Monthly Archives: June 2017

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People with Lynch syndrome have an increased risk of bowel cancer and cancer of the womb.

The condition is also known as hereditary non-polyposis colorectal cancer (HNPCC).

The syndrome also increases the risk of the disease reoccurring, but hospitals can screen patients to check if they are at risk.

Bowel Cancer UK said that a lack of systematic testing means that 95 per cent of the 175,000 people with Lynch syndrome are unaware that they have the condition.

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An estimated 1,100 cases of bowel cancer can be attributed to Lynch syndrome each year, with many of those affected under the age of 50, according to the charity.

The children and siblings of those with Lynch syndrome have a 50 per cent chance of having the condition themselves.

Those with the condition can benefit from regular monitoring and better awareness of symptoms of cancers that they are at increased risk of being diagnosed with.

There are no symptoms of Lynch syndrome, and sometime the first sign a person has Lynch syndrome is when the symptoms of bowel or womb cancer develop.

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Bowel cancer risk factors

This will generally happen a a younger age than people whose cancers are not caused by inherited faulty genes.

Bowel cancer that doesnt run in families usually develops in people over the age of fifth, however people with Lynch syndrome can be affected at the age of 40 or even younger.

Macmillan Cancer Support urged people to be particularly aware of symptoms including

- Blood in stools - Diarrhoea or constipation - Unexplained weight loss - Pain in the tummy

If a person has a suspected cancer believed to be caused by Lynch Syndrome, genetic tests can be done.

Those who do carry the gene might need regular bowel cancer screening from a younger age - such as 25 - and women might need to be screened for womb or ovarian cancer.

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Professor Nicoline Hoogerbrugge, head of the Radboud university medical centre expert centre on hereditary cancers, Nijmegen, The Netherlands, has said there is an urgent need to find families carrying a mutation for Lynch syndrome in order to decrease mortality from the disease.

The expert has spoken out in favour of raising the age limit for testing.

By implementing appropriate prevention measures, deaths from Lynch syndrome in affected families can be reduced by more than 60 percent over 15 years.

Professor Joris Veltman, Director of the Institute of Genetic Medicine at Newcastle University, Newcastle, United Kingdom, said: It is very important to recognise whether a person suffers from sporadic or familiar cancer, as this identifies family members at risk who can take preventative measures.

For this, genetic tests need to be done in cancer patients."

This study shows that we should extend these genetic tests to older colorectal cancer patients of whom a significant number suffer from familiar cancer.

Read the original post:
Do YOU have Lynch syndrome? Genetic condition is common cause of killer bowel cancer - Express.co.uk

June 26, 2017 PET scan of a human brain with Alzheimer's disease. Credit: public domain

Many genes linked to late-onset Alzheimer's disease (AD) are expressed in myeloid cells and regulated by a single protein, according to research conducted at the Icahn School of Medicine at Mount Sinai and published June 19 in the journal Nature Neuroscience.

Mount Sinai researchers led an international, genome-wide study of more than 40,000 people with and without the disease and found that innate immune cells of the myeloid lineage play an even more central role in Alzheimer's disease pathogenesis than previously thought.

Specifically, the research team identified a network of genes that are implicated in AD and expressed by myeloid cells, innate immune cells that include microglia and macrophages. Furthermore, researchers identified the transcription factor PU.1, a protein that regulates gene expression and, thus, cell identity and function, as a master regulator of this gene network.

"Our findings show that a large proportion of the genetic risk for late-onset AD is explained by genes that are expressed in myeloid cells, and not other cell types," says Alison Goate, DPhil, Professor of Neuroscience and Director of The Ronald M. Loeb Center for Alzheimer's Disease at the Icahn School of Medicine at Mount Sinai and principal author of the study. "Dysregulation of this network is certainly a cause of Alzheimer's, but we have more work to do to better understand this network and regulation by PU.1, to reveal promising therapeutic targets."

Using a combination of genetic approaches to analyze the genomes of 14,406 AD patients, and 25,849 control patients who do not have the disease, researchers found that many genes which are known to influence the age at which AD sets in, are expressed in myeloid cells. This work pinpointed SPI1, a gene that encodes the transcription factor PU.1, as a major regulator of this network of AD risk genes and demonstrated that lower levels of SPI1/PU.1 are associated with later age at onset of AD.

To test the hypothesis that SPI1 expression levels influence expression of other AD risk genes and microglial function, the researchers used a mouse microglial cell line, BV2 cells that can be cultured in a dish. When researchers knocked down expression of SPI1, the gene that produces PU.1 in cells, they found that the cells showed lower phagocytic activity (engulfment of particles), while overexpression of SPI1 led to increased phagocytic activity. Many other AD genes expressed in microglia also showed altered expression in response to this manipulation of SPI1 expression.

"Experimentally altering PU.1 levels correlated with phagocytic activity of mouse microglial cells and the expression of multiple AD genes involved in diverse biological processes of myeloid cells," says Dr. Goate. "SPI1/PU.1 expression may be a master regulator capable of tipping the balance toward a neuroprotective or a neurotoxic microglial function."

The researchers stress that because the PU.1 transcription factor regulates many genes in myeloid cells, the protein itself may not be a good therapeutic target. Instead, further studies of PU.1's role in microglia and AD pathogenesis are necessary, as they may reveal promising downstream targets that may be more effective in modulating AD risk without broad effects on microglial function. Increased understanding is crucial to facilitating the development of novel therapeutic targets for a disease that currently has no cure.

Explore further: Phagocytes in the braingood or bad?

More information: Kuan-lin Huang et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease, Nature Neuroscience (2017). DOI: 10.1038/nn.4587

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Alzheimer's disease risk linked to a network of genes associated with myeloid cells - Medical Xpress

Newswise Between 15 and 20 percent of black people carry a genetic mutation that puts them at risk for certain chronic kidney disease, but only about half of them develop the illness a variance that long has puzzled researchers. Now a study has found that the gene mutations toxic effects require higher than normal levels of a protein called suPAR to trigger the onset and progression of the disease.

The results of the study, published in a research article in the journal Nature Medicine today, could lead soon to new treatments for chronic kidney disease that target these risk factors, according to Dr. Jochen Reiser, the senior author of the paper. Reiser is the chairperson of the Department of Internal Medicine and Ralph C. Brown MD Professor of Medicine at Rush University Medical Center, Chicago.

Chronic kidney disease or CKD for short is a progressive failure of function that prevents kidneys from fulfilling their role filtering waste from the blood stream. Nearly 17 percent of people in the U.S. have chronic kidney disease, and approximately 4 percent require dialysis and/or a kidney transplant due to kidney failure. Currently, there are no drugs that can treat CKD in an effective way.

Study analyzed samples from more than 1,000 people with genetic risk for CKD

For the study recounted in the Nature Medicine paper, Reiser worked with a team that included researchers at Emory University, Harvard University, Johns Hopkins University, the National Institute of Health, Ruprecht Karls University of Heidelberg, the Israel Institute of Technology and others. Together, they looked at two well-known genetic risk factors for CKD in black people, the mutated G1 or G2 variations in the gene known as apolipoprotein L1 (APOL1). To be at risk for developing CKD, an individual must have inherited two of these gene variants, one from each parent.

The study analyzed blood samples for suPAR levels, screened for APOL1 gene mutations and measured kidney function from two separate cohorts of black patients 487 people from the Emory Cardiovascular Biobank, 15 percent of whom had a high-risk APOL1 genotype; and 607 from the multi-center African American Study of Kidney Disease and Hypertension, including 24 percent with the high-risk mutation.

Using these two large, unrelated cohorts, the researchers found that plasma suPAR levels

independently predict renal function decline in individuals with two copies of APOL1 risk variants. APOL1-related risk is reduced by lower levels of plasma suPAR and strengthened by higher levels.

The team then went on and used purified proteins to study if suPAR and APOL1 bind to each other. They found that the mutated G1 and G2 variant did so particularly well on whats known as a receptor on the surface of kidney cells, in this case the suPAR activated receptor alphavbeta3 integrin. This binding appears to be a key step in the disease onset adds Dr. Kwi Hye Ko, a scientist at Rush and the studys co-first author.

This binding causes kidney cells to change their structure and function, permitting disease onset. Using cell models and genetically engineered mice, the authors then could reproduce kidney disease changes upon expression of APOL1 gene variants, but the disease required the presence suPAR.

Without elevated suPAR levels, genetic mutation much less likely to trigger disease

Everybody has suPAR, which is produced by bone marrow cells, in their blood, with normal levels around 2400 picogram per milliliter (pg/ml). As levels of suPAR rise, risk for kidney disease rises in turn.

Patients with levels above 3000 picogram per milliliter carry a much higher risk for kidney disease in the general population. Black people are particularly at risk, given the studys finding that suPAR activates its receptor on kidney cells that then attract the APOL1 risk proteins. Over time, these assaults can damage and eventually destroy the kidney.

On the other hand, without high levels of suPAR, the ability of the genetic mutation of APOL1 to exert its damaging effects is impaired, which helps identify patients in most need of suPAR lowering or future anti-suPAR therapy.

Patients with APOL1 mutations who don't get kidney disease have more commonly low suPAR levels," said Dr. Salim Hayek, co-first author of the paper and a cardiologist at Emory University School of Medicine. "The suPAR level needs to be high to activate the mechanism in the kidney that enables APOL1 proteins" and set off the chain of events the genetic mutation can trigger.

suPAR is to the kidneys as cholesterol is to the heart

Like some other pathological gene mutations, the APOL1 variations may have persisted in the population, in this case in Africa, because they could protect people from infection with the parasites known as trypanosome. explained Sanja Sever, PhD, co-correspondent author of the paper and associate professor of medicine at Harvard Medical School. In the United States, however, fighting parasitic trypanosomes isnt a significant concern, while lifestyle and environmental pressures such as obesity promote the rise in suPAR levels. This scenario sets up people for high risk of kidney disease.

Reiser has spent his career studying a scarring type of chronic kidney disease, focal segmental glomerulosclerosis. In past studies, he discovered that suPAR not only is a marker for kidney disease, but also a likely cause.

What we are learning today is that suPAR in a general way is to kidneys what cholesterol is to the heart, a substance that can cause damage if levels rise too high, or a substance that can likely make many forms of kidney disease worse, Reiser says. Based on these fundamental insights, suPAR level testing may become a routine test at many institutions around the world.

Like cholesterol, suPAR levels vary from person to person. Some environmental factors can contribute significantly to elevated suPAR levels. "Lifestyle is a big factor, bigger than we thought," Reiser says.

Smoking, weight gain and even frequent infections can add up and send suPAR to dangerous heights. Weight loss and smoking cessation can help bring levels down, but once elevated, suPAR may not recede to a healthy level again, said Dr. Melissa Tracy, co-author of the study and an associate professor of cardiology at Rush. People at genetic risk for kidney disease should aim to live a healthy life to keep suPAR levels low.

Link:
Catalyst for Genetic Kidney Disease in Black People Identified - Newswise (press release)