Chase Cancer Center shows that many relatives of patients who undergo testing for a gene linked to breast and ovarian cancers misinterpret the results, and less than half of those who could benefit from genetic testing say they plan to get tested themselves—despite the fact that knowing your genetic status may help catch the disease in its earliest stages.
‘People don’t always understand genetic information, so there’s confusion,’ says study author Mary B. Daly, MD, PhD, chair of the Department of Clinical Genetics at Fox Chase. ‘Family members are either not understanding what they’re hearing, not realising it has implications for them, or they’re not hearing it at all.’
For a long time, Daly says she ‘naively’ assumed that, once one family member knew whether or not they carried genes linked to breast and ovarian cancers—known as BRCA1/2—their entire family would understand the result, and what it meant for their own genetic risk. ‘Over time, we realised that wasn’t happening, or it wasn’t happening very well.’
Some genetic information is straightforward, says Daly. For example, when a woman learns she carries BRCA1/2 that means her parents, siblings and children may also carry the gene. But there are more ‘indeterminate’ results, which are harder to interpret, she adds. If a woman with a strong family history of breast and ovarian cancers tests negative for the BRCA1/2 genes, that does not mean her relatives are not at risk, says Daly—her siblings could still carry the gene, or there could be additional genes present that predispose them to cancer that clinicians don’t yet know how to test for.
‘When you look at some of these families who are so full of breast and ovarian cancer, and the person tests negative, you think there’s got to be something going on here. We just can’t find it. That’s a difficult thing for someone to explain to a relative,’ says Daly.
To understand better what was (and was not) being communicated after people underwent genetic testing, Daly and her team called 438 relatives of 253 people who had undergone genetic testing and said they’d shared their results. More than one-quarter of family members reported the test result incorrectly. They were most likely to understand positive results—like their family member carries the BRCA1/2 gene. But only 60% understood the so-called ‘indeterminate’ results, where their relative tested negative for the gene but they and other family members could still be at risk. Nearly one-third said they had trouble understanding the result.
Concerningly, only half (52%) of family members whose relative tested positive for the BRCA1/2 gene said they planned to get tested themselves. Among those whose relative tested negative for the BRCA1/2 gene, but knew the gene was present in their families (meaning they could still carry the gene), only 36% said they were going to find out their own genetic risk. ‘These findings imply the family members did not fully understand the significance of these results for their own risk,’ says Daly.
People were more likely to share their results with adult children than parents or siblings, and particularly with female relatives. ‘Over and over you hear people say ‘I’m doing this for my children’s sake,” says Daly.
As part of the study, Daly and her colleagues had asked half of the people getting tested to participate in two coaching sessions to help them communicate their results to relatives, such as through role playing. However, these people were no more likely to communicate the result of their tests than people who had simply sat through educational sessions about overall health. ‘It didn’t matter which group they were in, unfortunately,’ says Daly. ‘That disappointed me.’
But it also inspired her to develop the next project—exploring the effect of directly reaching out to the relatives of someone who underwent genetic testing (with that person’s permission), to see if hearing the results from an expert who’s not personally involved in the situation helps family members understand what they mean. Fox Chase Cancer Center

Some women with endometriosis, a chronic inflammatory disease, are predisposed to ovarian cancer, and a genetic screening might someday help reveal which women are most at risk, according to a University of Pittsburgh Cancer Institute (UPCI) study, in partnership with Magee-Womens Research Institute (MWRI).
Monday at the American Association for Cancer Research (AACR) Annual Meeting 2014, UPCI and MWRI researchers will present the preliminary results of the first comprehensive immune gene profile exploring endometriosis and cancer.
‘A small subset of women with endometriosis go on to develop ovarian cancer, but doctors have no clinical way to predict which women,’ said senior author Anda Vlad, M.D., Ph.D., assistant professor of obstetrics, gynecology and reproductive sciences at MWRI. ‘If further studies show that the genetic pathway we uncovered is indicative of future cancer development, then doctors will know to more closely monitor certain women and perhaps take active preventative measures, such as immune therapy.’
Endometriosis is a painful, often invasive and recurrent condition that happens when the tissue that lines the uterus grows outside of the uterus, causing inflammation. It affects approximately one in 10 women.
By screening tissue samples from women with benign endometriosis, endometriosis with pre-cancerous lesions and endometriosis-associated ovarian cancer, Dr. Vlad and her colleagues identified the complement pathway, which refers to a series of protein interactions that trigger an amplified immune response, as the most prominent immune pathway that is activated in both endometriosis and endometriosis-associated ovarian cancer.
‘If, as our study indicates, a problem with the immune system facilitates cancer growth through chronic activation of the complement pathway, then perhaps we can find ways to change that and more effectively prime immune cells to fight early cancer, while controlling the complement pathway,’ said lead author Swati Maruti Suryawanshi, Ph.D., a post-doctoral research fellow at MWRI. EurekAlert

By linking antibodies to certain diseases, researchers at UC Santa Barbara have found a way to uncover and confirm environmental triggers
By cross referencing the amino acid sequence of peptides strongly associated with illnesses with a library of known peptides, researchers may be able to map antigens with identical sequences to their environment, thus uncovering and confirming environmental triggers for diseases such as Type-1 diabetes, schizophrenia, and autism.
You may be sensitive to gluten, but you’re not sure. Perhaps you can’t put your finger on a recurring malaise, and your doctor is at a loss to figure it out. A diagnostic method recently developed by UC Santa Barbara professor Patrick Daugherty can reveal — on a molecular level — the factors behind conditions thought to have environmental triggers. By decoding an individual’s immune system, this elegant and accurate method can demystify, diagnose and provide further insight into conditions like celiac disease, multiple sclerosis, pre-eclampsia and schizophrenia.

‘We have two goals,’ said Daugherty, a researcher with the Department of Chemical Engineering at UCSB and the campus’s Center for BioEngineering. ‘We want to identify diagnostic tests for diseases where there are no blood diagnostics … and we want to figure out what might have given rise to these diseases.’

The process works by mining an individual’s immunological memory — a veritable catalogue of the pathogens and antigens encountered by his or her immune system.

‘Every time you encounter a pathogen, you mount an immune response,’ said Daugherty. The response comes in the form of antibodies that are specific to the antigens — molecular, microbial, chemical — your body is resisting, and the formation of ‘memory cells’ that are activated by subsequent encounters with the antigen. Responses can vary, from minor reactions — a cough, or a sneeze — to serious autoimmune diseases in which the body turns against its own tissues and its immune system responds by destroying them, such as in the case of Type 1 diabetes and celiac disease.

‘The trick is to determine which antibodies are linked to specific diseases,’ said Daugherty. Celiac disease sufferers, for example, will have certain antibodies in their blood that bind to specific peptides — short chains of amino acids — present in wheat, barley and rye. These peptides are the gluten that is the root of allergies and sensitivities in some people. Like a lock and key, these antibodies — the locks — bind only to certain sequences of amino acids that comprise the peptides — the keys.

‘People with celiac disease have two particular antibody types in their blood, which have proved to be enormously useful for diagnosis,’ said Daugherty.

However, sheer variety and number of antibodies present in a person’s blood at any given time has been a challenge for researchers trying to link specific illnesses with specific antibody molecules. One antigen can stimulate the production of many antibodies in response. What’s more, each individual’s antibodies to even the same antigen differ slightly in their form. The idea of using molecular separation to find the disease antibodies has been around for over 20 years, said Daugherty, but no one had figured quite how to sift through the vast amount of molecules.

To sort through perhaps tens of thousands of antibody molecules present in a person’s blood, the research team — including John T. Ballew from UCSB’s Biomolecular Science and Engineering graduate program, now a postdoctoral associate with the Koch Institute for Integrative Cancer Research at MIT — mixed a sample of a subject’s blood, which contains the antibody molecules, with a vast number of different peptides (about 10 billion).

‘All the keys associate with their preferred lock,’ said Daugherty. ‘The peptides that can bind to an antibody, do so.’ The researchers then pull out the disease-bound pairs, in a process that progressively decreases the number of antibodies-peptide pairs that are most unique to a particular disease. Repeated with subsequent patients who may have the same symptoms, phenotypes or genetic dispositions, continues to whittle down the size of the peptide pool. Further in vitro evolution of the best draft peptides can identify the particular sequence of amino acid keys that fit into the antibody locks. This sequence can be used to confirm the antibodies in question as the biomarkers specifically associated with the disease.

‘The diagnostic performance of the reagents generated with this approach is excellent,’ said Daugherty. ‘We can discover biomarkers with as little as a drop of blood, and the peptides discovered can be adapted into preferred low cost testing platforms widely used in clinical practice.’

The amino acid sequence of the evolved peptides, when cross-referenced with a database of known proteins, can identify the antigens (that contain the same peptide sequence). This, in turn, can then yield clues into what factors in the patient’s environment may have contributed to the disease. The process may be used to gain insight on diseases that are thought to have environmental triggers, including Type-1 diabetes, autism, schizophrenia/bipolar disorder, Crohn’s disease, Parkinson’s disease, and perhaps even Alzheimers disease. In cases, such as Graves’ disease, where an antibody is identified as the cause (as opposed to simply an indicator) knowing the antibody’s structure can lead to more effective therapies.

‘If you can get rid of the antibody, you can treat the disease,’ said Daugherty. ‘By finding these keys, you can block the antibody.’ University of California – Santa Barbara

Findings show how a genetic mutation in untreated patients is linked to aggressive cancer later in life. It was previously thought that the mutation only occurred in response to therapy.

The research highlights why relapses could occur in some men following hormone therapy. And it could help identify those patients that will develop fatal prostate cancer much earlier for life-extending therapy.

Prostate cancer is the most common cancer in men in the UK, with more than 40,000 new cases diagnosed every year. Treatment options for patients diagnosed with early stage prostate cancer vary from ‘watchful waiting’ to hormone-withdrawal therapy, radiotherapy or surgery.

Additional tests for indicators of aggressive cancer are necessary to help categorise patients so that those with a low-risk of the disease spreading can avoid unnecessary treatment, and those diagnosed with a high-risk can be targeted for more aggressive first line therapy.

Hormone-withdrawal therapy often results in a dramatic remission, however the disease invariably relapses with a resistant form of the cancer. A third of these are due to an increase in copy number of a particular gene called the ‘androgen receptor’. The gene is on the X-Chromosome and so there is normally only one copy of this gene present in men. Prostate cancer thrives on male hormones, and one way that they develop to grow better is to increase the number of copies of the androgen receptor gene. This also enables the cancer to resist therapy.

Lead researchers Dr Jeremy Clark and Prof Colin Cooper from UEA’s school of Biological Sciences carried out the research at the Institute of Cancer Research, London, and at UEA.

Dr Clark said: ‘By the age of 60, the majority of men will have signs of prostate cancer. However, only a small proportion of men will die of the disease. The question is – which of these cancers are dangerous and which are not? Deciding which cancers are going to progress and kill the patient is key to effective patient treatment.’

‘Prostate cancer thrives on male hormones, and cutting the supply of hormones to the cancer is a main avenue of therapy. Prostate cancer only kills the patient when it becomes immune to these therapies. A third of these killer cancers are immune to therapy because they have boosted the number of male hormone receptor (AR) genes in their DNA. This gene boosting, also known as amplification, has been thought to be a response of the tumour to the hormone reduction therapy itself.

‘Our research has shown that an early form of this hormone-gene boosting is present in a number of prostate cancers that have never been treated with hormone reduction therapy. We think that it is these cancers that will grow and kill the patient.

‘This discovery can be used to identify these killer cancers in patients much earlier than is currently possible. Patients could then be selected for more aggressive therapy before the cancer has developed full immunity.’

The research team looked at biomarkers from almost 600 patients prior to hormone-withdrawal therapy. But the method of identification used was labour intensive and time consuming. Developing ways of identifying patients for early therapeutic intervention will be key to implementing this discovery in the clinic. The research team are currently looking at more rapid ways of identifying patients that will develop aggressive cancer. University of East Anglia