A genomic analysis of clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, from 72 patients has uncovered 31 genes that are key to development, growth and spread of the cancer, say researchers from Mayo Clinic in Florida. Eight of these genes had not been previously linked to kidney cancer, and six other genes were never known to be involved in any form of cancer.

Their stud is the most extensive analysis to date of gene expression’s role in ccRCC tumor growth and metastasis. The ccRCC subtype accounts for 80 percent of all kidney cancer cases.
This study is a thorough analysis, because overexpressed genes were functionally tested in kidney cancer cells to ensure they were important to some aspect of the cancer process, says the study’s senior investigator, molecular biologist, John A. Copland, Ph.D.

“The power of this study is that we looked at genes discovered to be over-expressed in patients’ tumours and determined their function in kidney cancer, which has not been done on a large scale before,” he says. “This is a seminal step in identifying key pathways and molecules involved in kidney cancer so that specific therapies that target these new genes can be developed to treat this cancer.” Mayo Clinic

Use of exome sequencing improved the ability to identify the underlying gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes (enzymes that are involved in basic energy production), according to a study in the July 2 issue of JAMA.

Defects of the mitochondrial respiratory chain have emerged as the most common cause of childhood and adult neurometabolic disease, with an estimated prevalence of l in 5,000 live births. Clinically these disorders can present at any time of life, are often seen in association with neurological impairment, and cause chronic disability and premature death. The diagnosis of mitochondrial disorders remains challenging, according to background information in the article. Examples of problems caused by mitochondrial diseases include a type of epilepsy; mitochondrial encephalopathy; lactic acidosis; and a syndrome that includes stroke-like episodes.

Robert W. Taylor, Ph.D., F.R.C.Path., of Newcastle University, Newcastle upon Tyne, U.K., and colleagues studied whether a whole-exome sequencing approach could help define the molecular basis of mitochondrial disease. Whole-exome sequencing is a complex laboratory process that determines the entire unique sequence of an organism’s exome (the collection of exons, which are relatively small lengths of a whole genome and contain instructions for the body to build proteins).

The study included 53 patients, referred to 2 national centres in the United Kingdom and Germany between 2005 and 2012, who had biochemical evidence of multiple respiratory chain complex defects. The majority (51/53 [96 percent]) of the patients presented during childhood (<15 years old) and most (66 percent) developed symptoms within the first year of life. The most frequent clinical features were muscle weakness, central neurological disease, cardiomyopathy, and abnormal liver function; a combination of these abnormalities was present in most cases. Following whole-exome sequencing, presumptive causal variants were identified in 28 patients (53 percent) and possible causal variants were identified in 4 (8 percent). Together these accounted for 32 patients (60 percent) and involved 18 different genes. Distinguishing clinical features included deafness and kidney involvement associated with one gene, and cardiomyopathy with two genes. In 20 patients with prominent heart disease, the causative mutation was detected in 80 percent, while the detection rate was much lower in patients with liver disease (33 percent). It was not possible to confidently identify the underlying genetic basis in 21 patients (40 percent). “In the pre-exome era, the systematic biochemical characterization of 53 patients with multiple respiratory chain complex defects led to detection of the underlying genetic basis in only 1 patient. The work presented herein demonstrates the effect of whole-exome sequencing in this context, which has defined the genetic etiology in 32 of 53 patients (60 percent) with a confirmed biochemical defect …,” the authors write. “Our findings contrast with large-scale candidate gene analysis using conventional and next-generation sequencing approaches, both of which had a lower diagnostic yield (10 percent-13 percent) and by definition did not discover new potential disease genes.” “Additional study is required to determine the utility of this approach compared with traditional diagnostic methods in independent patient populations,” the researchers conclude. JAMA Network

Researchers at King’s College London have identified a genetic variant associated with an increased risk of stroke and heart attack.

Stroke and heart attack are caused when arteries, already clogged up by fatty substances (a condition known as atherosclerosis), become completely blocked by the formation of a blood clot. Risk factors for this include smoking, high blood pressure and high cholesterol.

The findings suggest a new genetic link caused by a variation in a protein known as ‘glycoprotein IIIa’. This genetic variant is found in platelets, a type of blood cell involved in the formation of blood clots.

These findings may, in future, allow clinicians to identify patients who are at particularly high risk of stroke or heart attack by looking for the genetic variant. This would represent advancement on current practice, which mainly addresses risk factors such as smoking and high blood pressure.

Previous findings surrounding this genetic variant have been inconsistent and the study at King’s represents the first large-scale meta-analysis of the literature, including over 50,000 participants from a combined total of 82 studies.

In the UK over 150,000 people have a stroke every year. Stroke is the third largest cause of death after heart disease and cancer. A stroke occurs when blood supply to part of the brain is cut off, leading to damage of brain cells. There are around 103,000 heart attacks in the UK each year, caused by blockage of a coronary artery that supplies blood to the heart and resulting in damage to heart muscles.

In the first research paper, which examined stroke patients, researchers found that carrying the PlA2 genetic variant of glycoprotein IIIa was associated with an increased risk of thrombotic stroke – that is, stroke caused by a blood clot. This equated to a higher risk of around 10-15 per cent, which was even stronger (amounting to a 70 per cent increase in risk) in people who carried two copies of this gene variant. The variant was not associated with haemorrhagic stroke, which is caused by bleeding into the brain.

The second research paper found that the same genetic variant was also associated with an increased risk of heart attack. This link was stronger in younger than in older patients, which is likely to reflect the greater influence of other cardiovascular risk factors in older patients (such as smoking and high cholesterol), according to the researchers.

Albert Ferro, Professor of Cardiovascular Clinical Pharmacology at King’s College London, said: ‘The genetic risk found in stroke and heart attack patients is likely to be caused by over-active platelets. Under normal circumstances, platelets help your body form clots to stop bleeding, but in these patients platelet activation has the undesired effect of causing their narrowed arteries to be blocked off completely. In future it may be possible to reduce the chances of this happening by examining patients for this variant on a blood test, so that if they carry the PlA2 form – and especially if they carry two copies of it – such patients could be identified for a more determined reduction of risk factors such as smoking, high blood pressure or high cholesterol.’ King’s College London

Researchers from Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and other centres have identified novel mutations in a well-known cancer-causing pathway in lung adenocarcinoma, the most common subtype of lung cancer. Knowledge of these mutations could potentially identify a greater number of patients with treatable mutations because many potent cancer drugs that target these mutations already exist. In addition, these findings may expand the number of possible new therapeutic targets for this disease.

In this new study researchers from the Cancer Genome Atlas (TCGA) Research Network, led by Dana-Farber scientist Matthew Meyerson, MD, PhD, examined the genomes, RNA, and some protein from 230 lung adenocarcinoma samples. In three-quarters of the samples, the scientists ultimately identified mutations that put a cell-signalling pathway known as the RTK/RAS/RAF pathway into overdrive.

“Lung adenocarcinoma is the leading cause of human cancer death. This is because there are so many ways to develop the disease, and many different pathways are altered in this cancer,” said Meyerson, who is also a Broad senior associate member. “In recent years, we have made enormous progress in lung adenocarcinoma treatment by targeting EGFR, ALK, and other mutated proteins. Through this study, we are able to add to the range of such alterations and therefore gain potential new therapeutic targets.”

Mutations affecting the RTK/RAS/RAF pathway can cause it to become stuck in the “on” state. As a result, signals that promote cancer cell proliferation and survival are produced continuously. However, drugs are currently available that curb aberrant activity of this pathway and prompt therapeutic responses in patients.

“About 10% of patients have tumours with EGFR mutations, and these patients uniquely benefit from anti-EGFR therapy,” said Alice Berger, a post-doctoral fellow in the Meyerson lab and co-author of the study. “We were motivated to find genetic aberrations in patients that lack EGFR mutations and that might be similarly suitable for therapeutic targeting. Ultimately, we want to be able to provide every patient with an effective drug for their specific cancer.”

In the group’s initial scan of the tumour samples, researchers identified gene mutations that would increase RTK/RAS/RAF pathway activity in 62 percent of the samples. The affected genes are oncogenes, or genes that have the potential to cause cancer when mutated or expressed at high levels. Consequently, these tumour samples were classified as oncogene-positive. To identify additional alterations, the investigators looked at DNA copy number changes, or changes in gene number resulting from the deletion or amplification (multiplication) of sections of DNA in the genome. In doing so, they detected amplification of two oncogenes, ERBB2 and MET, which are part of the RTK/RAS/RAF pathway in the “oncogene negative” cancers. Gene amplification usually leads to increased expression of the encoded protein in cells.

Now that these amplifications have been identified in cancers without other activity of the RTK/RAS/RAF pathway, clinicians may be able to treat patients whose tumours have specific gene changes with drugs that are either currently available or under development.

“It is quite striking that we have now identified an actionable mutation in over 75 percent of patients with lung adenocarcinoma, a significant improvement from a decade ago,” said Meyerson.

Additional analysis identified other genes that may play important roles in lung cancer development. Mutations in one of these genes, NF1 — a known tumour suppressor gene that regulates the RTK/RAS/RAF pathway — had previously been reported in lung cancer. Mutations of NF1 also put that pathway into overdrive. Another mutated gene, RIT1, is also part of the RTK/RAS/RAF pathway, and this is the first study to associate mutation of this gene with lung cancer. Dana-Farber Institute

Genetics could be the key to explaining nation’s levels of happiness, according to research from the University of Warwick.

Economists at the University’s Centre for Competitive Advantage in the Global Economy (CAGE) have looked at why certain countries top the world happiness rankings. In particular they have found the closer a nation is to the genetic makeup of Denmark, the happier that country is. The research could help to solve the puzzle of why a country like Denmark so regularly tops the world happiness rankings.

Dr Eugenio Proto and Professor Andrew Oswald found three forms of evidence for a link between genetic makeup and a nation’s happiness.

Firstly they used data on 131 countries from a number of international surveys including the Gallup World Poll, World Value Survey and the European Quality of Life Surveys. The researchers linked cross-national data on genetic distance and well-being.

Dr Proto said: “The results were surprising, we found that the greater a nation’s genetic distance from Denmark, the lower the reported wellbeing of that nation. Our research adjusts for many other influences including Gross Domestic Product, culture, religion and the strength of the welfare state and geography.

The second form of evidence looked at existing research suggesting an association between mental wellbeing and a mutation of the gene that influences the reuptake of serotonin, which is believed to be linked to human mood.

Dr Proto added: “We looked at existing research which suggested that the long and short variants of this gene are correlated with different probabilities of clinical depression, although this link is still highly debated. The short version has been associated with higher scores on neuroticism and lower life satisfaction. Intriguingly, among the 30 nations included in the study, it is Denmark and the Netherlands that appear to have the lowest percentage of people with this short version.”

The final form of evidence looked at whether the link between genetics and happiness also held true across generations, continents and the Atlantic Ocean.

Professor Oswald said: “We used data on the reported wellbeing of Americans and then looked at which part of the world their ancestors had come from. The evidence revealed that there is an unexplained positive correlation between the happiness today of some nations and the observed happiness of Americans whose ancestors came from these nations, even after controlling for personal income and religion.” University of Warwick