Researchers discover genes involved in colorectal cancer

A jumping gene with the fairy tale name "Sleeping Beauty" has helped to unlock vital clues for researchers investigating the genetics of colorectal cancer.

A study published today used the Sleeping Beauty transposon system to profile the repertoire of genes that can drive colorectal cancer, identifying many more than previously thought. Around one third of these genes are mutated in human cancer, which provides strong evidence that they are driver mutations in human tumours.

The collaborative project funded by Cancer Research UK and the Wellcome Trust was led by Dr David Adams from the Wellcome Trust Sanger Institute, and Dr Douglas Winton, of the Cancer Research-UK Cambridge Research Institute.

"These findings, when combined with mutation data from human colon cancers, will drive forward our understanding of the processes that lead to colorectal cancer," says Dr Adams, senior author from the Sanger Institute. "They demonstrate how many genes can contribute to this cancer and how these genes work together in the development of this disease".

The Sleeping Beauty transposon system induces genetic mutations at random, identifying and tagging candidate cancer genes, the drivers that cause colorectal cancer. This system has become critical in uncovering the genetic pathways that cause cancer, and, in this study, the team identify more than 200 genes that can be disrupted in human colorectal cancers.

Colorectal (bowel) cancer is the third most common cancer in the UK, and the second most common cause of cancer deaths after lung cancer; just under 40,000 people were diagnosed with bowel cancer in the UK in 2008 – around 110 people every day – a figure which has shown little improvement over the last decade.

"Our research provides a rich source of candidate genes that represent potential diagnostic, prognostic and therapeutic targets, and defines the breadth of genes that can contribute to cancer of the intestine," says Dr Winton, senior author from the Cancer Research UK Cambridge Research Institute. "It is becoming increasingly clear that cancers are driven by mutations in disparate collections of genes and it is essential that we tease apart the important changes."

Current thinking is that perhaps around 50 major drivers are mutated in any one cancer cell, but the number and identity of all of the cancer drivers, and how many drivers are found in each type of cancer, is largely unknown. By performing screens for cancer genes in the mouse and by then comparing them to data from human tumours the team identified a rich catalogue of new candidate genes helping to refine the genes that genetic pathways that drive bowel cancer development.

"At its heart, cancer is a disease driven by faulty genes," says Dr Lesley Walker, director of cancer information at Cancer Research UK. "Research suggests that each cancer cell has a number of 'driver' faults that make them grow out of control, as well as 'passenger' faults that they pick up as the disease develops. This technique is helping us to tease out the key drivers of bowel cancer, laying the foundations for more effective, targeted treatments for the disease in the future."

The research complements studies by The Cancer Genome Atlas and the International Cancer Genome Consortium, which are cataloguing the mutations responsible for cancer development using next generation DNA sequencing.

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Gene discovered as cause of fatal condition

Medical scientists have for the first time identified a gene responsible for a fatal abdominal condition that afflicts tens of thousands of people across the world.

An international team led by Matt Bown, a vascular surgeon from the University of Leicester, identified a single gene that is linked to the development of abdominal aortic aneurysms (AAAs).

What is more, the team discovered that the gene, LRP1, was not linked to other cardiovascular diseases, suggesting that it is specific to AAA.

An AAA is a swelling of the main blood vessel in the back of the abdomen which can burst, causing dangerous internal bleeding. The only treatment to prevent this happening is surgery. This is performed when the AAA grows over a certain size as the risk of the AAA bursting is low when it is small. Unfortunately there is no treatment to prevent small AAAs from growing and despite detecting AAAs by screening, and surgery, many thousands of people still die from burst AAA each year.

Mr Bown, senior lecturer in surgery in the Department of Cardiovascular Sciences at the University, said: "The study involved over 2000 people from Leicestershire as well as many more from around the globe.

"Since AAAs often run in families, the research team compared the genes of people with AAAs to those without and discovered that one gene, LRP1, was associated with AAA.

"Abdominal aortic aneurysm is an important disease since it commonly affects the older population and can only be treated by surgery. Through this research we have identified a gene that is associated with AAA and the further investigation of the function of this gene in relation to AAA may help us understand more about the disease and how to treat it without resorting to operations.

"This is a tremendously exciting discovery that is the culmination of over a decade of research work across 6 countries and is a testament to the research excellence of the people involved.

"I would also like to extend my thanks to the volunteers who have participated in this research project over the last 10 years – without them this work would not have been possible."

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Scientists identify genes that may signal long life in naked mole-rats

Scientists at the University of Liverpool have identified high levels of a number of genes in the naked mole-rat that may suggest why they live longer than other rodents and demonstrate resistance to age-related diseases.

The Liverpool team has recently generated the first whole-genome sequencing data of the naked mole-rat - a rodent that lives for more than 30 years and is resistant to cancer - to understand its longevity and resistance to disease. Scientists, in collaboration with Harvard University, have now compared the levels of its genes with genes in wild mice to investigate what makes naked mole-rats different to other rodents.

They found that genes associated with mitochondria, that provide energy to cells, and genes that affect respiration and the decisions cells make, are expressed at unusually high levels in the naked mole-rat compared to the same genes in wild mice. In animals and humans these genes are thought to play a role in influencing and adapting to cell damage, which is thought to be one of the significant causes of ageing.

Naked mole-rats, however, also have increased levels of oxidative stress, which is an imbalance in reactive molecules containing oxygen. This can lead to mutations in the cells and the growth of cancerous tumours. To date, cancer has not been detected in the naked mole-rat, but these new findings suggest that the rodent has mechanisms of regulating gene responses to limit the potential negative impact of oxidative stress on cells. The research will help scientists focus on particular areas of the genome to further understanding into how the body ages.

Dr Joao Pedro Magalhaes, from the University's Institute of Integrative Biology, said: "The naked mole-rat is native to the deserts of East Africa and has unique physical traits that allow it to survive in harsh environments for many years. It has a lack of pain sensation in its skin and has a low metabolic rate that allows it to live underground with limited oxygen supply.

"It has been of interest to scientists for some time and we hope that by studying its genome it will help us understand the mechanisms of ageing and how the body protects itself from disease.

"These findings add further evidence to research that suggests genes responsible for mitochondria and oxireduction are associated with the ageing processes. It also provides some clues as to how naked mole-rats protect themselves against high levels of oxidative stress. The high levels of genes connected to energy production and cell decision-making systems may help in creating an intracellular environment that prevents cancer and other age-related diseases.

"This work provides candidate genes for specifying resistance to ageing and cancer that we can build on in future studies. The next stage of the research will be to observe what happens to the cells if gene levels change from high to low and vice-versa."

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A gene for Lou Gehrig's disease and frontotemporal dementia identified

Frontotemporal dementia and amyotrophic lateral sclerosis, also known as Lou Gehrig's disease -- two fatal neurodegenerative disease with distinct symptoms -- are triggered by a common mutation in many cases, according to researchers who say they have identified the mutated gene.

In the study, reported in the September 21 online issue of Neuron, the scientists described the discovery of a genetic mutation that is accountable for almost 12 percent of familial FTD and more than 22 percent of familial ALS samples studied.

They also report that the defect is the strongest genetic risk factor found to date for the more common, non-inherited, sporadic forms of these diseases. It was found in 3 percent of sporadic FTD and 4 percent of sporadic ALS samples in the largest clinical patient series.

The study was led by scientists at the Mayo Clinic in Florida, in collaboration with researchers at UCSF, the University of British Columbia and UCLA. The finding emerged from the identification and study of a family stricken by both ALS and FTD, reported last year. In that study, led by the UCSF scientists and published in the Journal of Neurology, Neurosurgery and Psychiatry, the researchers honed in on the region in which the gene was located.

"Both clinically and at the molecular level this discovery is going to significantly improve our understanding of these diseases," said co-author Adam Boxer, MD, PhD, of the UCSF Memory and Aging Center, the lead author on the 2010 paper. The discovery makes it possible to develop a diagnostic test for the mutation, as well as to create animal models that may be used to help unravel the molecular mysteries connecting the mutation to the diseases, he said.

In the current study, a detailed molecular genetic characterization of the family that Boxer described was done in the laboratory of senior author Rosa Rademakers, PhD, from the Mayo Clinic. She and colleagues identified the gene and the specific mutation within it.

The mutation consists of from hundreds to thousands of extra copies of a six-letter DNA sequence GGGGCC strung end to end within a region of human chromosome nine. The mutation occurs within a gene of unknown function called C9ORF72.

After identifying the mutation, the Mayo researchers searched for it in DNA from other patients with both familial and sporadic forms of the diseases, where they found the strong associations.

FTD is characterized by disturbances in decision making, language skills, behavior and emotional expression, and is as common as Alzheimer's disease in people younger than 65, according to Boxer. ALS is a neuromuscular disease, leading to muscle paralysis and respiratory failure, often within three to five years. However, it is not unusual for patients diagnosed with one of the two diseases to exhibit symptoms of the other.

Since 2006, six separate groups have reported evidence for a genetic link between the disorders and the same chromosomal region. In the study led by Boxer last year, the researchers described clinical aspects of the disease within the family, and homed in more closely to the gene than others had.

The pattern of protein deposition in the brains of family members in the study may eventually shed light on common aspects of the neurodegenerative process that occurs in both diseases, Boxer said.

There is only one standard medical treatment for ALS, riluzole, which extend life for about six months, he said.

There is no known effective treatment to slow FTD. However, neurologists have generally become much better at recognizing the degenerative disorder, according to Boxer.

Boxer and Bruce Miller, MD, the director of the UCSF Memory and Aging Center and a co-author of both studies, are leaders in FTD research, diagnosis and patient care.

"Ten years ago some neurologists did not acknowledge the existence of FTD," Boxer says. "Today we are much better at diagnosing the disease, although sometimes it still takes an expert to distinguish it from Alzheimer's or from psychiatric disorders.

"We're actively trying to develop treatments for FTD, and we believe this discovery will pave the way for major advances in these efforts."

The researchers used a technique called linkage analysis to narrow the search for the gene by comparing affected and unaffected family members. Another group of scientists -- reporting in the same online edition of Neuron on the same gene -- found that C9ORF72 emerged as being significantly associated with FTD and ALS in a genome-wide scan of patients in Finland.

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New lung cancer gene found

A major challenge for cancer biologists is figuring out which among the hundreds of genetic mutations found in a cancer cell are most important for driving the cancer’s spread.

Using a new technique called whole-genome profiling, MIT scientists have now pinpointed a gene that appears to drive progression of small cell lung cancer, an aggressive form of lung cancer accounting for about 15 percent of lung cancer cases.

The gene, which the researchers found overexpressed in both mouse and human lung tumors, could lead to new drug targets, says Alison Dooley, a recent PhD recipient in the lab of Tyler Jacks, director of MIT’s David H. Koch Institute for Integrative Cancer Research. Dooley is the lead author of a paper describing the finding in the July 15 issue of Genes and Development.

Small cell lung cancer kills about 95 percent of patients within five years of diagnosis; scientists do not yet have a good understanding of which genes control it. Dooley and her colleagues studied the disease’s progression using a strain of mice, developed in the laboratory of Anton Berns at the Netherlands Cancer Institute, that deletes two key tumor-suppressor genes, p53 and Rb.

“The mouse model recapitulates what is seen in human disease. It develops very aggressive lung tumors, which metastasize to sites where metastases are often seen in humans,” such as the liver and adrenal glands, Dooley says.

This kind of model allows scientists to follow the disease progression from beginning to end, which can’t normally be done with humans because the fast-spreading disease is often diagnosed very late. Using whole-genome profiling, the researchers were able to identify sections of chromosomes that had been duplicated or deleted in mice with cancer.

They found extra copies of a few short stretches of DNA, including a segment of chromosome 4 that turned out to include a single gene called Nuclear Factor I/B (NFIB). This is the first time NFIB has been implicated in small cell lung cancer, though it has been seen in a mouse study of prostate cancer. The gene’s exact function is not known, but it is involved in the development of lung cells.

Researchers in Jacks’ lab collaborated with scientists in Matthew Meyerson’s lab at the Dana-Farber Cancer Institute and the Broad Institute to analyze human cancer cells, and found that NFIB is also amplified in human small cell lung tumors.

That makes a convincing case that the gene truly is playing an important role in human small cell lung cancer, says Barry Nelkin, a professor of oncology at Johns Hopkins University School of Medicine, who was not involved in this research.

“The question, always, with mouse models is whether they can tell you anything about a human disease,” Nelkin says. “Some tell you something, but in others, there may be only a similarity in behavior, and the genetic changes are nothing like what is seen in humans.”

The NFIB gene codes for a transcription factor, meaning it controls the expression of other genes, so researchers in Jacks’ lab are now looking for the genes controlled by NFIB. “If we find what genes NFIB is regulating, that could provide new targets for small cell lung cancer therapy,” Dooley says.

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