The team headed by Angel Rodríguez Nebreda, ICREA researcher at IRB, identifies for the first time in mice that the p38 MAPK protein is required for the survival and proliferation of colon cancer cells.

In the same study the scientists demonstrate that a p38 inhibitor that has been used in clinical trials for inflammatory diseases shrinks the tumours in mice.
A team headed by Angel R. Nebreda at the Institute for Research in Biomedicine (IRB) identifies a dual role of the p38 MAPK protein in colon cancer. The study demonstrates that, on the one hand, p38 is important for the optimal maintenance of the epithelial barrier that protects the intestine against toxic agents, thus contributing to decreased tumour development. Intriguingly, on the other hand, once a tumour has formed, p38 is required for the survival and proliferation of colon cancer cells, thus favouring tumour growth.

The protein p38 is a member of the MAPK family—molecules that transmit signals from outside the cell inside, thus allowing an appropriate and dynamic cell response. This protein is expressed in all cells of the body and it performs highly diverse functions depending on the context and tissue involved.

Nebreda’s group at IRB focuses on the function of p38 in cancer. Their work describes the essential role of p38 in tumour progression for the first time in vivo. Furthermore, the scientists demonstrate that the treatment of mice with a p38 inhibitor previously used in clinical assays causes a considerable reduction in tumour size. The study provides useful information for clinicians and pharmaceutical companies about the role of p38 in the context of colon cancer. Colorectal cancer is now the second leading cause of cancer-related death in the world.

‘p38 inhibitors may have clinical applications, but probably—and this forms part of the medicine of the future—these will be in combination with other drugs. We are trying to find out what p38 inhibitors should be combined with to make the tumour, which is now smaller, finally disappear,’ explains the Spanish scientist Nebreda, head of the Signalling and Cell Cycle Lab at IRB, BBVA Foundation Cancer Research Professor and ICREA research professor.

The role of p38 in cancer is not clear cut. In this same study, Indian-born Jalaj Gupta who recently obtained his PhD in Nebreda’s lab and is first author of the work, demonstrates that this same protein in a pre-tumoral context, favoured by inflammation of the colon—also known as colitis—impedes tumour development.

It is well-known that patients with chronic inflammation of the intestine, such as that caused by Crohn’s disease, have a greater incidence of colon tumours that the healthy population. In order to study the relationship between inflammation and cancer, Nebreda’s team use mouse models that reproduce this inflammatory context.

‘Given that p38 regulates inflammation and also functions as a tumour suppressor in some mouse models, our study addressed how these two functions are integrated during the colon tumorigenesis associated with inflammation’, says Gupta.

An important finding of the present study is related to the contribution of p38 to the maintenance of an intact epithelial barrier, a structure that protects the intestine from toxic agents and pathogens. Mice genetically depleted of p38 in the epithelial cells that form the intestinal barrier were subjected to a cancer-inducing protocol that causes mutations and inflammation.

These animals developed twice as many tumours as a group of p38-expressing mice subjected to the same protocol. The tumour-suppressing capacity of p38 has also been described in cancer of the liver and lung.

‘Our study highlights the complexity of p38 functions, both in cancer and in the normal maintenance of tissues, and shows why an inhibitor of this molecule could effectively have undesirable side effects. This is why it is necessary to study in depth the patients and contexts in which treatment with such inhibitors would be suitable,’ explains Gupta.

‘All drugs currently used to treat cancer have side effects,’ states Nebreda, ‘and in this regard p38 inhibitors would be no exception. However, the administration of such inhibitors to colon cancer patients may be a useful strategy to shrink the tumour in a few days before its surgical removal’.

Nebreda goes on to explain that the basic research performed in his lab seeks to understand better the biology of tumour cells, the roles of the molecules involved and the mechanisms that allow tumour progression. ‘We try to take this basic information a step further so that it becomes clinically useful when designing new treatments,’ says the researcher, who joined IRB, in Barcelona, in 2010, after working in USA, UK, Germany and the CNIO in Madrid. IRB Barcelona

Today we know that women carrying BCRA1 and BCRA2 gene mutations have a 43% to 88% risk of developing from breast cancer before the age of 70. Taking critical decisions such as opting for preventive surgery when the risk bracket is so wide is not easy. Spanish National Cancer Research Centre (CNIO) researchers are conducting a study that will contribute towards giving every woman far more precise data about her personal risk of suffering from cancer.
The paper has been authored by 200 researchers from 55 research groups from around the world and describes two new genes that influence the risk of women developing breast and ovarian cancer when they are carriers of BCRA1 and BCRA2 mutations.
According to Ana Osorio, lead author of the study and a researcher in the Human Genetics Group, at CNIO: ‘The aim is to create a test that includes all known genetic variants that affect the risk of developing cancer, and at what age, in order to be able to compile a personalised profile for each patient.’ Osorio and Javier Benitez, the Director of the CNIO’s Human Cancer Genetics Programme, have jointly co-ordinated the work of all the participants in the study.
The finding is part of an international effort by the scientific community to get a more precise understanding of genomic information. Researchers are trying to identify genes associated with cancer as well as the reasons why the same mutated gene affects different people in different ways.
In the specific case of BRCA1 and BRCA2 genes, malfunctions may be caused by thousands of different mutations. However, the effects of these mutations can depend on other DNA variants found in other genes. These DNA variants may be caused by a single change in a chemical component from the 3 billion that make up the human genome. These single changes, known as SNPs (Single-nucleotide polymorphisms), do not inactivate genes and nor are they pathological in and of themselves, but they can play an important role when high-risk mutations already exist.
Understanding the genome to this degree of detail demands a lot of work. The weight of each risk-modulating element is small, so thousands of samples are needed for the effect to show in the data.
To do the work for the study that has been published, the researchers created a consortium called CIMBA (The Consortium of Investigators of Modifiers of BRCA1/2) in 2006, made up of research groups from around the world. CIMBA, with data from more than 40,000 carriers of BRCA1 and BRCA2 mutations, has the largest number of samples from which mutation interactions with SNPs can be studied.
Up to now, CIMBA has managed to associate more than 25 SNPs with the risk of developing breast or ovarian cancer in carriers of BRCA1/2 mutations. The study led by CNIO researchers adds at least two more to the list.
To find them, the study’s authors worked in two phases: they first analysed samples from 1,787 Spanish and Italian carriers of BRCA1/2 mutations, and managed to identify 36 potentially interesting SNPs; they later investigated their importance in a further 23,463 CIMBA samples. They thus discovered 11 SNPs that indicate risk, especially so in the case of two of them. Their influence is small—the largest risk multiplier is just 1.12—which is to say 12% on the base risk.
As Osorio explains: ‘The weight of each of these SNPs is very small, but with the 27 already described, the risk might increase or decrease for a woman who is a carrier of mutations.’
The newly discovered SNPs are in two genes known as NEIL2 and OGG1, and not by chance. The researchers went straight to the place where they found them. This way of working distinguishes this study from others that look for BRCA1/2 risk modulators by brute force: analysing and comparing everything to everything.
What advantages does searching with a compass offer? As well as being a more efficient strategy, it has allowed CNIO researchers to validate a hypothesis on how BRCA1/2 work. They also provide clues that might be useful for treatments already being used.
The hypothesis showed them where to look: in the genes of one of the DNA repair pathways. Cells have several ways to repair DNA, and one of them includes the use of BRCA1 and BRCA2 when they are non-mutated. If BRCA1 and BRCA2 do not fulfil their role because they are defective, another repair pathway takes over; if none of these pathways are functional the —cancerous— cell dies. So researchers hypothesised that there may be SNP risk modulators on this alternative repair route.
The hypothesis was correct. NEIL2 and OGG1, the genes that host the two SNPs that show the highest risk of developing cancer, intervene in the initiation of the alternative repair mechanism to BRCA1/2. ‘They are also basic genes for eliminating toxic waste generated by oxidative stress from cells,’ adds Benítez.
The result could also have interesting clinical implications. One of the drugs used against breast cancer that is associated to BRCA1 and BRCA2 mutations —called PARP inhibitors— acts by deactivating the alternative repair pathway. The authors therefore note in the study that: ‘These discoveries could have implications not only for determining risk but also in terms of treatment for carriers of BRCA1/2 mutations with PARP inhibitors.’ CNIO

Researchers at the RIKEN Center for Life Science Technologies, in collaboration with Osaka City University and Kansai University of Welfare Sciences, have used functional PET imaging to show that levels of neuroinflammation, or inflammation of the nervous system, are higher in patients with chronic fatigue syndrome than in healthy people.

Chronic fatigue syndrome, which is also known as myalgic encephalomyelitis, is a debilitating condition characterised by chronic, profound, and disabling fatigue. Unfortunately, the causes are not well understood.
Neuroinflammation—the inflammation of nerve cells—has been hypothesised to be a cause of the condition, but no clear evidence has been put forth to support this idea. Now, in this clinically important study, the researchers found that indeed the levels of neuroinflammation markers are elevated in CFS/ME patients compared to the healthy controls.
The researchers performed PET scanning on nine people diagnosed with CFS/ME and ten healthy people, and asked them to complete a questionnaire describing their levels of fatigue, cognitive impairment, pain, and depression. For the PET scan they used a protein that is expressed by microglia and astrocyte cells, which are known to be active in neuroinflammation.

The researchers found that neuroinflammation is higher in CFS/ME patients than in healthy people. They also found that inflammation in certain areas of the brain—the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons—was elevated in a way that correlated with the symptoms, so that for instance, patients who reported impaired cognition tended to demonstrate neuroinflammation in the amygdala, which is known to be involved in cognition. This provides clear evidence of the association between neuroinflammation and the symptoms experienced by patients with CFS/ME.
Though the study was a small one, confirmation of the concept that PET scanning could be used as an objective test for CFS/ME could lead to better diagnosis and ultimately to the development of new therapies to provide relief to the many people around the world afflicted by this condition. Dr. Yasuyoshi Watanabe, who led the study at RIKEN, stated, ‘We plan to continue research following this exciting discovery in order to develop objective tests for CFS/ME and ultimately ways to cure and prevent this debilitating disease.’ RIKEN

The same gene family that may have helped the human brain become larger and more complex than in any other animal also is linked to the severity of autism, according to new research from the University of Colorado Anschutz Medical Campus.
The gene family is made up of over 270 copies of a segment of DNA called DUF1220. DUF1220 codes for a protein domain – a specific functionally important segment within a protein. The more copies of a specific DUF1220 subtype a person with autism has, the more severe the symptoms, according to a paper.
This association of increasing copy number (dosage) of a gene-coding segment of DNA with increasing severity of autism is a first and suggests a focus for future research into the condition Autism Spectrum Disorder (ASD). ASD is a common behaviourally defined condition whose symptoms can vary widely – that is why the word ‘spectrum’ is part of the name. One federal study showed that ASD affects one in 88 children.
‘Previously, we linked increasing DUF1220 dosage with the evolutionary expansion of the human brain,’ says James Sikela, PhD, a professor in the Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine. Sikela led the autism study which also involved other members of his laboratory.

‘One of the most well-established characteristics of autism is an abnormally rapid brain growth that occurs over the first few years of life. That feature fits very well with our previous work linking more copies of DUF1220 with increasing brain size. This suggests that more copies of DUF1220 may be helpful in certain situations but harmful in others.’

The research team found that not only was DUF1220 linked to severity of autism overall, they found that as DUF1220 copy number increased, the severity of each of three main symptoms of the disorder — social deficits, communicative impairments and repetitive behaviours – became progressively worse.
In 2012, Sikela was the lead scientist of a multi-university team whose research established the link between DUF1220 and the rapid evolutionary expansion of the human brain. The work also implicated DUF1220 copy number in brain size both in normal populations as well as in microcephaly and macrocephaly (diseases involving brain size abnormalities).

Jack Davis, PhD, who contributed to the project while a postdoctoral fellow in the Sikela lab, has a son with autism and thus had a very personal motivation to seek out the genetic factors that cause autism.

The research by Sikela, Davis and colleagues at the Anschutz campus in Aurora, Colo., focused on the presence of DUF1220 in 170 people with autism.
Strikingly, Davis says, DUF1220 is as common in people who do not have ASD as in people who do. So the link with severity is only in people who have the disorder.

‘Something else is at work here, a contributing factor that is needed for ASD to manifest itself,’ Davis says. ‘We were only able to look at one of the six different subtypes of DUF1220 in this study, so we are eager to look at whether the other subtypes are playing a role in ASD.’
Because of the high number of copies of DUF1220 in the human genome, the domain has been difficult to measure. As Sikela says, ‘To our knowledge DUF1220 copy number has not been directly examined in previous studies of the genetics of autism and other complex human diseases .So the linking of DUF1220 with ASD is also confirmation that there are key parts of the human genome that are still unexamined but are important to human disease.’ University of Colorado Denver

In a new study, researchers from North Carolina State University, UNC-Chapel Hill and other institutions have taken the first steps toward creating a roadmap that may help scientists narrow down the genetic cause of numerous diseases. Their work also sheds new light on how heredity and environment can affect gene expression.
Pinpointing the genetic causes of common diseases is not easy, as multiple genes may be involved with a disease. Moreover, disease-causing variants in DNA often do not act directly, but by activating nearby genes. To add to the complexity, genetic activation is not like a simple on/off switch on a light, but behaves more like a ‘dimmer switch’ – some people may have a particular gene turned all the way up, while others have it only turned halfway on, completely off, or somewhere in between. And different factors, like DNA or the environment, play a role in the dimmer switch’s setting.
According to Fred Wright, NC State professor of statistics and biological sciences, director of NC State’s Bioinformatics Center and co-first author of the study, ‘Everyone has the same set of genes. It’s difficult to determine which genes are heritable, or controlled by your DNA, versus those that may be affected by the environment. Teasing out the difference between heredity and environment is key to narrowing the field when you’re looking for a genetic relationship to a particular disease.’
Wright, with co-first author Patrick Sullivan, Distinguished Professor of Genetics and Psychiatry at UNC-Chapel Hill and director of the Center for Psychiatric Genomics, and national and international colleagues, analyzed blood sample data from 2,752 adult twins (both identical and fraternal) from the Netherlands Twin Register and an additional 1,895 participants from the Netherlands Study of Depression and Anxiety. For all 20,000 individual genes, they determined whether those genes were heritable – controlled by the DNA ‘dimmer switch’ – or largely affected by environment.
‘Identical twins have identical DNA,’ Wright explains, ‘so if a gene is heritable, its expression will be more similar in identical twins than in fraternal twins. This process allowed us to create a database of heritable genes, which we could then compare with genes that have been implicated in disease risk. We saw that heritable genes are more likely to be associated with disease – something that can help other researchers determine which genes to focus on in future studies.’
‘This is by far the largest twin study of gene expression ever published, enabling us to make a roadmap of genes versus environment,’ Sullivan says, adding that the study measured relationships with disease more precisely than had been previously possible, and uncovered important connections to recent human evolution and genetic influence in disease.
The Netherlands Twin Register has followed twin pairs for over 25 years and in collaboration with the longitudinal Netherlands Study of Depression and Anxiety established a resource for genetic and expression studies. Professor Dorret Boomsma, who started the twin register, says, ‘in addition to the fundamental insights into genetic regulation and disease, the results provide valuable information on causal pathways. The study shows that the twin design remains a key tool for genetic discovery.’ EurekAlert