By analysing DNA in more than 3,000 tumours, scientists led by Li Ding, PhD, at The Genome Institute have identified 127 repeatedly mutated genes that likely drive the growth of a range of cancers in the body. The discovery sets the stage for devising new diagnostic tools and more personalised cancer treatments aimed at the unique genetic changes found in individual tumours.
The research shows that some of the same genes commonly mutated in certain cancers also occur in seemingly unrelated tumours. For example, a gene mutated in 25 percent of leukaemia cases in the study also was found in tumours of the breast, rectum, head and neck, kidney, lung, ovary and uterus.
Based on the findings, the researchers envision that a single test that surveys errors in a swath of cancer genes eventually could become part of the standard diagnostic workup for most cancers. Results of such testing could guide treatment decisions for patients based on the unique genetic signatures of their tumours.
New insights into cancer are possible because of advances in genome sequencing that enable scientists to analyse the DNA of cancer cells on a scale that is much faster and less expensive today than even a few years ago. While earlier genome studies typically have focused on individual tumour types, the current research is one of the first to look across many different types of cancer.
‘This is just the beginning,’ said senior author Li Ding, PhD, of The Genome Institute at Washington University. ‘Many oncologists and scientists have wondered whether it’s possible to come up with a complete list of cancer genes responsible for all human cancers. I think we’re getting closer to that.’
The new research analysed the genes from 3,281 tumours – a collection of cancers of the breast, uterus, head and neck, colon and rectum, bladder, kidney, ovary, lung, brain and blood. In addition to finding common links among genes in different cancers, the researchers also identified a number of mutations exclusive to particular cancer types.
Looking at a large number of tumours across many different cancers gives the researchers the statistical power they need to identify significantly mutated genes. These genetic errors occur frequently in some cancers and rarely in others but are nevertheless thought to be important to cancer growth. The research was conducted as part of The Cancer Genome Atlas Pan-Cancer effort, funded by the National Cancer Institute and the National Human Genome Research Institute, both at the National Institutes of Health (NIH).
While the average number of mutated genes in tumours varied among the cancer types, most tumours had only two to six mutations in genes that drive cancer. This may be one reason why cancer is so common, the researchers said. ‘While cells in the body continually accumulate new mutations over the years, it only takes a few mutations in key driver genes to transform a healthy cell into a cancer cell,’ noted Ding. Washington University School of Medicine at St. Louis

The trajectory of amyloid plaque build-up—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study.
Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. ‘Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,’ said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.

Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.
Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.
‘It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,’ Dr. Davatzikos said. ‘This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.’
The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analysed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analysing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.
Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).

Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.

A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.

‘This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,’ said Dr Davatzikos. ‘The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.’ Perelman School of Medicine at the University of Pennsylvania

An international consortium has shown for the first time evidence of substantial overlap of genetic risk factors shared between bipolar disorder, major depressive disorder and schizophrenia and less overlap between those conditions and autism and attention deficit-hyperactivity disorder (ADHD), according to a study.
The root cause of psychiatric illnesses such as bipolar disorder, major depressive disorder schizophrenia, autism and ADHD is not fully understood. For more than 125 years, clinicians have based diagnosis on a collection of symptoms observed in patients.

But, scientists have since identified that the five psychiatric disorders share a common genetic link and are now moving toward understanding the molecular underpinnings of psychiatric illness. The precise degree to which these disorders share common ground has remained unknown, until now.

The project is led by the Cross-Disorder Group of the Psychiatric Genomics Consortium and is the largest genetic study of psychiatric illness to date.

The findings provide insight into the biological pathways that may predispose an individual to disease and could ultimately lead to the development of new therapeutic avenues to treat the five major psychiatric illnesses.

‘This is a very large scale study using a new, innovative statistical method,’ said study co-senior author Kenneth S. Kendler, M.D., professor of psychiatry, and human and molecular genetics in the Virginia Commonwealth University School of Medicine, and an internationally recognised psychiatric geneticist.

‘Prior to this model, we have not been able to address these questions. These results give us by far the clearest picture available to date of the degree of genetic similarity between these key psychiatric disorders. We hope that this will help us both in developing a more scientifically based diagnostic system and understanding the degree of sharing of the biological foundation these illnesses,’ he said.

The study builds on findings published earlier this year in The Lancet, which reported that specific single nucleotide polymorphisms, or SNPs, are associated with a range of psychiatric disorders that can occur during childhood or adulthood.

Next, the group will examine other disorders for which molecular genetic data is accumulating including eating disorders, obsessive compulsive disorder and drug use disorders.

Since 2007, the Cross-Disorder Group of the Psychiatric Genomics Consortium has reviewed scientific literature of genome-wide association studies, or GWAS, on psychiatric disorders. To date, GWAS data from more than 19 countries has been gathered by the consortium. Virginia Commonwealth University

A biomarker test developed initially to identify early acute kidney injury (AKI) after surgery has been shown to successfully detect AKI in emergency room patients with a variety of urgent health issues.
The test measures the protein neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker of early AKI. It was invented by researchers at Cincinnati Children’s Hospital Medical Center to detect AKI earlier than existing methods, and to more promptly begin treatment.
‘The majority of our studies on NGAL have been performed in well controlled settings of hospital-acquired AKI, such as cardiac surgery, contrast administration or other critically ill patients,’ said Prasad Devarajan, MD, senior author and director of Nephrology and Hypertension at Cincinnati Children’s. ‘The purpose of this study was to determine the biomarker’s accuracy in a diverse group of patients admitted from the emergency department, where patients with early signs of AKI are often misdiagnosed.’
The study involved patients admitted through the emergency room of Fernando Fonseca Hospital in Portugal, which also closely collaborated on the study. The findings demonstrate the NGAL test, which uses a single drop of blood and provides results within 15 minutes, was able to accurately distinguish AKI from reversible transient kidney dysfunction.
Of 616 patients who participated in the study, individuals who were subsequently diagnosed with true AKI had the highest levels of NGAL detected at the time of hospital admission. The study also identified a cut-off point in NGAL levels above which the risk of acute kidney injury increases tenfold.
Results of a study previously published in 2008 by Devarajan showed that the NGAL test predicted AKI in pediatric heart surgery patients within hours instead of days, allowing treatment that prevented serious damage to kidneys. Prior to the NGAL test, serum creatinine was the only reliable method for detecting kidney damage; however, the long wait for results often resulted in permanent kidney damage.
With a growing number of patients coming to emergency rooms with community-acquired AKI, Devarajan says having a rapid, reliable method of detecting kidney injury is increasingly important.
‘This latest study showed that this simple laboratory test provides an accurate prediction of acute kidney injury and its severity in a diverse clinical setting,’ said Devarajan. ‘The identification of biomarkers that differentiate intrinsic AKI from transient reversible forms of renal dysfunction and predict outcomes is a high priority.’ Cincinnati Children’s Hospital Medical Center

Researchers have found that antibodies against the human papillomavirus (HPV) may help identify individuals who are at greatly increased risk of HPV-related cancer of the oropharynx, which is a portion of the throat that contains the tonsils.
In their study, at least 1 in 3 individuals with oropharyngeal cancer had antibodies to HPV, compared to fewer than 1 in 100 individuals without cancer. When present, these antibodies were detectable many years before the onset of disease. These findings raise the possibility that a blood test might one day be used to identify patients with this type of cancer.
The results of this study were carried out by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health, in collaboration with the International Agency for Research on Cancer (IARC).
Historically, the majority of oropharyngeal cancers could be explained by tobacco use and alcohol consumption rather than HPV infection. However, incidence of this malignancy is increasing in many parts of the world, especially in the United States and Europe, because of increased infection with HPV type 16 (HPV16). In the United States it is estimated that more than 60 percent of current cases of oropharyngeal cancer are due to HPV16. Persistent infection with HPV16 induces cellular changes that lead to cancer.
HPV E6 is one of the viral genes that contribute to tumour formation. Previous studies of patients with HPV-related oropharynx cancer found antibodies to E6 in their blood.
‘Our study shows not only that the E6 antibodies are present prior to diagnosis—but that in many cases, the antibodies are there more than a decade before the cancer was clinically detectable, an important feature of a successful screening biomarker,’ said Aimee R. Kreimer, Ph.D., the lead Investigator from the Division of Cancer Epidemiology and Genetics, NCI.
Kreimer and her colleagues tested samples from participants in the European Prospective Investigation into Cancer and Nutrition Study, a long-term study of more than 500,000 healthy adults in 10 European countries. Participants gave a blood sample at the start of the study and have been followed since their initial contribution.
The researchers analysed blood from 135 individuals who developed oropharyngeal cancer between one and 13 years later, and nearly 1,600 control individuals who did not develop cancer. The study found antibodies against the HPV16 E6 protein in 35 percent of the individuals with cancer, compared to less than 1 percent of the samples from the cancer-free individuals. The blood samples had been collected on average, six years before diagnosis, but the relationship was independent of the time between blood collection and diagnosis. Antibodies to HPV16 E6 protein were even found in blood samples collected more than 10 years before diagnosis.
The scientists also report that HPV16 E6 antibodies may be a biomarker for improved survival, consistent with previous reports. Patients in the study with oropharyngeal cancer who tested positive for HPV16 E6 antibodies prior to diagnosis were 70 percent more likely to be alive at the end of follow-up, compared to patients who tested negative.
‘Although promising, these findings should be considered preliminary,’ said Paul Brennan, Ph.D., the lead investigator from IARC. ‘If the predictive capability of the HPV16 E6 antibody holds up in other studies, we may want to consider developing a screening tool based on this result.’ National Cancer Institute